atrial-natriuretic-factor and Hypertension

Heart has a recognized endocrine function as it produces several biologically active substances with hormonal properties. Among these hormones, the natriuretic peptide (NP) system has been extensively characterized and represents a prominent expression of the endocrine function of the heart. Over the years, knowledge about the mechanisms governing their synthesis, secretion, processing, and receptors interaction of NPs has been intensively investigated. Their main physiological endocrine and paracrine effects on cardiovascular and renal systems are mostly mediated through guanylate cyclase-A coupled receptors. The potential role of NPs in the pathophysiology of heart failure and particularly their counterbalancing action opposing the overactivation of renin-angiotensin-aldosterone and sympathetic nervous systems has been described. In addition, NPs are used today as key biomarkers in cardiovascular diseases with both diagnostic and prognostic significance. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors in the current management of heart failure, novel promising molecules, including M-atrial natriuretic peptide (a novel atrial NP-based compound), have been tested for the treatment of human hypertension. The development of new drugs is currently underway, and we are probably only at the dawn of novel NPs-based therapeutic strategies. The present article also provides an updated overview of the regulation of NPs synthesis and secretion by microRNAs and epigenetics as well as interactions of cardiac hormones with other endocrine systems.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Heart; Heart Failure; Humans; Hypertension; Natriuretic Peptides

Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.

Topics: Atrial Fibrillation; Atrial Natriuretic Factor; Heart; Heart Failure; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptides

Hypertension is a common pathological condition predisposing to a higher occurrence of cardiovascular diseases and events. Unfortunately, treatment of hypertension is still suboptimal worldwide. More efforts are needed to implement the availability of anti-hypertensive drugs. The family of natriuretic peptides, including atrial and brain natriuretic peptides (ANP and BNP), play a key role on blood pressure regulation through the natriuretic, diuretic and vasorelaxant effects. A large number of experimental and human studies, ranging from pathophysiological to genetic investigations, supported ANP as the most relevant component of the family able to modulate blood pressure and to contribute to hypertension development. On this background, it is expected that ANP-based therapeutic approaches may give a significant contribution to the development of efficacious therapies against hypertension. Since native ANP cannot be administered due to its short half-life, several approaches were attempted over the years to overcome the difficulties inherent to the ANP instability. These approaches included ANP recombinant and fusion peptides, gene therapy, inhibition of ANP degradation by neprilysin inhibition, and designer peptides. The most relevant achievements in the field are discussed in this article. Based on the available evidence, therapies targeting ANP represent efficacious and clinically applicable anti-hypertensive agents.

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptides

Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.

Topics: Animals; Atrial Appendage; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Remodeling; Biomarkers; Cyclic GMP; Diabetes Mellitus; Fibrosis; Gene Expression Regulation, Developmental; Heart Atria; Heart Failure; Humans; Hypertension; Lipid Metabolism; Metabolic Syndrome; Mice; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Prognosis; Protein Processing, Post-Translational; Pulmonary Arterial Hypertension; Receptors, Guanylate Cyclase-Coupled; Secretory Vesicles; Ventricular Remodeling; Water-Electrolyte Balance

Atrial natriuretic peptide (ANP) is of major importance in the maintenance of electrolyte balance and normal blood pressure. Reduced plasma ANP levels are associated with the increased risk of cardiovascular disease. Corin is a type II transmembrane serine protease that converts the ANP precursor to mature ANP. Corin deficiency prevents ANP generation and alters electrolyte and body fluid homeostasis. Corin is synthesized as a zymogen that is proteolytically activated on the cell surface. Factors that disrupt corin folding, intracellular trafficking, cell surface expression, and zymogen activation are expected to impair corin function. To date, CORIN variants that reduce corin activity have been identified in hypertensive patients. In addition to the heart, corin expression has been detected in non-cardiac tissues, where corin and ANP participate in diverse physiological processes. In this review, we summarize the current knowledge in corin biosynthesis and post-translational modifications. We also discuss tissue-specific corin expression and function in physiology and disease.

Topics: Animals; Atrial Natriuretic Factor; Catalytic Domain; Cell Membrane; Cytoplasm; Electrolytes; Female; Gene Deletion; Gene Expression Regulation; Homeostasis; Humans; Hypertension; Kidney; Mice; Myocardium; Protein Domains; Protein Folding; Protein Precursors; Protein Processing, Post-Translational; Protein Transport; Serine Endopeptidases; Trypsin; Uterus

The natriuretic peptide system plays an important role in regulation of blood pressure. The purpose of this study was to comprehensively examine the associations among NPPA gene SNPs, serum atrial natriuretic peptide (ANP) levels, and hypertension. In 736 new-onset hypertensive cases and 736 age- and sex-matched controls, we measured concentrations of serum NT-proANP and genotyped 3 tag-SNPs in NPPA. Serum ANP levels were significantly lower in hypertensive patients than in controls (Wilcoxon two sample test P = 0.011). The difference was also significant in male (P = 0.0161) and female subgroups (P = 0.0011). Compared with the reference group, participants with the highest quartile of ANP levels had a significant decreased risk of hypertension (odds ratio = 0.56, P = 0.0006). The nonsynonymous SNP rs5063 (p.Val32Met) seemed to be associated with ANP levels (P = 0.0209). eQTL analysis found that rs198358 was associated with NPPA gene expression in testis (1.66 × 10

Topics: Adult; Aged; Asian People; Atrial Natriuretic Factor; Case-Control Studies; China; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies; Quantitative Trait Loci; Risk Factors

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Diseases; Diabetes Complications; Hepatitis; Humans; Hypertension; Kidney; Mice; Natriuretic Peptide, C-Type; Polymorphism, Genetic; Protein Precursors; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Sodium

Prevalence of cardiovascular (CV) disease is increasing worldwide. One of the most important risk factors for CV disease is hypertension that is very often related to obesity and metabolic syndrome. The search for key mechanisms, linking high blood pressure (BP), glucose and lipid dysmetabolism together with higher CV risk and mortality, is attracting increasing attention. Cardiac natriuretic peptides (NPs), including ANP and BNP, may play a crucial role in maintaining CV homeostasis and cardiac health, given their impact not only on BP regulation, but also on glucose and lipid metabolism. The summa of all metabolic activities of cardiac NPs, together with their CV and sodium balance effects, may be very important in decreasing the overall CV risk. Therefore, in the next future, cardiac NPs system, with its two receptors and a neutralizing enzyme, might represent one of the main targets to treat these multiple related conditions and to reduce hypertension and metabolic-related CV risk.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Peptide, Brain; Prognosis; Receptors, Atrial Natriuretic Factor; Risk Assessment; Risk Factors; Signal Transduction

LCZ-696, sacubitril/valsartan, is a dual-acting molecule consisting of the angiotensin II (Ang II) receptor blocker valsartan and the neprilysin (neutral endopeptidase) inhibitor AHU-377 with significant beneficial effects in patients with hypertension and heart failure (HF). Several recent studies have demonstrated a higher effectiveness of LCZ-696 compared to valsartan in the treatment of hypertension and HF. The rationale for the development and the Food and Drug Administration approval of LCZ-696 was based on the concept of an additive effect of the Ang II receptor blocker valsartan and the neutral endopeptidase (neprilysin) inhibitor AHU-377 for the treatment of hypertension and HF. The synergism from these drugs arises from the vasodilating effects of valsartan through its blockade of Ang II type 1 receptor and the action of natriuretic peptides atrial natriuretic peptide and B-type natriuretic peptide (BNP) by preventing their catabolism with neprilysin resulting in increase of cyclic guanosine monophosphate. This action of neprilysin is associated with increased natriuresis, diuresis, and systemic vasodilation, since these peptides have been shown to have potent diuretic, natriuretic, and vasodilating effects. In addition, it reduces the levels of N terminal pro-BNP. Therefore, administration of LCZ-696 results in significant reduction of wall stress from pressure and volume overload of the left ventricle as demonstrated by the reduction of N terminal pro-BNP, both significant constituents of hypertension and HF, and it is safe, well tolerated and is almost free of cough and angioedema.

Topics: Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Clinical Trials as Topic; Cough; Cyclic GMP; Diuresis; Drug Combinations; Heart Failure; Heart Ventricles; Humans; Hypertension; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Renin-Angiotensin System; Stroke Volume; Tetrazoles; Valsartan; Vasodilation

The pathologic consequences of sodium retention in the CKD population can lead to hypertension, edema, and progressive disease. Sodium excess is responsible for increases in oxidative stress, which alters kidney vasculature. As progression of CKD occurs, hyperfiltration by remaining nephrons compensates for an overall decrease in the filtered load of sodium. In the later stages of CKD, compensatory mechanisms are overcome and volume overload ensues. Nephrotic syndrome as it relates to sodium handling involves a different pathophysiology despite a common phenotype. Extrarenal sodium buffering is also examined as it has significant implications in the setting of advanced CKD.

Topics: Animals; Atrial Natriuretic Factor; Diet, Sodium-Restricted; Homeostasis; Humans; Hypertension; Nephrotic Syndrome; Oxidative Stress; Renal Insufficiency, Chronic; Renin-Angiotensin System; Skin; Sodium; Sympathetic Nervous System; Vasopressins

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and an increase of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and an increase in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age. There is an increased prevalence of salt-sensitive hypertension with advancing age that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand.

Topics: Age Factors; Aging; Arteries; Atrial Natriuretic Factor; Bufanolides; Hemodynamics; Humans; Hypertension; Ligands; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulse Wave Analysis; Signal Transduction; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Vascular Stiffness

Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), an important hormone in regulating salt-water balance and blood pressure. This review focuses on the regulation of corin function and potential roles of corin defects in hypertensive, heart, and renal diseases.. Proprotein convertase subtilisin/kexin-6 has been identified as a primary enzyme that converts zymogen corin to an active protease. Genetic variants that impair corin intracellular trafficking, cell surface expression, and zymogen activation have been found in patients with hypertension, cardiac hypertrophy, and pre-eclampsia. Reduced corin expression has been detected in animal models of cardiomyopathies and in human failing hearts. Low levels of circulating soluble corin have been reported in patients with heart disease and stroke. Corin, ANP and natriuretic peptide receptor-A mRNAs, and proteins have been colocalized in human renal segments, suggesting a corin-ANP autocrine function in the kidney.. Corin is a key enzyme in the natriuretic peptide system. The latest findings indicate that corin-mediated ANP production may act in a tissue-specific manner to regulate cardiovascular and renal function. Corin defects may contribute to major diseases such as hypertension, heart failure, pre-eclampsia, and kidney disease.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Female; Heart Diseases; Humans; Hypertension; Kidney; Kidney Diseases; Pre-Eclampsia; Pregnancy; Proprotein Convertases; Receptors, Atrial Natriuretic Factor; Serine Endopeptidases

Studies evaluating the association between the atrial natriuretic peptide (ANP) genetic polymorphism and the risk of essential hypertension (EH) have reported inconsistent results. The aim of this meta-analysis was to provide a more reliable estimation of the possible relationship between the atrial natriuretic peptide genetic polymorphism and the risk of essential hypertension (EH).. Relevant articles were searched to identify all case-control or cohort design studies of the associations between ANP polymorphism and EH. The heterogeneity was checked using the Q test and the inconsistent index (I²). The odds ratio (OR) test and 95% confidence interval (CI) were calculated in a fixed or random effects model to evaluate the strength of association. Begg's test and Egger's test were applied to evaluate the publication bias.. A total of 25 case-control studies including 5520 cases and 5210 controls exploring the association between ANP polymorphism and EH were available for this meta-analysis. No significant association between the T2238C polymorphism and overall EH risk under the five genetic models was found (C vs. T: OR = 1.1, 95%CI = 0.94-1.2, p = 0.38; TC vs. TT: OR = 1.1, 95%CI = 0.88-1.5, p = 0.32; CC vs. TT: OR = 1.3, 95%CI = 0.90-1.9, p = 0.16; (CC + TC) vs. TT: OR = 1.1, 95%CI = 0.88-1.4, p = 0.35; CC vs. (TT + TC): OR = 1.1, 95%CI = 0.83-1.4, p = 0.55). We also found that the G1837A polymorphism had no significant association with overall EH risk (A vs. G: OR = 1.3, 95%CI = 0.96-1.9, p = 0.090; GA vs. GG: OR = 1.5, 95%CI = 0.83-2.6, p = 0.19; AA vs. GG: OR = 0.87, 95%CI = 0.34-2.3, p = 0.78; (AA + GA) vs. GG: OR = 1.5, 95%CI = 0.86-2.5, p = 0.17; AA vs. (GG + GA): OR = 1.3, 95%CI = 0.85-2.0, p = 0.22). In the analysis of the T1766C polymorphism, after removing the study of Nkeh, the 1766C allele suggested a protective effect in the model of TC vs. TT (OR = 0.64, 95%CI = 0.47-0.86, p = 0.003) and (CC + TC) vs. TT (OR = 0.64, 95%CI = 0.48-0.87, p = 0.004).. This meta-analysis suggested that no significant relationships between ANP T2238C, G1837A gene polymorphisms and the risk of essential hypertension exist. Conversely, the ANP T1766C gene polymorphism may be associated with the risk of essential hypertension, and the 1766C allele may be a protective factor against EH. However, due to the number of limited articles on the T1766C polymorphisms, further studies are still needed to accurately prove the association between the T1766C gene polymorphism and the risk of essential hypertension.

Topics: Alleles; Atrial Natriuretic Factor; Case-Control Studies; Genetic Predisposition to Disease; Humans; Hypertension; Odds Ratio; Polymorphism, Single Nucleotide; Risk Factors

Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10(-7) and 10(-8 )M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10(-8) and 10(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

Topics: Adrenal Glands; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Atrial Natriuretic Factor; Cells, Cultured; Humans; Hypertension

Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na(+) handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34±5y; 9 male) and 13 MHT (32±4y; 10male) were studied. Pro-ANP (1-30) PgI2, PRA and total exchangeable Na(+)24 (ENa(+)) were measured. Under low sodium intake, PRA (4.2±0.5ng.ml.h; p<0.05) and Pro-ANP (78.6±2pg/ml, p<0.05) were higher than in NMHT under (3.1±0.4ng.ml.h and 69.8±3 pg/ml). After 72h of high Na(+) intake, Pro-ANP (1-30) increased significantly only in MHT (82.1±3pg/ml, p<0.05). PgI2, under low sodium intake (1.83±0.2pg/24h), increased in MHT after 72h under high sodium (2.58±0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16±0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61±0.36 pg/24h; p=ns). A significant correlation between variations in ENa(+) and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa(+) in MHT (r=0.95; p<0.001) while a negative correlation between ENa(+) variations and ENa(+) (r=0.81, p<0.05) was observed in NMHT. ENa(+) variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Homeostasis; Humans; Hypertension; Male; Renin; Sodium

Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dopamine; Humans; Hypertension; Kidney; Sodium; Sodium-Potassium-Exchanging ATPase

Atrial natriuretic peptide (ANP) plays a pivotal role in modulation of vascular function and it is also involved in the pathophysiology of several cardiovascular diseases. We provide an updated overview of the current appraisal of ANP vascular effects in both animal models and humans. We describe the physiological implications of ANP vasomodulatory properties as well as the involvement of ANP, through its control of vascular function, in hypertension and heart failure. The principal molecular mechanisms underlying regulation of vascular tone, that is natriuretic peptide receptor type A/cyclic guanylate monophosphate, natriuretic peptide receptor type C, nitric oxide system, are discussed. We review the literature on therapeutic implications of ANP in hypertension and heart failure, examining the potential use of ANP analogues, neutral endopeptidase (NEP) inhibitors, ACE/NEP inhibitors, angiotensin receptor blocker (ARB)/NEP inhibitors, the new dual endothelin-converting enzyme (ECE)/NEP inhibitors and ANP-based gene therapy. The data discussed support the role of ANP in different pathological conditions through its vasomodulatory properties. They also indicate that ANP may represent an optimal therapeutic agent in cardiovascular diseases.

Topics: Animals; Atrial Natriuretic Factor; Blood Vessels; Heart Failure; Humans; Hypertension

Blood pressure control is regulated by complicated physiological mechanisms, which are dependent upon cardio-vascular, neurological, endocrine systems and the kidneys. The kidneys plays an important role in the regulation of blood pressure based on sodium and water balance, renin-an. giotensin-aldosterone axis, sympathetic activity as well as other regulatory substances like: natriuretic peptides (ANP, BNP) endothelin, dopamine, prostaglandins and nitric oxide (NO). In chronic kidney disease (CKD) patients hypertension is extremely common and is aggravated together with the lowering of renal clearance (GFR). The kidneys may be a cause and a culprit of hypertension.

Topics: Atrial Natriuretic Factor; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Renin-Angiotensin System; Water-Electrolyte Balance

The natriuretic peptides, specifically atrial natriuretic peptide (ANP), are increasingly recognized to play a fundamental role in blood pressure (BP) regulation. This role in BP regulation reflects the pluripotent cardiorenal actions of ANP, which include diuresis, enhancement of renal blood flow and glomerular filtration rate, systemic vasodilatation, suppression of aldosterone, and inhibition of the sympathetic nervous system. These actions of ANP, in addition to recent human studies demonstrating an association of higher plasma ANP with lower risk of hypertension, support the development of an ANP-based therapy for hypertension. M-ANP is a novel ANP-based peptide that is resistant to proteolytic degradation and possesses greater BP-lowering, renal function-enhancing, and aldosterone-suppressing properties than native ANP. In an animal model of hypertension, M-ANP lowers BP via multiple mechanisms, including vasodilatation, diuresis, and inhibition of aldosterone. Importantly, M-ANP enhances both glomerular filtration rate and renal blood flow despite reductions in BP. The pluripotent BP-lowering actions and concomitant enhancement of renal function associated with M-ANP are highly attractive characteristics for an antihypertensive agent and underscore the therapeutic potential of M-ANP. M-ANP currently is heading into clinical testing, which may advance this novel strategy for human hypertension.

Topics: Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Biological Availability; Blood Pressure; Drug Evaluation, Preclinical; Glomerular Filtration Rate; Humans; Hypertension; Natriuresis; Renal Circulation; Sympathetic Nervous System; Therapies, Investigational; Vasodilation

The natriuretic peptide (NP) family includes atrial natriuretic peptide (ANP), B-type natriuretic peptide, C-type natriuretic peptide and their receptors NPR-A, NPR-B and NPR-C. The effects exerted by this hormonal system in the control of cardiovascular, renal and endocrine functions have been extensively investigated. Moreover, the involvement of NP in the pathogenesis of cardiovascular diseases has been demonstrated. Among the NP components, NPR-C has been described, at the time of its discovery, as the clearance receptor of NP devoid of any physiological functions. Emerging roles of NPR-C, however, have been highlighted over the last few years in relation to its effects on the cardiovascular system and other organs. These effects appear to be directly mediated through distinct cAMP-dependent intracellular mechanisms. Moreover, evidence has been accumulated on a potential pathophysiological role of NPR-C in human diseases. Ongoing studies from our group are revealing its involvement in the mediation of antiproliferative effects exerted on vascular cells by a molecular variant of human ANP. Thus, a new appraisal of NPR-C is overcoming the traditional view of a mere clearance receptor. This review focuses on the most important evidence supporting an involvement of NPR-C in mediating some of the actions of NP and its direct implication in cardiovascular diseases. The current state of knowledge highlights the need of further studies to better clarify the specific roles of NPR-C in pathophysiological processes.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Peptide, C-Type; Obesity; Phenotype

The natriuretic peptide precursor A (NPPA) gene, found on chromosome 1p36, encodes the precursor from which atrial natriuretic polypeptide (ANP) is derived. Due to the action of ANP, it is thought that the NPPA gene is involved in the control of blood pressure. Animal studies have shown that genetically reduced ANP concentration leads to salt-sensitive hypertension, whereas genetically increased ANP concentration leads to hypotension. These studies have encouraged researchers to search the human NPPA gene for polymorphisms that contribute to hypertension and its sequelae such as stroke and cardiovascular disease. This report provides a comprehensive review of studies exploring NPPA polymorphisms in relation to hypertension and hypertension-related outcomes.

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Polymorphism, Genetic

Topics: Amphibians; Animals; Atrial Natriuretic Factor; Bufanolides; Cardenolides; Hormones; Humans; Hypertension; Mammals; Ouabain; Plant Growth Regulators; Saponins; Sodium Chloride, Dietary; Steroids

Vasopeptidase inhibitors (VPI) are a new promising class of drugs, that simultaneously inhibit Angiotensin - Converting Enzyme (ACE) and an enzyme Neutral Endopeptidase (NEP), that cleaves the natriuretic peptides. These drugs, such as omapatrilat, sampatrilat, fasidotrilat, by combined inhibition of ACE and degradation of natriuretic peptides and in turn by inhibiting the Renin - Angiotensin - Aldosterone system and potentiating the Natriuretic Peptide system and Kinin system should decrease the mortality rate in the group of patients with hypertension being not adequately controlled with ACE inhibitors. Thus, finding the new therapeutic strategy using drugs that act on the hormonal systems other than Renin - Angiotensin - Aldosterone system seems to be crucial. The aim of the study was to compare the molecular aspects of the conventional schemes that are being used in the antihypertension therapy to the new drugs from the vasopeptidase inhibitors group--with focusing on the natriuretic peptide system (NPS)--and, taking these considerations, making clues about therapeutical implications to reveal promising results in antihypertension treatment.

Topics: Alanine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Humans; Hypertension; Mesylates; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Sympathetic Nervous System; Thiazepines; Tyrosine; Vascular Resistance

Topics: Atrial Natriuretic Factor; Gene Expression Regulation; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptides; Receptors, Atrial Natriuretic Factor; Transcription, Genetic

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study is the first, and, so far, the only endpoint trial in patients with hypertension and left ventricular hypertrophy (LVH) to show a divergent therapeutic outcome of one treatment modality over another with equivalent blood pressure control. The purpose of this article is to review post hoc sub-analyses of LIFE study data and other clinical studies that offer some insight into possible treatment-related differences contributing to the superior stroke outcome of losartan versus atenolol beyond blood pressure reduction.. Relevant randomized clinical trials and review articles were identified through a MEDLINE search of English-language articles published between 1990 and 2006 using the search terms losartan, atenolol, LIFE, hypertension, and LVH. Articles describing major clinical studies, new data, or mechanisms pertinent to the LIFE study were selected for review.. Differences in blood pressure or in the distribution of add-on medications were not evident between study groups in the LIFE study. Thus, the observed outcomes benefits favoring losartan may involve other possible mechanisms, including differential effects of losartan and atenolol on LVH regression, left atrial diameter, atrial fibrillation, brain natriuretic peptide, vascular structure, thrombus formation/platelet aggregation, serum uric acid, albuminuria, new-onset diabetes, and lipid metabolism. Alternative explanations for the LIFE study findings have also been put forward, including the choice of atenolol as an appropriate active comparator and differential effects between treatment groups on central pulse pressure. Additional clinical trials are needed to determine if the beneficial effects of losartan seen in LIFE are shared by other inhibitors of the renin-angiotensin system.. Sub-analyses of the LIFE study data suggest that losartan's stroke benefit may arise from a mosaic of mechanisms rather than a single action. Further studies are expected to continue to delineate the mechanisms of differential responses to treatments in LIFE.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atenolol; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiovascular Agents; Cohort Studies; Drug Utilization; Endothelium, Vascular; Follow-Up Studies; Heart Atria; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Models, Biological; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Precursors; Randomized Controlled Trials as Topic; Research Design; Risk; Risk Factors; Stroke; Thrombosis; Treatment Outcome

It is now well accepted that alterations in kidney function, due either to primary renal disease or to inappropriate hormonal influences on the kidney, are a cardinal characteristic in all forms of hypertension, and lead to a reduced ability of the kidneys to excrete sodium and the consequent development of elevated arterial pressures. However, it is also apparent that many extrarenal factors are important contributors to altered kidney function and hypertension. Central to many hypertensinogenic processes is the inappropriate activation of the renin-angiotensin system (RAS) and its downstream consequences by various pathophysiologic mechanisms. There may also be derangements in arachidonic acid metabolites, endothelium derived factors such as nitric oxide and carbon monoxide, and various paracrine and neural systems that normally interact with or provide a counteracting balance to the actions of the RAS. Thus, when the capacity of the kidneys to maintain sodium balance and extracellular fluid volume within appropriate ranges is compromised, increases in arterial pressure become necessary to re-establish normal balance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Carbon Monoxide; Cyclooxygenase Inhibitors; Eicosanoids; Heme; Heme Oxygenase (Decyclizing); Hypertension; Hypertension, Renal; Renin-Angiotensin System

It is generally accepted that the essential hypertension (EH) is caused by interactions among congenital gene, multiple pathogenetic pressor factors, and disorder of physiologic depressor factors. The central nervous system may play a key role in the development of EH. The underlying mechanisms, however, are not well understood. Studies show that peptidergic transmitters in the limbic forebrain are involved in long-term regulation of arterial pressure and in the pathogenesis of EH. In the limbic forebrain there are peptidergic pressor and depressor circuits. The former includes corticotropin releasing factor-, substance P-, and angiotensin II-circuits; and the latter includes beta-endorphin- and atrial natriuretic peptide-circuits. These circuits extensively interconnect and interact with each other. The altered functions of them may be the pathogenesis of EH. In this review, we focus on the roles of limbic peptidergic circuits in regulation of arterial pressure, relevant to the neurogenetic mechanisms in developing EH.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Corticotropin-Releasing Hormone; Humans; Hypertension; Limbic System; Neuropeptides; Substance P

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Gene Expression Regulation; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Transcription, Genetic

A growing number of mammalian genes whose expression is inducible by hypoxia have been identified. Among them, atrial natriuretic peptide (ANP) synthesis and secretion is increased during hypoxic exposure and plays an important role in the normal adaptation to hypoxia and in the pathogenesis of cardiopulmonary diseases, including chronic hypoxia-induced pulmonary hypertension and vascular remodeling, and right ventricular hypertrophy and right heart failure. This review discusses the roles of ANP and its receptors in hypoxia-induced pulmonary hypertension. We and other investigators have demonstrated that ANP gene expression is enhanced by exposure to hypoxia and that the ANP so generated protects against the development of hypoxic pulmonary hypertension. Results also show that hypoxia directly stimulates ANP gene expression and ANP release in cardiac myocytes in vitro. Several cis-responsive elements of the ANP promoter are involved in the response to changes in oxygen tension. Further, the ANP clearance receptor NPR-C, but not the biological active NPR-A and NPR-B receptors, is downregulated in hypoxia adapted lung. Hypoxia-sensitive tyrosine kinase receptor-associated growth factors, including fibroblast growth factor (FGF) and platelet derived growth factor (PDGF)-BB, but not hypoxia per se, inhibit NPR-C gene expression in pulmonary arterial smooth muscle cells in vitro. The reductions in NPR-C in the hypoxic lung retard the clearance of ANP and allow more ANP to bind to biological active NPR-A and NPR-B in the pulmonary circulation, relaxing preconstricted pulmonary vessels, reducing pulmonary arterial pressure, and attenuating the development of hypoxia-induced pulmonary hypertension and vascular remodeling.

Topics: Animals; Atrial Natriuretic Factor; Becaplermin; Cardiovascular Diseases; Dose-Response Relationship, Drug; Down-Regulation; Fibroblast Growth Factor 1; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Hypertension; Hypoxia; Luciferases; Mice; Models, Biological; Platelet-Derived Growth Factor; Protein Binding; Proto-Oncogene Proteins c-sis; Rats; Signal Transduction; Time Factors

Blood pressure is maintained for preventing from the progression of damage of central nervous system. Endocrine system plays important roles in the prevention from the damage through the functional deviation. Hypertension is one of the results of the endocrinological deviation. Although the hypertension induced by the endocrinological deviation is a risk for the progression of metabolic syndrome, it is important in the maintaining activity of central nervous system.

Topics: Aged; Aging; Arteriosclerosis; Atrial Natriuretic Factor; Blood Volume; Cardiac Output; Central Nervous System; Endocrine System; Glucocorticoids; Growth Substances; Humans; Hypertension; Metabolic Syndrome; Parathyroid Hormone; PPAR gamma; Renin-Angiotensin System; Risk; Vascular Resistance; Vasopressins

The serine proteases of the trypsin superfamily are versatile enzymes involved in a variety of biological processes. In the cardiovascular system, the importance of these enzymes in blood coagulation, platelet activation, fibrinolysis, and thrombosis has been well established. Recent studies have shown that trypin-like serine proteases are also important in maintaining cardiac function and contribute to heart-related disease processes. In this review, we describe the biological function of corin, tissue kallikrein, chymase and urokinase and discuss their roles in cardiovascular diseases such as hypertension, cardiac hypertrophy, heart failure, and aneurysm.

Topics: Animals; Aortic Aneurysm, Abdominal; Atrial Natriuretic Factor; Cardiomegaly; Chymases; Heart; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Ischemia; Serine Endopeptidases; Tissue Kallikreins; Urokinase-Type Plasminogen Activator

Topics: Atrial Natriuretic Factor; Biomarkers; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hypertension; Hyperthyroidism; Immunoradiometric Assay; Kidney Failure, Chronic; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Reference Values; Specimen Handling; Tachycardia, Supraventricular

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30-50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear. Furthermore, the abundance of data in the literature makes it difficult to piece together the puzzle of hypertension and to define candidate genes involved in the dynamic of blood pressure regulation. In this review, we attempt to highlight the genetic basis of hypertension pathogenesis, focusing on the most important existing genetic variations of candidate genes and their potential role in the development of this disease. Our objective is to review current knowledge and discuss limitations to clinical applications of genotypic information in the diagnosis, evaluation and treatment of hypertension. Finally, some principles of pharmacogenomics are presented here along with future perspectives of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cytokines; Endothelins; Epithelial Sodium Channels; Genetic Variation; Humans; Hypertension; Models, Cardiovascular; Pharmacogenetics; Receptors, Adrenergic, beta; Renin-Angiotensin System; Signal Transduction; Sodium; Sodium Channels

Plasma levels of natriuretic peptides are elevated in patients with chronic kidney disease owing to impairment of renal function, hypertension, hypervolemia, and/or concomitant heart disease. Proteinuria and/or immunosuppression also contribute to enhanced plasma levels and increased urinary excretion of natriuretic peptides. Atrial natriuretic peptide (ANP) and particularly brain natriuretic peptide (BNP) levels are linked independently to left ventricular mass and function and predict total and cardiovascular mortality. ANP and BNP decrease significantly during hemodialysis treatment but increase again during the interdialytic interval. Intraperitoneal administration of ANP decreases peritoneal fluid and glucose absorption, as well as lymphatic flow rate. Successful kidney transplant normalizes the plasma levels of natriuretic peptides in the majority of patients. In experimental animals but not in humans, ANP administration protects against ischemic acute renal failure. Since proANP31-67 peptide does not cause hypotension, this vessel dilator may protect the kidney during acute renal failure by intrarenal vasodilation and stimulation of endogenous prostaglandin E2 synthesis.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Hypertension; Kidney Diseases; Kidney Transplantation; Natriuretic Peptides; Peritoneal Dialysis; Renal Replacement Therapy

In spite of a significant improvement in control of numerous predisposing risk factors, stroke remains a major health problem and a common cause of death and disability in our societies. Genetic predisposition to stroke development exists and has been documented in both animal models and in humans. However, a precise definition of genetic factors responsible for common forms of stroke is still lacking, mainly due to its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations. In contrast, important breakthroughs have been reached for monogenic forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An animal model of stroke, the stroke-prone spontaneously hypertensive rat, has provided valuable information on genetic factors involved in stroke predisposition. Among them, the gene-encoding atrial natriuretic peptide has been identified as a stroke gene in both the stroke-prone spontaneously hypertensive rat and, subsequently, in two different human populations. In particular, structural alterations of the gene are consistently present in diseased individuals, suggesting an important role of mutation-dependent mechanisms in stroke predisposition. Finally, the recent use of intermediate disease phenotypes provides a reductionist approach that may contribute to important accumulating information on genes contributing to cerebrovascular accidents.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Genetic Linkage; Genetic Predisposition to Disease; Humans; Hypertension; Rats; Risk Factors; Stroke

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Coronary Disease; Diabetes Mellitus; Humans; Hypertension; Liver Failure; Mice; Natriuretic Peptide, Brain; Oxidative Stress; Peptides; Rats

Topics: Animals; Atrial Natriuretic Factor; Calmodulin-Binding Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Mutation; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Rats; Receptors, Adrenergic, beta; Renin-Angiotensin System

Topics: Animals; Atrial Natriuretic Factor; Blood Volume; Cardiomegaly; Catecholamines; Humans; Hypertension; Hyperthyroidism; Hypothyroidism; Myocardial Contraction; Receptors, Thyroid Hormone; Renin-Angiotensin System; Thyroxine; Triiodothyronine; Vascular Resistance; Vasopressins

Adrenomedullin, a 52-amino acid residue peptide, has numerous biological actions which are of potential importance to cardiovascular homeostasis, growth and development of cardiovascular tissues and bone, prevention of infection, and regulation of body fluid and electrolyte balance. Studies in man using intravenous infusion of the peptide have demonstrated that, at plasma levels detected after myocardial infarction or in heart failure, adrenomedullin reduces arterial pressure, increases heart rate and cardiac output, and activates the sympathetic and renin-angiotensin systems but suppresses aldosterone. The thresholds for these responses differ, being lower under some experimental circumstances for arterial pressure than for the other biological effects. Adrenomedullin administration inhibits the pressor and aldosterone-stimulating action of angiotensin II in man. By contrast, the pressor effect of norepinephrine is little altered by concomitant adrenomedullin administration. Although in the absence of a safe, specific antagonist of the actions of endogenous adrenomedullin it is difficult to be certain about the physiological and pathophysiological importance of this peptide in man, current evidence suggests that it serves to protect against cardiovascular overload and injury. Hope has been expressed that adrenomedullin or an agonist specific for adrenomedullin receptors might find a place in the treatment of cardiovascular disorders.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiotonic Agents; Endothelins; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Hypopituitarism; Peptides

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Humans; Hypertension; Natriuresis; Natriuretic Peptides; Neprilysin; Protease Inhibitors; Pyridines; Recombinant Proteins; Thiazepines; Vasodilation

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Hypertension; Pyridines; Renin-Angiotensin System; Sodium, Dietary; Stress, Physiological; Thiazepines

This literature review presents current information on mechanisms of realization and action of natriuretic peptides in heart failure and hypertension. Significant role in degradation of natriuretic peptides belongs to neutral endopeptidase. Basing on theoretical and experimental data novel class of drugs - inhibitors of neutral endopeptidase - has been developed. The paper contains discussion of first results of the use of drugs from this class for the treatment of chronic heart failure.

Topics: Atrial Natriuretic Factor; Chronic Disease; Heart Failure; Humans; Hypertension; Neprilysin

Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic/diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.

Topics: Aldosterone; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Capsaicin; Endothelin-1; Hypertension; Neurons, Afferent; Renin; Sodium, Dietary; Sympathetic Nervous System

The natriuretic peptide and renin-angiotensin systems are physiological counterparts with opposite roles in the regulation of electrolyte balance and blood pressure. In both systems, membrane-bound, zinc-dependent peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II, and neutral endopeptidase (NEP) degrades the natriuretic peptides. Simultaneous inhibition NEP and ACE by a single molecule (a vasopeptidase inhibitor) is a new therapeutic approach in hypertension. Wider applications for vasopeptidase inhibitors being studied include their role as cardioprotective agents in heart failure, as renoprotective agents in chronic renal failure and diabetic nephropathy, and as vasculoprotective agents in endothelial dysfunction and athersclerosis.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Enzyme Inhibitors; Humans; Hypertension; Models, Biological; Peptide Hydrolases; Peptidyl-Dipeptidase A

The review presents current data on production, release and reception of natriuretic peptides (NUP) with special focus on NUP effects on blood circulation, urination in arterial hypertension and cardiac failure; analyses interaction between NUP and renin-angiotensin-aldosterone system, effects of new drugs influencing these systems.

Topics: Animals; Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Myocardium; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin-converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin-angiotensin-aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agent's effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long-term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Heart Failure; Humans; Hypertension; Lisinopril; Mesylates; Natriuretic Peptide, Brain; Neprilysin; Pyridines; Randomized Controlled Trials as Topic; Thiazepines; Tyrosine

Most cardiovascular traits of interest can be defined as "complex traits," with the first step in the identification of genetic factors affecting such traits being the detection of quantitative trait loci (QTLs). Animal models have proven particularly useful in this regard. However, only very few of the QTLs identified to date have led to the identification of candidate genes. We describe an example of our own work where the combination of anatomical and a biochemical intermediate phenotypes have led to the identification of the natriuretic peptide precursor A (Nppa) gene as a candidate gene for left ventricular hypertrophy (LVH). Combined with the power of comparative genetics, these strategies will continue to improve the chances of finding candidate genes for cardiovascular traits such as susceptibility to heart diseases, hypertension, and hypertension-induced end-organ damage.

Topics: Animals; Atrial Natriuretic Factor; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Models, Animal; Natriuretic Peptide, C-Type; Phenotype; Protein Precursors; Quantitative Trait, Heritable

Guanylyl cyclases (GC) exist as soluble and particulate, membrane-associated enzymes which catalyse the conversion of GTP to cGMP, an intracellular signalling molecule. Several membrane forms of the enzyme have been identified up to now. Some of them serve as receptors for the natriuretic peptides, a family of peptides which includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), three peptides known to play important roles in renal and cardiovascular physiology. These are transmembrane proteins composed of a single transmembrane domain, a variable extracellular natriuretic peptide-binding domain, and a more conserved intracellular kinase homology domain (KHD) and catalytic domain. GC-A, the receptor for ANP and BNP, also named natriuretic peptide receptor-A or -1 (NPR-A or NPR- 1), has been studied widely. Its mode of activation by peptide ligands and mechanisms of regulation serve as prototypes for understanding the function of other particulate GC. Activation of this enzyme by its ligand is a complex process requiring oligomerization, ligand binding, KHD phosphorylation and ATP binding. Gene knockout and genetic segregation studies have provided strong evidence for the importance of GC-A in the regulation of blood pressure and heart and renal functions. GC-B is the main receptor for CNP, the latter having a more paracrine role at the vascular and venous levels. The structure and regulation of GC-B is similar to that of GC-A. This chapter reviews the structure and roles of GC-A and GC-B in blood pressure regulation and cardiac and renal pathophysiology.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cardiomyopathies; Down-Regulation; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Isoenzymes; Natriuretic Peptide, Brain; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Structure-Activity Relationship

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biopsy; Coronary Angiography; Coronary Disease; Electrocardiography; Heart Failure; Humans; Hypertension

Hypertension is a debilitating disease with significant socioeconomic and emotional impact. Despite recent success in the development of traditional pharmacotherapy for the management of hypertension, the incidence of this disease is on the rise and has reached epidemic proportions by all estimates. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau, and novel approaches for the treatment and control of hypertension must be explored. We have begun to investigate the possibility of treating and/or curing hypertension by using genetic means. In this review, we will provide evidence in favor of targeting of the renin-angiotensin system by antisense gene therapy as an effective strategy for the lifelong prevention of hypertension in the spontaneously hypertensive rat model. In addition, we will discuss the properties of an ideal vector for the systemic delivery of genes and the potential experimental hurdles that must be overcome to take this innovative approach to the next level of evaluation.

Topics: Adenoviridae; Adrenomedullin; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; DNA, Antisense; Genetic Therapy; Genetic Vectors; Green Fluorescent Proteins; HIV; Humans; Hypertension; Kallikreins; Luminescent Proteins; Mutation; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptides; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Retroviridae; Transfection

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP-Dependent Protein Kinases; Endothelins; Gene Targeting; Genetic Engineering; Genetic Therapy; Humans; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Receptors, Endothelin; Renin-Angiotensin System

Topics: Atrial Natriuretic Factor; Autonomic Nervous System; Blood Coagulation Disorders; Bradykinin; Cardiac Output; Diastole; Endothelins; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Pregnancy; Prenatal Exposure Delayed Effects; Renin-Angiotensin System; Vascular Resistance

Excessive accumulation of adipose tissue is associated with profound alterations in the cardiovascular system. including an increase in systemic blood pressure. It now appears clear that a central feature of obesity-associated hypertension is related to changes in sodium handling that may result from abnormalities in sympathetic nervous system activity, the renin-angiotensin-aldosterone system, natriuretic peptides, and kidney function. In this paper we review the role of these factors in the development of obesity-associated hypertension, thereby focusing on the potential role of adipose tissue in these alterations.

Topics: Adipose Tissue; Atrial Natriuretic Factor; Hypertension; Models, Biological; Obesity; Renin-Angiotensin System; Research Personnel; Sodium

The literature review reflects new aspects of humoral regulation in hypertension and target-organ damages with special regard to natriuretic peptide system(NPS) and adrenomedullin(AM). NPS and AM are recently discovered regulators which serve as antihypertensive and target-organ protective factors. These peptides have both diuretic and natriuretic properties and a relaxing effect on the vasculature. Moreover, they antagonize the proliferative and hypertrophic stimuli in the vasculature and heart. Recently, progressive technics of molecular biology clearly revealed crucial roles of these peptides for cardiovascular regulation in both normal and pathological states including hypertension and related organ damages. Natriuretic peptides, potentially AM, are new therapeutic tools for heart failure and main targets for further development of new antihypertensive drugs such as vasopeptidase inhibitor.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Natriuretic Peptide, Brain; Peptides

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Cattle; Dogs; Heart Failure; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; RNA, Messenger; Swine; Vasodilation

Topics: Acute Kidney Injury; Animals; Arrhythmias, Cardiac; Ascites; Atrial Natriuretic Factor; Cardiovascular Diseases; Cerebrovascular Disorders; Heart Failure; Humans; Hypertension; Hyperthyroidism; Hypothyroidism; Kidney; Liver Cirrhosis; Myocardial Infarction; Sodium; Thyroxine

The atrial natriuretic peptide (ANP), a component of the natriuretic peptide family, was discovered in 1981 when de Bold and his coworkers observed a natriuretic effect induced by infusion of atrial extracts in rats. Subsequently, an impressive amount of research has been carried out in order to identify the structure of the active peptide and its receptors, to characterize the biological functions of ANP and its involvement in the pathophysiology of diseases and, finally, its direct contributory role in the pathogenesis of some cardiovascular disorders. ANP plays a key role in the regulation of salt and water balance, as well as of blood pressure homeostasis. In addition, ANP is involved in the pathophysiology of hypertension and heart failure, and exerts a cellular antiproliferative effect in the cardiovascular system. More recently, a direct contributory role of ANP in the development of hypertension and of cerebrovascular disorders has been suggested by the use of molecular genetic approaches. Therefore, our understanding of the pathophysiologic relevance of ANP has changed over time, finally leading to the identification of ANP as a potential determinant of cardiovascular diseases, rather than as a simple marker of cardiac and vascular dysfunctions. This novel view of ANP may open interesting research pathways.

Topics: Animals; Atrial Natriuretic Factor; Cardiology; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Agents

Vasopeptidase inhibition is a new concept in blood pressure management. A single molecule simultaneously inhibits two enzymes that regulate cardiovascular function: neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE)[1]. Development of vasopeptidase inhibitors stemmed from the need for new and more efficacious antihypertensive agents that not only reduce blood pressure but also treat hypertension as part of a larger syndrome involving endothelial dysfunction [2]. By inhibiting NEP and ACE, vasopeptidase inhibitors enhance the natriuretic peptide and kallikrein-kinin systems and inhibit the renin-angiotensin-aldosterone system. This article outlines the pharmacodynamic effects of the vasopeptidase inhibitor omapatrilat on biomarkers of NEP and ACE activity in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Neprilysin; Pyridines; Renin-Angiotensin System; Thiazepines; Vasodilator Agents

Vasopeptidase inhibitors are a new class of drugs capable of inhibiting both angiotensin-converting enzyme and neutral endopeptidase 24.11. This involves simultaneous inhibition with a single molecule of two key enzymes, ACE and NEP, which are both involved in the regulation of cardiovascular homeostasis in many ways. This includes metabolism of several vasoactive peptides and their clearance from the circulation, therefore contributing to neurohumoral modulation, which might have therapeutic advantages in the prevention of endothelial dysfunction in hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Bradykinin; Endothelins; Endothelium, Vascular; Humans; Hypertension; Neprilysin; Nitric Oxide; Nitric Oxide Synthase; Receptors, Endothelin

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelium, Vascular; Heart Failure; Humans; Hypertension; Neprilysin; Receptors, Angiotensin; Renin-Angiotensin System

The precision by which sodium balance is regulated suggests an intricate interaction between modulatory factors released from intra- and extrarenal sources. Intrarenally produced dopamine has a central role in this interactive network. Dopamine, produced in renal tubular cells acts as an autocrine and paracrine factor to inhibit the activity of Na+,K+-ATPase as well as of a number of sodium influx pathways. The natriuretic effect of dopamine is most prominent under high salt diet. The antinatriuretic effects of noradrenaline, acting on alpha-adrenoceptors and angiotensin II are opposed by dopamine as well as by atrial natriuretic peptide (ANP). Several lines of evidence have suggested that ANP acts via the renal dopamine system and recent studies from our laboratory have shown that this effect is attributed to recruitment of silent D1 receptors from the interior of the cell towards the plasma membrane. Taken together, the observations suggest that dopamine coordinates the effects of antinatriuretic and natriuretic factors and indicate that an intact renal dopamine system is of major importance for the maintenance of sodium homeostasis and normal blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Dopamine; Epinephrine; Humans; Hypertension; Kidney; Kidney Tubules; Natriuretic Agents; Signal Transduction

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Disease Models, Animal; Heart Failure; Humans; Hypertension; Neprilysin; Renin-Angiotensin System

The recent development of genetic mouse models presenting life-long alterations in expression of the genes for atrial natriuretic peptide (ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this hormone in chronic blood pressure homeostasis. Transgenic mice overexpressing a transthyretin-ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the ANP or NPR-A genes are hypertensive compared with their respective wild-type counterparts. The chronic hypotensive action of ANP is determined by vasodilation of the resistance vasculature, which is probably mediated by attenuation of vascular sympathetic tone at one or several prejunctional sites. Under conditions of normal dietary salt consumption, the hypotensive action of ANP is dissociated from the natriuretic activity of the hormone. However, during elevated dietary salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for maintenance of blood pressure constancy, inasmuch as the ANP gene "knockout" mice (ANP -/-) develop a salt-sensitive component of hypertension in association with failure to adequately downregulate plasma renin activity. These findings imply that genetic deficiencies in ANP or natriuretic receptor activity may be underlying causative factors in the etiology of salt-sensitive variants of hypertensive disease and other sodium-retaining disorders, such as congestive heart failure and cirrhosis.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Hypertension; Hypotension; Mice; Mice, Knockout; Mice, Transgenic; Phenotype; Renin-Angiotensin System; Sodium Chloride; Vasodilation; Water-Electrolyte Balance

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension

Available data suggest that hypertensive cardiopathy is principally determined by the phenoconversion that allows the myocyte to adapt to the new working conditions by re-expressing a fetal program. Nevertheless, in clinical conditions, the scheme is different. The above phenotype is modified by trophic factors, which originate from ischemia, senescence, diabetes, genetics, or neurohormonal reactions. This review only focuses on some of the most recent advances concerning the permanent changes in the myocyte. Changes in extracellular matrix have been excluded. Recently, emphasis has been on the kinetic basis of the myocardial dysfunction at the myosin level, the potential therapeutic utilization of transferring the adrenergic receptor gene, the participation of NO synthases in the adaptational process, the existence of an abnormal excitation-contraction coupling due to a redistribution of Ca2+ sparks, the role of the microtubule as a determinant of sarcomere motion, and the multifactorial origin of cell death by apoptosis.

Topics: Adenosine Triphosphate; Animals; Atrial Natriuretic Factor; Autocrine Communication; Cardiomegaly; Cell Death; Cytoskeleton; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Humans; Hypertension; Models, Cardiovascular; Muscle Proteins; Myocardial Contraction; Myocardium; Nitric Oxide; Phenotype; Rats; Receptors, Adrenergic, beta

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Humans; Hypertension; Protease Inhibitors; Pyridines; Thiazepines

Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Thiazepines

Topics: Adrenomedullin; Angiotensin II; Atrial Natriuretic Factor; Catecholamines; Endothelins; Humans; Hypertension; Nitric Oxide; Peptides

Essential hypertension probably results from combinations of small genetic variations that are partly normal variations and may not be appreciably harmful individually. Strategies to identify genes contributing to hypertension are discussed in this review. Gene targeting approaches, especially gene titration, have been used in these studies of hypertension. Gene titration experiments vary the expression of a chosen gene product by generating animals having different numbers of copies of the gene coding for the product. Gene titration is powerful for analyzing quantitative variations seen in common polygenic disorders, such as kidney diseases, diabetes mellitus, and atherosclerosis, as well as hypertension, because it allows tests of causation by determining the effects on a phenotype by changes in expression of the altered gene and because it matches normal quantitative variations more closely than is possible with classic transgenic mice. The use of zero-copy (gene "knockout") animals generated by gene disruption for studies of qualitative gene effects is also discussed. These various gene targeting experiments help identify genes regulating BP, promote a better understanding of the pathophysiology of the condition, and help identify potential targets for therapies.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelin-1; Gene Targeting; Humans; Hyperaldosteronism; Hypertension; Mice; Mice, Knockout; Models, Genetic; Mutation; Nitric Oxide Synthase; Receptor, Bradykinin B2; Receptors, Bradykinin; Renin-Angiotensin System; Syndrome

There are significant gender-specific differences in the incidence of hypertension and the clinical outcome of cardiovascular disease between premenopausal women and age-matched men, suggesting that sex hormones such as estrogen (E) might be responsible for the observed cardioprotective effects. This cardioprotective action of E is thought to involve lipoproteins. However, the effect of E on the lipid profile accounts for about 50% of the reduction in cardiovascular disease, indicating that there might be other mechanisms by which E exerts its cardioprotective effects. At present, the underlying mechanism of E action is poorly understood. In this review, the interplay between E, the natriuretic peptides (NP) and the renin-angiotensin system (RAS) is examined. It is hypothesized that E might, through endocrine and/or paracrine action, modulate cardiac NP in females by affecting the RAS either directly or indirectly.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Estrogens; Female; Homeostasis; Humans; Hypertension; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Rats; Receptors, Estrogen; Renin-Angiotensin System; Testosterone

After 100 years of measurement, reasons for interindividual and populational variation in blood pressure have proven difficult to identify. Use of 24-hr blood pressure monitoring has revealed additional intra-individual variation. Variability in kidney function, extracellular sodium and potassium (Na:K) balance, and factors affecting water, sodium, and potassium resorption obviously affect blood pressure. Alterations in these and additional factors predict development of hypertension. In recent decades the molecular revolution has increased scrutiny of genetic factors contributing to interindividual and populational differences in blood pressure and hypertension. Most investigations across populations and environments have focused on components of the renin-angiotensin-aldosterone system. DNA polymorphisms within this system clearly are associated with blood pressure and hypertension; however, these associations tend to vary across race and ethnicity, ecological settings, and sex. There is clear evidence that polymorphisms at the renin, angiotensinogen, and angiotensin-converting enzyme loci influence both blood pressure and hypertension. In addition, evidence suggests gene-gene and gene-environment interactions along with sex-specific actions of these loci on blood pressure.

Topics: Atrial Natriuretic Factor; Blood Pressure; Endothelin-1; Environment; Female; Humans; Hypertension; Male; Nitric Oxide; Polymorphism, Genetic; Renin-Angiotensin System

This update reviews the remarkable progression in several cardiovascular gene transfer domains. The first chemical gene therapy protocols to stimulate angiogenesis in ischemic myocardium are discussed and both the great expectations as well as remaining hurdle are highlighted. In experimental models of restenosis and heart failure gene therapy shows promising results. Important question regarding vector-related limitations and suboptimal in vivo delivery systems will require expeditious attention for gene therapy to become a more widely applicable option in cardiovascular diseases.

Topics: Animals; Arteriosclerosis; Atrial Natriuretic Factor; Cardiovascular Diseases; Coronary Disease; Endothelial Growth Factors; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Heart Failure; Humans; Hypertension; Lymphokines; Mice; Neovascularization, Physiologic; Rabbits; Superoxide Dismutase; Thrombosis; Tissue Plasminogen Activator; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Atrial Natriuretic Factor; Heart Diseases; Hemodynamics; Humans; Hypertension; Natriuretic Peptide, C-Type

Sodium balance in patients with renal failure varies with the severity and clinical manifestations of renal disease. Progressive chronic renal insufficiency is typified by an adaptive increase in the sodium excretion rate per nephron as the total glomerular filtration rate declines. This increase is caused, at least in part, by the effect of atrial natriuretic peptide and other natriuretic peptides, whose release is augmented in the setting of volume expansion and renal failure. However, exogenous administration of natriuretic peptides in clinical chronic and acute renal disease does not consistently increase renal sodium excretion. As the glomerular filtration rate progressively declines towards end-stage renal disease, total renal sodium excretion eventually decreases, and extracellular volume expansion, hypertension, and edema develop. Sodium removal, induced by high dose diuretics or via convective ultrafiltration during dialysis, is necessary to decrease the extracellular volume to normal.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Diuretics; Edema; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis; Sodium

An update on renal genetic mechanisms of spontaneous hypertension in rats and in human essential hypertension is presented. The findings are discussed, highlighting the search of a possible link between the discovered genetic abnormality and the renal function changes that may determine the disease. The analogies (and/or differences) between the numerous positive findings obtained in animal models and the relatively scarce ones obtained in humans are discussed.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Calmodulin-Binding Proteins; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Endothelins; Family; Humans; Hypertension; Mixed Function Oxygenases; Models, Cardiovascular; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Renin; Sodium Channels

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.

Topics: Animals; Atrial Natriuretic Factor; Cell Differentiation; Guanylate Cyclase; Humans; Hypertension; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Nitric Oxide; Proteins; Receptors, Atrial Natriuretic Factor; Signal Transduction

Human essential hypertension is generally recognized as a multifactorial disease based on genetic diathesis. Despite the usefulness of SHR and Dahl rats as laboratory tools, the genetic diathesis including the development of hypertension in these rats remains unclear. Rapid advances in embryonic engineering and molecular biological techniques may make it possible to develop transgenic mice and gene-targeted mice and open new avenues for the molecular investigation of human disease. This report introduces genetically engineered mice with hypertension and hypotension.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Humans; Hypertension; Kallikrein-Kinin System; Mice; Mice, Transgenic; Mutation; Nitric Oxide Synthase; Rats; Receptors, Adrenergic, alpha-2; Renin-Angiotensin System; Sodium-Hydrogen Exchangers

Hypertension is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD), often occurring early in the disease before the renal function starts to decrease. The pathogenesis of this early hypertension is controversial.. To review studies on the pathogenesis of early and late hypertension in ADPKD.. Studies on ADPKD and hypertension were retrieved from Medline from the last 20 years, with an emphasis on the last 10 years. These studies, together with selected published abstracts from recent hypertension and nephrology meetings, were reviewed critically.. Cyst growth, renal handling of sodium, activation of the renin-angiotensin-aldosterone system, volume expansion, an elevated plasma volume, and increased plasma atrial natriuretic peptide and plasma endothelin levels have all been found to be associated with hypertension in ADPKD. In some studies an inappropriate activity of the renin-angiotensin-aldosterone system that could be related to cyst growth and intrarenal ischemia was found. An increase in renal vascular resistance has been demonstrated and might be caused by intrarenal release of angiotensin II. Interestingly, the protective effect of angiotensin converting enzyme inhibitors on the renal function could not be demonstrated in ADPKD patients with a moderately decreased renal function. The importance, if any, of endothelial vasodilatory factors is not known. Sympathetic nervous activity seems to be increased in ADPKD, but the importance of this for the blood pressure level is not known.. The pathogenesis of hypertension in ADPKD is complex and likely to be dependent on the interaction of hemodynamic, endocrine and neurogenic factors.

Topics: Atrial Natriuretic Factor; Blood Pressure; Endothelium, Vascular; Hemodynamics; Humans; Hypertension; Kidney Tubules; Polycystic Kidney, Autosomal Dominant; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Because diuretic drugs remain the main treatment for disorders of sodium and water metabolism, the quest for improved diuretic and natriuretic agents continues in the hope of achieving fewer side effects and a more rational basis in pathophysiology. One aim has been to enhance endogenous diuretic and natriuretic activity by selective manipulation of atrial natriuretic peptide and related compounds. The first approach has been to inhibit degradation of these peptides using inhibitors of their main catabolic enzyme, neutral endopeptidase, and to offset any antagonistic effect of the renin-angiotensin system by combination with an angiotensin-converting enzyme inhibitor. The second and more recent approach has been to inhibit breakdown of the second messenger of atrial natriuretic peptide, cGMP, using phosphodiesterase inhibitors. As yet, neutral endopeptidase inhibition has not advanced successfully beyond animal experimentation and phosphodiesterase inhibition is still in its infancy. Both strategies suffer from the problem that, on the one hand, neutral endopeptidase metabolizes a variety of bioactive peptides, including endothelin, and it is not possible to develop inhibitors that will be selective for a given peptide; whereas, on the other hand, there are several phosphodiesterase isoforms metabolizing cGMP and cAMP, both second messengers for many different bioactive compounds, and selective inhibitors are still under development.

Topics: Animals; Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Neprilysin; Phosphoric Diester Hydrolases

The explosion of new knowledge about the complex mechanisms mediating high blood pressure is providing new targets for drug therapy of hypertension and other cardiovascular disorders. This article reviews the current status of several new approaches in the management of hypertension, including vasopressin antagonists, natriuretic peptide clearance inhibitors, endothelin antagonists, renin inhibitors, angiotensin receptor antagonists, and selective T-type calcium ion channel antagonists.

Topics: Animals; Antihypertensive Agents; Arginine Vasopressin; Atrial Natriuretic Factor; Endothelins; Humans; Hypertension

Topics: Atrial Natriuretic Factor; Blood Pressure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Sodium, Dietary; Ventricular Dysfunction, Left; Ventricular Function, Left

This paper deals with a literature survey on natriuretic peptides (NP) and their clinical use in prognostic stratification and therapy of arterial hypertension and cardiac failure. After a brief historical introduction, the phylogenesis of NP is analyzed and the reasons of their preservation in the evolution are emphasized. The biochemistry of the NP is then treated, and the structure, synthesis, mechanism of cellular action and systems of regulation are analyzed. Subsequently, the authors have analyzed the physiology of the NP as well as their hemodynamic and biohumoral effects and actions on the central nervous system. A literature review on the significance of NP in arterial hypertension, on their usefulness as indicators of damage and on their therapeutic practice is then made. In particular, the possible future applications in the prevention of atherosclerotic damage are analyzed. The significance of NP and of their metabolites in heart failure and the prognostic implication of these peptides particularly in ischemic heart failure are then discussed. The most important papers on this topic are described. Finally the studies on the use of NP in the therapy of heart failure are analyzed and a guide on research of this topic is defined.

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; DNA; Endothelins; Female; Gene Targeting; Genetic Vectors; Hypertension; Male; Mice; Mice, Inbred Strains; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Sequence Homology, Nucleic Acid; Stem Cells

Natriuretic peptides are produced in the brain, heart and vasculature, and cause vasodilation, sodium excretion, and diuresis. Recent advances indicate that they play important roles in blood-pressure homeostasis, both in normal and in pathophysiological conditions. Although therapeutic interventions which elevate plasma natriuretic peptide levels do not have great antihypertensive efficacy, animal studies suggest that they may be useful in combination treatment strategies.

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Receptors, Peptide

Our laboratory has characterized a model of salt sensitive hypertension, the salt sensitive spontaneously hypertensive rat (SHR-S), in which dietary NaCl supplementation increases blood pressure by reducing norepinephrine release by nerve terminals in the anterior hypothalamic area (AHA), thus reducing activation of sympathoinhibitory neurons in the AHA. This, in turn, results in increased sympathetic outflow and higher blood pressure in the SHR. Two mechanisms have been shown to contribute to this effect: (i) reduced noradrenergic input into AHA via baroreflex pathways and (ii) local inhibition of NE release in AHA by the inhibitory neuromodulator atrial natriuretic peptide (ANP). Studies employing microinjection of a blocking monoclonal antibody to ANP directly into the AHA and the nucleus tractus solitarius (NTS) demonstrated for the first time that endogenous ANP in the brain is functionally active in the tonic control of blood pressure and baroreflex sensitivity in the SHR-S but plays a lesser role in the normotensive Wistar Kyoto (WKY) control. In the WKY, excitation of NTS neurons by baroreflex afferents leads to activation of sympathoinhibitory neurons in NTS and AHA, strong inhibition of sympathetic nervous system outflow, and a decrease in arterial pressure. In SHR-S, brain ANP acts at the levels of the NTS and the AHA to perturb this baroreflex regulatory pathway. ANP tonically activates sympathoinhibitory neurons in the caudal NTS of SHR-S, thereby restraining the rise in arterial pressure, and tonically inhibits baroreflex responsiveness to alterations in blood pressure. Thus ANP appears to act at a number of sites in brain to facilitate the development and maintenance of sympathetically mediated hypertension in the SHR-S model.

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Hypothalamus, Anterior; Norepinephrine; Rats

Both population (mass) strategies and targeted strategies for the management of high blood pressure are necessary. However, it has yet to be proven that reducing blood pressure by lifestyle changes in the population will confer the same cardiovascular benefit that results from lowering blood pressure by drugs. It is important to identify and correct those factors in hypertensive patients, such as obesity, smoking, elevated lipids, and diabetes, that confer high risk for an adverse cardiovascular event. It is now recognized that cardiovascular risk involves not only diet and lifestyle effects but that the structural and functional abnormalities resulting from high blood pressure are of great importance. There is a need to develop and validate new noninvasive methods for quantitating these structural and functional changes, together with assessment of endothelial dysfunction, hormonal profiling, and identification of susceptible genes so that high risk patients with hypertension can be selected for drug therapy. In the future, selection of an appropriate antihypertensive drug for an individual patient should also involve consideration of risk factors, structural changes, hormonal status, and genetic consideration. Central inhibition of peripheral sympathetic action by imidazoline receptor agonists, such as moxonidine, may lead to reversal of these structural and functional abnormalities without adverse effects on the central nervous system.

Topics: Adrenergic alpha-Antagonists; Atrial Natriuretic Factor; Forecasting; Genetic Markers; Humans; Hypertension; Renin; Risk Factors

Although it has been recognized for almost 70 years that there is a substantial genetic component to the pathogenesis of hypertension, only recently have systematic efforts been made to identify the responsible genetically determined mechanisms. In the case of several rare syndromes, spectacular progress has been made in identifying the underlying molecular mechanisms responsible for the clinical expression. Glucocorticoid-suppressible aldosteronism and Liddle's syndrome, each inherited as an autosomal-dominant condition, complete the list. In the case of randomly selected patients and families with essential hypertension, inheritance involves many genes and progress has been far more modest. Probably the most promising lead has involved the genes governing the structure of angiotensinogen, the substrate in the renin reaction. Linkage has been established and confirmed. At the moment, however, neither the relation of the genetic abnormality to the underlying mechanisms, nor the contribution of this abnormality to hypertension in the individual patient, has been defined. We know less about other candidate genes, with the exception of studies that rigorously ruled out a contribution. The development of the concept of the "intermediate phenotype," a physiological feature that makes it possible to identify a homogeneous subpopulation, should help to sort out many of these issues. Unfortunately, the identification and characterization of intermediate phenotypes is substantially more difficult at the moment than are the genetic studies, and so progress is likely to be slow. The field is complicated by the reporting of claims made on the basis of small patient samples. In the case of polymorphisms in the angiotensin-converting enzyme gene as a risk factor for tissue injury, for example, substantial follow-up studies have systematically failed to confirm the original report, which was based on a small patient sample. The fact that the same DNA collection is likely to be examined many times for multiple gene candidates creates a setting in which type I errors are likely, and so we are likely to see many more examples. Caveat lector. Again, the development of relevant intermediate phenotypes will make the spurious association less likely.

Topics: Angiotensinogen; Atrial Natriuretic Factor; Genes, Dominant; Humans; Hyperaldosteronism; Hypertension; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Genetic; Racial Groups; Renin-Angiotensin System; Syndrome

The effects of long-term high calcium diet and physical exercise and their combined effects on the development of hypertension, plasma and tissue atrial natriuretic peptide, and arterial function were studied in spontaneously hypertensive rats with Wistar-Kyoto rats serving as normotensive controls. Hypertensive rats were made to exercise by running on a treadmill up to 900 m/day. Calcium supplementation was instituted by increasing the calcium content of the chow from 1.1% to 2.5%. During the 23-week study, calcium supplementation attenuated the rise in blood pressure in both trained and nontrained hypertensive animals, whereas exercise training had no significant effect on blood pressure. The high calcium diet alone was associated with reduced plasma and ventricular tissue contents of atrial natriuretic peptide, both of which were increased by exercise. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Neither increased dietary calcium nor endurance training affected the contractile sensitivity of endothelium-intact preparations to potassium chloride or norepinephrine. However, a high calcium diet enhanced the arterial relaxation induced by the return of potassium to the organ bath upon precontraction with potassium-free solution, and also moderately augmented relaxations to acetylcholine, sodium nitrite, and isoproterenol. Exercise training did not affect the potassium relaxation rate, but enhanced responses to acetylcholine, isoproterenol, and sodium nitrite. In conclusion, enhanced arterial potassium relaxation, a response reflecting the function of the vascular sodium pump, paralleled well the long-term blood pressure lowering action of increased dietary calcium intake in exercised and nonexercised hypertensive rats. However, augmented arterial relaxation to agonists could also be observed in the absence of reduced blood pressure following regular physical exercise.

Topics: Animals; Arteries; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium; Calcium, Dietary; Electrolytes; Heart Rate; Hypertension; Intracellular Membranes; Male; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstrictor Agents; Vasodilator Agents

Topics: Animals; Atrial Natriuretic Factor; Heart; Humans; Hypertension; Receptors, Atrial Natriuretic Factor

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Central Nervous System; Dogs; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Rats; Renin; Renin-Angiotensin System; Sheep

A number of pathophysiological phenomena linked to sleep disordered breathing are likely to affect vascular function. This report briefly reviews current knowledge regarding neurogenic vascular tone and a number of circulating hormones with vascular actions in obstructive sleep apnea (OSA). New evidence suggesting a role of the vascular endothelium in the development of vascular disease in OSA is also presented.

Topics: Aldosterone; Angiotensin II; Arginine; Atrial Natriuretic Factor; Endothelium; Humans; Hypertension; Sleep Apnea Syndromes; Snoring; Sympathetic Nervous System

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Humans; Hypertension; Natriuretic Peptide, C-Type

The natriuretic peptide family consists of three members: atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Atrial and brain natriuretic peptides possess similar effects, causing natriuresis, vasodilation, and suppression of the renin-angiotensin-aldosterone system. C-type natriuretic peptide has been suggested to exert its predominant effect on the vasculature, eliciting vasodilation and inhibiting the proliferation of vascular smooth muscle cells. Numerous studies have broadened our current knowledge of the regulation of natriuretic peptide gene expression, biosynthesis, and secretion, as well as structure of specific receptors. This has led to a better understanding of the renal, cardiovascular, and endocrine actions of natriuretic peptides in both normal and pathophysiological states, including hypertensive disease. Development of nonpeptide neutral endopeptidase inhibitors and antagonists for natriuretic peptide receptors may reveal the range of potential therapeutic application of atrial and other natriuretic peptides in hypertension.

Topics: Animals; Atrial Natriuretic Factor; Hemodynamics; Humans; Hypertension; Kidney; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins

Topics: Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Aromatic-L-Amino-Acid Decarboxylases; Atrial Natriuretic Factor; Carbidopa; Cattle; Dopamine; Dopamine Agonists; Dopamine Antagonists; Humans; Hypertension; Kidney; Kidney Tubules; Models, Biological; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine; Signal Transduction; Sodium; Sodium, Dietary

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Natriuresis; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins

We review evidence supporting the conclusion that renal dysfunction underlies the development of all forms of hypertension in humans and experimental animals. Indexes of global renal function are generally normal in the early stages of most genetic forms of hypertension, but renal function is clearly impaired in long-established hypertension. Studies in our laboratory over the past decade summarized below have established that the renal medulla plays an important role in sodium and water homeostasis and in the long-term control of arterial pressure. Development of implanted optical fibers for measurement of cortical and medullary blood flows with laser-Doppler flowmetry and techniques for delivery of vasoactive compounds into the medullary interstitial space enabled us to examine determinants of medullary flow (nitric oxide, atrial natriuretic peptides, kinins, eicosanoids, vasopressin, renal sympathetic nerves, etc). We have shown in spontaneously hypertensive rats that the initial changes of renal function begin as a reduction of medullary blood flow in the absence of changes of cortical flow. Long-term medullary interstitial infusion of captopril, which preferentially increased medullary blood flow, resulted in a lowering of arterial pressure. In normal Sprague-Dawley rats, selective reduction of medullary flow with medullary interstitial or intravenous infusion of small amounts of NG-nitro-L-arginine methyl ester resulted in hypertension. These and other studies we review show that although blood flow to the inner renal medulla comprises less than 1% of the total renal blood flow, changes in flow to this region can have a major effect on sodium and water homeostasis and on the long-term control of arterial blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Calcium Channel Blockers; Humans; Hypertension; Kidney Medulla; Laser-Doppler Flowmetry; Nitric Oxide; Peptide Fragments; Renal Circulation

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins

1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihypertensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an angiotensin converting enzyme (ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose-related manner in conscious dogs with tachycardia-induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metalloprotease inhibitor BMS-182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Failure; Hemodynamics; Hypertension; Neprilysin

Atrial natriuretic peptide (ANP) is a 28 amino-acid polypeptide secreted into the blood by atrial myocytes after atrial pressure and distension. Although its role in humans is not clear, it can produce a variety of physiologic effects including vasodilatation, natriuresis, and suppression of the renin-angiotensin-aldosterone axis. These actions are potentially useful in a variety of pathologic states such as hypertension and congestive heart failure, and diverse methods to augment the effects of ANP in these states have been devised. The results are exciting and, despite some problems, may lead to the pharmacologic use of enhancement of ANP actions in several clinical disorders.

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Natriuresis; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Vasodilation

The discovery of an endocrine activity of the heart in 1981 was fundamental in order to understand the regulation of the effective circulatory volume. Indeed, the hormone which is secreted by the atrial cells (ANF) when these are distended suddenly in the presence of an enhanced preload of the heart, acts very rapidly upon the kidneys and the vasomotor tone. Its action restores without delay the effective circulatory volume following the renal elimination of an appropriate fraction of salt and water and attenuates the pressor effects of the increased intravascular volume. In this regard, the hormone is an emergency mediator. ANF may also be a long-term regulator of salt and water homeostasis by modulating the renal excretion of sodium. Finally, its role in pathological conditions such as congestive heart failure or essential hypertension remains to be elucidated. Nevertheless, interesting therapeutic perspectives may be considered, based on the unusual inactivation of ANF by clearance receptors.

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Natriuresis; Plasma Volume; Sodium; Water-Electrolyte Balance

Our goals were (1) to use meta-analysis to determine whether pregnancy and the puerperium are accompanied by alterations in plasma atrial natriuretic peptide levels when compared with the nonpregnant state and (2) to evaluate the additional effects of hypertensive disease during pregnancy on plasma atrial natriuretic peptide levels.. Articles measuring atrial natriuretic peptide levels during pregnancy were reviewed. Data from articles meeting inclusion criteria were abstracted, and a meta-analysis was performed with the use of the maximum likelihood methods of Jennrich and Schluchter (Biometrics 1986;42:805-20).. The mean atrial natriuretic peptide level in nonpregnant control subjects was 28.7 pg/ml (95% confidence interval 22.5 to 36.7). The mean plasma atrial natriuretic peptide level rose 41% to 40.5 pg/ml (95% confidence interval 31.7 to 51.8) in the third trimester (p < 0.0001). It was 71.1 pg/ml (95% confidence interval 51.2 to 98.7) or 148% greater than the mean nonpregnant level during the first week post partum (p < 0.0001). Compared with levels in pregnant control subjects, plasma atrial natriuretic peptide levels increased 52% to 52.1 pg/ml (95% confidence interval 32.9 to 82.5) in women with gestational hypertension (p < 0.005) and 130% to 78.8 pg/ml (95% confidence interval 52.3 to 118.8) in women with preeclampsia (p < 0.0001). Chronic hypertension did not significantly alter atrial natriuretic peptide levels.. The 41% increase in atrial natriuretic peptide levels in the third trimester suggests that atrial stretch receptors sense the expanded blood volume as normal to moderately increased. The rise in atrial natriuretic peptide during the first week post partum is consistent with known hemodynamic changes and suggests that atrial natriuretic peptide may be involved in the postpartum diuresis. The marked increase in plasma atrial natriuretic peptide levels observed in preeclampsia is not likely to result from elevated arterial pressures alone but may reflect underlying factors unique to this disease process.

Topics: Atrial Natriuretic Factor; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values

Topics: Animals; Atrial Natriuretic Factor; Endothelins; Hypertension; Kidney; Signal Transduction

A 56-year-old white female presented with longstanding hyperkalemia, hyperchloremia, and hypertension. Renal function was normal. Plasma renin levels were low as were serum and urinary aldosterone. Plasma cortisol levels were normal. Fludrocortisone was ineffective in lowering serum potassium. Plasma renin and aldosterone levels responded appropriately to salt restriction and to postural changes. Plasma atrial natriuretic hormone (ANH) and urinary prostaglandins (PG) were normal. Salt loading resulted in suppression of renin and aldosterone levels and stimulation of plasma ANH and urinary PG but failed to increase potassium or chloride excretion. The persistent hyperkalemia, hyperchloremia, and suppressed renin-aldosterone axis were consistent with type II pseudohypoaldosteronism. Hydrochlorothiazide was effective in normalizing serum potassium levels and blood pressure. These studies exclude abnormalities in ANH and PG secretion in this disorder and are compatible with an abnormality in chloride reabsorption.

Topics: Aldosterone; Atrial Natriuretic Factor; Female; Humans; Hyperkalemia; Hypertension; Middle Aged; Potassium; Prostaglandins; Pseudohypoaldosteronism; Renin

Topics: Amino Acid Sequence; Atrial Natriuretic Factor; Heart Diseases; Heart Failure; Humans; Hypertension; Molecular Sequence Data; Natriuretic Peptide, Brain; Protease Inhibitors

Established essential hypertension is characterized by normal equilibrium between the intake and renal excretion of sodium. Urinary sodium excretion is interrelated with that of other ions, such as potassium and calcium, and that the response of blood pressure to salt ingestion can be conditioned by the simultaneous intake of varying levels of those ions. The authors address three aspects: the correlations between urinary excretion of sodium and calcium and sodium and potassium in a population of untreated essential hypertensive persons, the response of blood pressure during the escape induced by exogenous mineralocorticoid administration in mild essential hypertension, and the effect of intravenous calcium gluconate infusion on sodium excretion and renal function. The first part shows that sodium excretion is closely correlated with that of other ions in essential hypertension, and the second part shows that, to escape from the sodium-retaining effect of a mineralocorticoid, mild hypertensive subjects must have increased blood pressure within or near the cutoff point that defines salt sensitivity. Of interest, the elevation in blood pressure takes place while sympathetic nervous activity is blunted. The third part provides evidence to explain one of the mechanisms by which calcium influences renal function and enhances renal sodium excretion. The intrarenal effects of low doses of calcium are dependent on the renal production of prostaglandins.

Topics: Atrial Natriuretic Factor; Blood Pressure; Calcium; Electrolytes; Humans; Hypertension; Kidney; Mineralocorticoids; Sodium, Dietary

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Humans; Hypertension

Topics: Animals; Atrial Natriuretic Factor; Drug Therapy, Combination; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neprilysin; Nerve Tissue Proteins; Peptide Fragments

Proopiomelanocortin (POMC) is a protein that contains the amino acid sequences of numerous peptide hormones, including the melanocyte-stimulating hormones (MSH). MSH peptides of alpha, beta, and gamma primary structure are present in plasma, and all exhibit natriuretic activity. Intravenous infusion of alpha or beta-MSH leads to a time- and dose-dependent natriuresis, whereas gamma-MSH is reported to be natriuretic at low doses but antinatriuretic at high doses. The natriuretic activity of MSH peptides occurs without change in arterial pressure or renal hemodynamics, suggesting a possible direct tubular inhibition of sodium reabsorption. Intravenously infused gamma-MSH is associated with an increase in the plasma concentration of atrial natriuretic peptide. In addition, gamma-MSH also has a direct intrarenal natriuretic action that is dependent on the renal nerves. In rats, gamma-MSH-related peptides are involved in the reflex control of sodium excretion in situations such as the natriuresis that occurs (a) from the remaining kidney after acute unilateral nephrectomy, (b) from the contralateral kidney shortly after unilateral ureteral pressure elevation, and (c) after unilateral carotid artery traction. POMC-derived peptides (including MSH) are modulated in response to salt loading, and alterations in POMC metabolism and plasma peptide concentrations have been observed in genetically hypertensive rats and during the development of adrenal regeneration hypertension. In addition, plasma gamma-MSH levels are elevated in patients with severe congestive heart failure, and in primary hyperaldosteronism. These observations suggest a possible involvement of MSH-related peptides in sodium homeostasis as well as in certain forms of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Hemostasis; Humans; Hypertension; Infusions, Intravenous; Melanocyte-Stimulating Hormones; Natriuresis; Pro-Opiomelanocortin; Rats

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Kidney Tubules; Lithium; Natriuresis; Sodium

Atrial natriuretic peptide (ANP) is a hormone produced, stored and secreted by atrial muscle cells. By its natriuretic, diuretic and blood pressure lowering activities ANP is possibly an endogenic antagonist for the sodium-retaining, vasopressor renin-angiotensin-aldosterone system (RAAS). In diseases associated with increased intravascular volume ANP plasma concentrations have been found elevated, in those associated with decreased volume ANP has been found decreased. In essential hypertension and chronic heart or renal failure diagnostic conclusions may be drawn from the ANP plasma concentration. This review summarizes the present knowledge about physiology and pathophysiology of ANP and values in addition the diagnostic power of ANP measurements for clinical routine in hypertension, heart and renal failure.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Plasma Volume; Renin-Angiotensin System

The original observation by de Bold et al. (1981) of a rapid, massive, and short-lasting diuretic and natriuretic effect following injection of rat atrial extracts into intact rats, led to the identification, isolation and purification of the atrial natriuretic factor (ANF). ANF is stored in atrial myocytes and released into the blood stream by atrial distension. Available data suggest that the mechanism of ANF-induced natriuresis involves either renal hemodynamic effects, such as the increase in glomerular filtration rate and reduction of medullary tonicity, or direct effect on sodium transport in the medullary collecting ducts. ANF induces relaxation of vascular smooth muscle, decreases blood pressure and cardiac output. All these effects displayed by ANF are associated to the an inhibition of aldosterone, renin and vasopressin release. Most of these actions are mediated by specific high affinity receptors, which are coupled to a particulate guanylate cyclase. Although ANF levels are increased in some disorders, such as severe heart failure, hypertension, chronic renal failure, the role of the peptide is uncertain. To better define the potential physiopathological role and the possible therapeutic implications of this new hormonal system in conditions of disturbed body fluid and sodium homeostasis, further experimental and clinical data must be awaited.

Topics: Atrial Natriuretic Factor; Gene Expression Regulation; Heart Atria; Heart Diseases; Humans; Hypertension; Kidney Diseases; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Topics: Animals; Atrial Natriuretic Factor; Hemodynamics; Humans; Hypertension; Kidney Tubules; Polycystic Kidney, Autosomal Dominant; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Signal Transduction

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension

Topics: Animals; Atrial Natriuretic Factor; Eicosanoids; Female; Hemodynamics; Humans; Hypertension; Kidney; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Pregnancy, Animal

The generation of genetically modified animals by transgenic technology has proven to be a surprisingly versatile resource for researchers, providing an increasing number of new tools for biological investigation. As well as permitting the analysis of gene function and regulation in vivo, modifications of the techniques are being used to suppress or abolish the expression of specific genes, and further refinements have permitted the ablation of specific cell-types and the development of differentiated cell lines from tissue-specific tumours. In hypertension research, where many important questions have been frustratingly difficult to address by previously available methods, the advances afforded by transgenic studies have already been significant and are likely to be even more profound in the future. With the further development of these techniques, it may be possible to produce new and more representative models of essential hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Gene Expression Regulation; Hypertension; Models, Genetic; Renin

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Structure-Activity Relationship

Dopamine, an ancestral catecholamine, is physiologically natriuretic and vasodilating, thus essentially protecting against hypertension. Its actions are overshadowed by the opposite effects of its main biological partner, norepinephrine, and this is accentuated with aging. Clinical observations combined with molecular biology approaches to catecholamine-synthesizing and catecholamine-metabolizing enzymes and receptors permit the identification of some inborn defects. Subtle changes in the dopamine-norepinephrine balance may account for the enhanced peripheral noradrenergic activity seen in the setting of decreased dopaminergic activity in advanced age. These changes may contribute to the diminished ability of the aged kidney to excrete a salt load, as well as to the finding that systolic blood pressure increases with age in populations with a high, but not in those with a low, intake of salt. The attainment of advanced age in Western societies with adverse lifestyle changes (mental rather than physical stress, excess salt intake, overeating, sedentarism) appears to facilitate the development of hypertension. The adaptation to all the preceding lifestyle changes necessitates an increased dopamine generation, which may initially compensate to maintain appropriate natriuresis and vasodilation since many patients with initial borderline essential hypertension express their sympathetic hyperfunction, in addition to increased norepinephrine release, by excessive dopamine release. However, the progression of hypertension is accompanied by a peripheral dopaminergic deficiency and diminished ability to excrete salt. This may represent an eventual inadequacy of a phylogenetically redundant system resulting in decreased natriuresis and vasodilation and may account for the responsiveness of established chronic hypertension to salt restriction, diuretics, and dopaminomimetic medication.

Topics: Aging; Atrial Natriuretic Factor; Dopamine; Dopamine beta-Hydroxylase; Humans; Hypertension; Life Style; Receptors, Dopamine; Signal Transduction; Tyrosine 3-Monooxygenase

The cause of primary (essential) hypertension remains unknown, but a number of circulating hormones and endothelium-derived factors are probably involved. This review summarizes recent evidence on the roles of hyperinsulinemia, the renin-angiotensin system, atrial natriuretic factor, and three endothelium-derived factors--prostacyclin, endothelium-derived relaxing factor, and endothelin.

Topics: Animals; Atrial Natriuretic Factor; Epoprostenol; Hormones; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Models, Biological; Muscles; Nitric Oxide; Renin-Angiotensin System

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Heart Failure; Heart Rate; Humans; Hypertension; Myocardial Contraction; Rats; Rats, Inbred SHR; Tachycardia, Supraventricular

In this review, the authors examine the biochemical mechanism involved in synthesis and release of ANF and its physiological effects concerning kidney and cardiovascular system. In addition, the authors underline the possible interactions of ANF with other hormones, particularly with the renin-angiotensin-aldosterone system and with vasopressin. Finally, the authors consider the possible physiopathological implications of ANF in the genesis of hypertension and hydrosaline retention.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Coronary Disease; Heart Failure; Hemodynamics; Humans; Hypertension; Kidney; Renin-Angiotensin System

Hypertension results from abnormalities of the control systems that normally regulate blood pressure. These control systems include vascular, cardiogenic, renal, neurogenic, and endocrine mechanisms that interact in a complex but integrated manner to achieve blood pressure homeostasis. Multiple endogenous biologically active substances participate in the regulation of these control systems. Evidence suggests that abnormalities of these regulatory mechanisms resulting from altered genetic and environmental interactions play an important role in the pathogenesis of primary hypertension. Once hypertension develops, it tends to be self-perpetuating via amplifying mechanisms mediated by secondary structural changes in the blood vessels, heart, and kidney. These adaptative structural changes amplify and perpetuate hypertension by increasing systemic vascular resistance, enhancing cardiac output, and impairing renal sodium and water excretion. The long-term sequelae of hypertensive structural changes in these end organs are complications of atherosclerotic vascular disease, cardiac hypertrophy and failure, stroke, and renal failure. With the tools of molecular biology, our understanding of the molecular mechanisms underlying these abnormalities has increased enormously and continues to grow at a rapid pace, as illustrated by the discussion that follows. Our review of the molecular biology of hypertension will address systematically four key areas: 1) molecular biology of the control systems, 2) molecular mechanisms of cardiovascular structural changes, 3) genetics of hypertension, and 4) application of transgenic technology in studies of hypertension.

Topics: Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Disease Models, Animal; Endothelins; Gene Expression Regulation; Genes; Growth Substances; Humans; Hypertension; Renin-Angiotensin System; RNA, Messenger

Our studies with the prototypical NEP inhibitor SCH 34826 indicate the potential role of this class of compounds in cardiovascular modulation. The data assembled to date indicate that NEP inhibition elicits significant ANF-like effects in animals and man. The early data generated to date on SCH 34826, when considered with those data generated on other NEP inhibitors, indicate that NEP inhibition may have therapeutic utility in some forms of hypertension and congestive heart failure.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Dioxolanes; Dipeptides; Drug Synergism; Heart Failure; Humans; Hypertension; Neprilysin; Prodrugs; Rats

Topics: Animals; Atrial Natriuretic Factor; Body Water; Heart Failure; Humans; Hypertension; Myocardium; Protease Inhibitors; Renin-Angiotensin System; Sodium

Atrial natriuretic factor (ANF) is a recently discovered, volume responsive hormone with multiple potent antihypertensive actions. This article reviews data supporting hypothetical associations between ANF and essential hypertension, examines reports of plasma ANF concentrations in hypertension, discusses the efficacy of ANF and its analogs in the treatment of hypertension, and reviews future issues in ANF research. ANF has been shown to elicit vasodilatation, suppress plasma renin activity, inhibit the synthesis and release of aldosterone, antagonize sympathetically-mediated release of norepinephrine, and promote diuresis and natriuresis. A metaanalysis of plasma ANF concentrations reported in normal and hypertensive subjects reveals a 5 +/- 19 pg/mL (pooled, weighted mean and standard deviation) higher ANF level in age-matched, untreated hypertensives without evidence of end-organ damage. This difference may be inappropriately low given the increase in atrial filling pressures found in hypertension. Low doses of ANF elicit greater reductions in blood pressure in hypertensive subjects than in normals. Recently, inhibitors of the ANF-degrading enzyme, neutral endopeptidase, and of the ANF "clearance" receptor have enhanced the antihypertensive actions of endogenous or exogenously administered ANF. Human studies are currently in progress testing the antihypertensive efficacy of orally administered neutral endopeptidase inhibitors. The discovery of ANF has led to the elucidation of a family of natriuretic peptides from brain, heart, and kidney, and promises to enlarge our understanding of volume regulation in normal and pathophysiological states. The possibility that essential hypertension is associated with inappropriately low plasma ANF levels or altered responsiveness to ANF may offer new insights into the pathogenesis and treatment of hypertension.

Topics: Amino Acid Sequence; Amino Acids; Atrial Natriuretic Factor; Humans; Hypertension; Meta-Analysis as Topic; Molecular Sequence Data

The pathogenesis of essential hypertension may possibly involve a deficiency in, or a decreased response to, endogenous vasodilator and natriuretic factor(s). Searching for hereditary or familial defects, it is plausible to evaluate blood pressure (BP) regulating factors in (yet) normotensive offspring of hypertensive parents (OHyp), some of whom are in fact in a stage of prehypertension. Studies by our group demonstrated that compared with healthy offspring of normotensive parents, OHyp have plasma atrial natriuretic (ANF) factor levels that are unaltered on a low salt intake but often fail to increase normally in response to a high salt intake. Plasma levels of cyclic GMP, the presumed second messenger of ANF, also may tend to be decreased in certain OHyp. On the other hand, renal excretory responses of cyclic GMP and electrolytes to ANF infused in "physiological" dose were unchanged in some OHyp tested so far. In borderline to moderate, uncomplicated essential hypertension, plasma ANF levels are often "normal." This may be inappropriately low relative to the existing BP, although the relationship of circulating ANF to atrial pressures in essential hypertension remains to be clarified. A conversion to higher plasma ANF values may occur with cardiac complications such as left ventricular hypertrophy, enlargement, dysfunction, or overt heart failure. Acute or short-term elevation of circulating ANF within the physiological and pathophysiological range by ANF infusion produces an exaggerated natriuresis and lowers BP in essential hypertensive patients. We postulate a syndrome of ANF deficiency, characterized by an impaired response of circulating ANF to high salt intake and by low cyclic GMP levels in certain yet normotensive offspring of essential hypertensive parents and by inappropriately "normal" plasma ANF in some patients with uncomplicated essential hypertension. At the stage of prehypertension, a disturbance in the ANF - cyclic GMP pathway may be expressed primarily at the circulatory rather than at the renal level. Hypertension-prone humans also tend to have an exaggerated vascular reactivity to norepinephrine. Whether the two disturbances may be interrelated is presently unknown. Both defects may potentially predispose to the development of essential hypertension. Relative ANF deficiency, an enhanced natriuretic response to ANF, and a sustained antihypertensive effect of infused ANF may represent a rational basis for treatment of essential hypert

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension

The identification of the atrial natriuretic peptides (ANP) as a new hormonal system has provided a new perspective on the mechanisms controlling renal sodium excretion and abnormalities in sodium homeostasis. The present article focuses on the potential importance of ANP (ANF 99-126) in essential hypertension with particular reference to circulating ANP levels and the relationship between the ANP and the renin-angiotensin system in the control of sodium balance and blood pressure. There is now considerable evidence demonstrating that a substantial proportion of patients with essential hypertension have raised circulating ANP levels. Given the known biological actions of ANP, these raised levels point to important compensatory mechanisms. This is further supported by studies during alterations in dietary sodium intake, as sodium restriction high-lighted important relationships between ANP and the renin angiotensin system. The potential importance of ANP in essential hypertension is strengthened by recent demonstration of natriuretic and antihypertensive actions associated with small increases in circulating ANP as induced by administration of exogenous ANP. Furthermore, the recent development of orally active inhibitors of ANP metabolism now provides a basis to determine the therapeutic importance of specific manipulation of endogenous ANP levels in patients with essential hypertension.

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Sodium; Water-Electrolyte Balance

In normal pregnancy, cross-sectional clinical data do not consistently show plasma ANF concentration differences between early pregnancy and the nonpregnant state. Sequential data in the baboon (but not in rat) show a significant decrease in plasma ANF concentration and in cardiac filling pressures in early pregnancy. The latter data support the view that pregnancy is an underfill state secondary to a primary vasodilatation. Cross-sectional and longitudinal studies in normal pregnancy in humans show that plasma ANF levels tend rise to values that are, in the third trimester, higher than in the nonpregnant state. However, late postpartum sequential data (1.5-3 months) in humans do now show a significant drop in plasma ANF concentrations, suggesting that plasma ANF is not actually increased in normal pregnancy. In the baboon (but not in the rat) there is a steady rise in plasma ANF levels to values that are significantly higher in third trimester than before pregnancy. These data suggest that in human pregnancy, in contrast with the baboon, the plasma volume expansion induced by normal pregnancy is not sensed as such by the atria probably because of an isopressive adaptation of plasma volume to an enlarged vascular bed. However, acute decrease or increase of venous return induced by low sodium diet, changing position or infusion of isotonic saline are sensed as such by the atria in normal pregnancy as in the nonpregnant state.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular

Atrial natriuretic peptide (ANP) exhibits a wide spectrum of cardiovascular, endocrine, metabolic and renal actions. cGMP is the major mediator of ANP at the cellular level and only tissues possessing particulate guanylate cyclase appear to present ANP-induced actions. Three types of ANP receptors have recently been cloned. Two of them (A and B receptors) are homologous and contain guanylate cyclase catalytic domains. The C receptor could possibly regulate the metabolic fate of ANP. Data obtained by the radiation inactivation method suggest the presence of an inter- or intramolecular inhibitory component of nearly 90 kilodaltons that represses the catalytic activity of guanylate cyclase within its membrane environment. The mechanism of guanylate cyclase stimulation by ANP could involve this inhibitory component. Preliminary data suggest that the hyperresponsiveness of the particulate guanylate cyclase/cGMP system in hypertension occurs through modulation of the inhibitory component.

Topics: Animals; Atrial Natriuretic Factor; Cell Physiological Phenomena; Cyclic GMP; Humans; Hypertension; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Second Messenger Systems

This article provides a brief overview of atrial natriuretic factor (ANF). Considered by many investigators to be the putative "third factor" governing sodium excretion, ANF is a peptide actively secreted by the heart, with multiple target organ effectors. As such, ANF represents the first clearly documented cardiac hormone.

Topics: Animals; Atrial Natriuretic Factor; Edema; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Nephrotic Syndrome

Up to the present time, it has not been possible to establish the exact role that the renin-angiotensin system plays in the development and persistence of arterial hypertension in human beings. The tissular renin-angiotensin systems which have been studied in different tissular locations, cerebral, cardiac, vascular, play a role which consists in regulating the regional blood flow, in conjunction with the sympathetic nervous system. The tissular renin-angiotensin systems would then act when the physio-pathological alteration which initially caused to the triggering of the general renin-angiotensin system persists after arterial blood pressure has returned to normal levels. Although renin blocking is, in theory, the most efficient method for checking the renin-angiotensin system, in practical terms, the best therapeutical option is still the inhibition of the angiotensin converting enzyme. However, the obtention of an active orally administered compounds capable of inhibiting renin synthesis or action must be considered as an accomplishment still to come. Similarly, the discovery of compounds which are analogous to the natriuretic atrial peptides, and can be administered enterally, also represent a prospect worth bearing in mind for the treatment of arterial hypertension. Since we are aware of the importance of vasodilating renal prostaglandins and modulipin in maintaining renal function in the various forms of arterial hypertension, what must still be established is the role played by these prostanoids in the physiopathology of arterial hypertension in human beings.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Vessels; Brain; Heart; Humans; Hypertension; Kidney; Prostaglandins; Renin-Angiotensin System

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Hypotension; Kidney Failure, Chronic; Renal Dialysis

Topics: Animals; Atrial Natriuretic Factor; Catecholamines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Humans; Hypertension; Insulin Resistance; Renin-Angiotensin System; Sodium

Since the pathogenesis of essential hypertension has not yet been clarified, laboratory examinations are needed to identify secondary hypertension and to classify the patients with essential hypertension into subclasses. We reviewed the recent topics on hypertension-research related to laboratory examinations such as 1) recording of arterial pressure, 2) plasma renin activity and digitalis-like substances as the cause of essential hypertension, and 3) atrial natriuretic polypeptides and endothelin, as possible indices of atherosclerosis, one of major complications of hypertension.

Topics: Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Diagnosis, Differential; Digoxin; Endothelins; Humans; Hypertension; Peptides; Renin; Saponins

The heart atrium, as well as under certain pathophysiological conditions the ventricle, synthesize and release ANP. Exerting natriuretic, diuretic and vasorelaxant effects, this peptide plays an important role in the body's blood volume and blood pressure homeostasis. Whereas the pharmacological actions of ANP have been quite convincingly demonstrated, its physiological and pathophysiological role is less well defined. ANP plasma levels tend to be increased in diseases with salt and water retention, such as essential hypertension, congestive heart failure, renal failure or liver cirrhosis. With regard to its hemodynamic effects, ANP seems to be beneficial in patients with hypertension. ANP appears to have little therapeutic potential as a diuretic in patients with congestive heart failure and liver cirrhosis, possibly due to the decreased renal responsiveness to ANP in these diseases. However, ANP might to be a valuable therapeutic agent in acute renal failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Heart Failure; Homeostasis; Humans; Hypertension; Kidney Diseases; Liver Diseases

Because sleep apnoea syndrome is often associated with arterial hypertension, it has been suggested that sleep apnoea might be responsible for hypertension. This hypothesis is mainly based on epidemiological studies showing a statistically significant association between snoring and arterial hypertension; this association remains true even after data correction to take into account the increased frequency of snoring with age and overweight. However, this statistical link is no evidence of a cause-effect relationship, and the mechanism through which sleep apnoea syndrome could produce arterial hypertension remains unknown. Yet treatment of sleep apnoea syndrome seems to improve arterial hypertension, and this alone would justify a search for sleep apnoea syndrome in all patients presenting with arterial hypertension.

Topics: Atrial Natriuretic Factor; Catecholamines; Humans; Hypertension; Positive-Pressure Respiration; Prevalence; Protriptyline; Sleep Apnea Syndromes; Tracheotomy

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Heart Defects, Congenital; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Myocardium; Respiratory Distress Syndrome, Newborn

The literature review reflects new aspects of pathophysiology and pathogenesis of arterial hypertension with special regard to the role of tissue renin-angiotensin-systems, endothelial and growth factors. The arteriolar wall as well as different organs produce angiotensin, which is of higher regulatory capability than the circulating angiotensin. Natriuretic hormones, endogenous opioids, neuropeptide Y and other vasoactive peptides are accepted as new humoral factors and neuromediators with different influence on the blood volume and the peripheral resistance. The vessel endothelium produces potent vasoconstricting (e.g. endothelin and vasodilating (e.g. EDRF) factors. Finally, growth factors with their potential role in vessel wall and myocardial hyperplasia/hypertrophy are analyzed. Tissue systems, endothelial and growth factors as new elements of arterial hypertension pathogenesis may influence the further development of new antihypertensive drugs.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelium, Vascular; Growth Substances; Humans; Hypertension; Muscle, Smooth, Vascular; Nitric Oxide; Renin-Angiotensin System

Atrial natriuretic peptide (ANP) is secreted by the heart in response mainly to atrial distension and circulates in plasma in picomolar concentrations. It binds to receptors in blood vessels which it relaxes, renal glomeruli where it induces increased glomerular filtration rate, renal papilla to produce natriuresis, adrenal glomerulosa cells to inhibit aldosterone secretion, and median eminence and pituitary where it may inhibit vasopressin secretion. In experimental models of hypertension plasma levels of ANP are uniformly elevated, except in spontaneously hypertensive rats, in which plasma ANP may only rise transiently. The action of ANP on smooth muscle cells of the blood vessel wall results in production of cyclic GMP, which appears to be the second messenger producing relaxation of pre-contracted blood vessels. Mechanisms other than cGMP generation have been proposed but remain unproven as mediators of ANP action. Receptors for ANP in blood vessels are of two subtypes: B-receptors (or R1-receptors), which contain guanylate cyclase in their structure, and C-receptors (or R2-receptors), which have not been shown to the present to be biologically active. Our studies on vascular ANP receptors are reviewed. In several experimental models of hypertension such as saralasin-insensitive 2-kidney, 1-clip and 1-kidney, 1-clip Goldblatt hypertensive rats and in DOCA-salt hypertensive rats, we have found elevated plasma ANP, as well as decreased binding and ANP-induced vascular relaxation and blood pressure-lowering effects of ANP. Both the B and C ANP receptors appear decreased in density, even after acid washing of membranes to remove any retained circulating ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Vessels; Hypertension; Rats; Rats, Inbred SHR; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

The physiology, the pharmacology and the biochemistry of the atrial natriuretique factor (ANF) have been investigated and documented by numerous studies and works since its discovery and cloning ten years ago. More recently, the physiopathological aspect of ANF biosynthesis and secretion by the whole heart during overload and congestive heart failure was reported in experimental models and in human patients. Moreover the cyclic GMP which is the ANF second messenger, egressed from endothelial cells, was correlated with the production of ANF. Therefore the activation of heart endocrine function from ANF gene over-expression to peripheral cyclic GMP appeared as an independent prognosis indicator in congestive heart failure. Two types of ANF receptors have been recently cloned. One is the particulate guanylate cyclase, the second is a clearance receptor involved in the endocytosis and lysozomial degradation of ANF in target cells. Neutral endopeptidase, an ectoenzyme present in different tissues and particularly in the kidney is also capable to cleave ANF in unefficient peptide. The blockade of ANF metabolism by clearance receptor antagonists and neutral endopeptidase inhibitor potentializes the biological effect of exogenous and endogenous ANF particularly on the renal function. This approach of ANF metabolism-inhibition opens new ways on the future of ANF in cardiovascular therapeutic.

Topics: Atrial Natriuretic Factor; Cyclic GMP; Endopeptidases; Heart Failure; Humans; Hypertension; Myocardium; Prognosis; Receptors, Cell Surface

In initial studies of human atrial natriuretic factor (ANF) administered to man, 100 microns intravenous bolus doses infused in normal volunteers and patients with essential hypertension resulted in clear increases in urinary excretion of sodium (four- to sixfold), urine volume, calcium, magnesium, and phosphorous. In addition, in both groups an acute but short-lived fall in blood pressure and rise in heart rate was observed. In these studies and other high dose constant infusion experiments, the response of the renin-angiotension-aldosterone system and plasma catecholamines was varied, either remaining unchanged or showing stimulation when high doses of ANF caused acute and substantial falls in blood pressure. In contrast, constant low-dose infusions of ANF in both normal and hypertensive man (0.75-2 pmol/kg/min) have consistently shown clear suppression of plasma concentrations of renin, angiotensin II, and aldosterone by at least 50% of baseline values. Such "physiological" doses of ANF are not associated with sympathetic nervous system activation even though subtle but significant falls in blood pressure (particularly systolic) may occur.

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension

Atrial natriuretic peptide (ANP) infused intra-arterially into the forearm results in a dose-dependent vasodilator response of rapid onset. The maximal forearm vasodilator response to ANP amounts to about 60% of the maximal forearm vasodilator response to sodium nitroprusside and combined infusion of ANP and sodium nitroprusside has an additive vasodilator effect. ANP-induced vasodilation is greater than that of postjunctional alpha 1- or alpha 2-adrenoceptor blockade or of beta 2-adrenoceptor stimulation but is smaller than due to calcium entry blockade. ANP-induced vasodilation can easily be overcome by norepinephrine and to a lesser extent by angiotension II (Ang II). The similarity of the dose-response relationships for vasodilation and for natriuresis suggests that ANP may be equally effective on its renal and vascular targets. In patients with essential hypertension, intra-arterial infusion of ANP produced a greater vasodilator response than in normotensives and this was inversely related to plasma renin activity, suggesting greater vasodilator responsiveness to ANP in low-renin hypertension. ANP caused vasodilation in humans but this may become less apparent when ANP is infused into the systemic circulation because of cardiovascular sympathetic reflex mechanisms blunting ANP vasodilation. Although the role of ANP in circulatory disease states is unclear, it appears that it could serve a physiological function as an endogenous vasodilator (and natriuretic) principle for volume homeostasis in humans.

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Vasodilator Agents

The atrial natriuretic factor (ANF) is a circulating peptide, consisting of 24 to 28 amino acids. Atrial natriuretic factor is synthetized in atrial cardiomyocytes and stored in specific cytoplasmatic granules. It possesses potent diuretic, natriuretic, and vasorelexant properties. The possible role of ANF in the pathogenesis of hypertension and heart failure was investigated in animal models and in men. We were able to show that the release of ANF from cardiac atria is positively correlated with atrial pressures in both men and rats. In experimental studies, plasma levels of ANF measured by radioimmunoassay, were increased by up to four-fold after acute blood volume expansion. Atrial natriuretic factor release in response to volume loading was markedly attenuated in four-week-old spontaneously hypertensive rats as compared to age-matched normotensive Wistar-Kyoto rats, but a similar responsiveness was found in 16-week-old rats of both strains. This finding can be reconciled with the hypothesis that ANF plays a pathophysiological role in initiating but not maintaining high blood pressure. Clinical studies demonstrate elevated plasma concentrations of ANF in patients with organic heart disease. Further increments in plasma levels of ANF were obtained during physical exercise and after acute volume loading. In patients with congestive cardiomyopathy, the elevated plasma concentrations of ANF reached almost normal levels following improvement of their hemodynamic disturbances after treatment with converting-enzyme inhibitors. These findings suggest that in patients with organic heart disease, plasma concentrations of ANF reflect the hemodynamic burden of the heart and may, therefore, be used as a noninvasive marker of the efficacy of the current cardiac therapy.

Topics: Animals; Atrial Natriuretic Factor; Heart Failure; Hemodynamics; Humans; Hypertension; Rats; Rats, Inbred SHR

Atrial natriuretic factor (ANF) is a humoral agent isolated in recent years from cardiac atrial tissue, and produced by atrial cardiocytes as a peptide precursor containing 152 amino acids. In secretory atrial granules, it is stored in reserve form as a prohormone and released into circulation as a 28-amino acid peptide from the C-terminal portion of the peptide precursor representing the active circulating hormone. ANF possesses potent natriuretic, myorelaxant, vasodilatory and blood pressure-lowering properties. Besides, it inhibits renin, aldosterone and vasopressin secretion. It is present also in the CNS and its function is closely related to the sympathetics nerves. By its direct renal and vascular effect, renin-angiotensin-aldosterone system and vasopressin inhibition and, by its neuromodulatory action on the central and sympathetic nerves, ANF plays an important role in electrolyte, volume and pressure homeostasis. The development of a radioimmunoassay for ANF determination in the plasma of rats and man enabled us to follow up its changes under various experimental conditions (water deprivation, increased or decreased salt intake, effect of anaesthetics, ontogenetic changes in ANF concentration during development of hypertension in the spontaneously hypertensive rat) and in clinical studies (effect of ECV expansion in controls, arterial hypertension, liver cirrhosis as well as ANF changes in congestive heart failure or chronic renal failure). These findings of ours have supported the concept that ANF represents an important adaptive and corrective mechanism mobilized during intravascular volume and blood pressure changes in an effort to normalize these. ANF is expected to find use also in the treatment of oedema, arterial hypertension and acute renal failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Edema; Homeostasis; Hypertension; Rats; Rats, Inbred WKY; Water-Electrolyte Balance

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension

The physiological actions of the atrial peptide system are discussed in relation to its potential role in the aetiology and treatment of hypertension and congestive heart failure (CHF). Atrial natriuretic factor (ANF) exerts marked natriuretic, diuretic and vasodilatory effects and has been demonstrated to reduce blood pressure by several mechanisms, actions which serve to protect the central circulation against volume and pressure overload. It was initially believed that CHF may relate to a deficiency of ANF, but studies of experimentally induced and human CHF have shown elevated levels of circulating ANF, reflecting a compensatory increase in response to reduced cardiac output. In contrast, plasma levels of ANF in hypertension not complicated by CHF are normal and it might be speculated that hypertension reflects an attenuated ANF response to increase cardiac volume and/or pressure. ANF may play an important role in these cardiovascular disease states and, with the availability of synthetic ANF analogues, may also have therapeutic potential.

Topics: Animals; Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension

An impressive amount of research has been produced in the last 8 years on the possible role of ANF in cardiovascular disease. This is a brief and non-inclusive review of this work. In particular, the potential significance of ANF in hypertension and congestive heart failure is discussed.

Topics: Animals; Atrial Natriuretic Factor; Heart; Heart Failure; Humans; Hypertension; Myocardium

Topics: Atrial Natriuretic Factor; Endocrine System Diseases; Heart Diseases; Humans; Hypertension; Kidney Failure, Chronic

Administration of atriopeptin III (125, 250 and 500 ng/kg, intravenously) into pentobarbitone anaesthetized normotensive and DOCA-salt hypertensive rats had no effect on blood pressure or renal haemodynamics. Urine flow and absolute and fractional sodium excretion were increased by 48-90% from the lowest to the highest dose of atriopeptin III in the normotensive group, but were increased by over twice these amounts in the DOCA-salt hypertensive rats. Fractional lithium excretion and calculated proximal tubular fluid reabsorption were unaffected by the peptide in the normotensive rats, but in the hypertensive group atriopeptide III increased fractional lithium excretion by 25-50% and decreased proximal tubular reabsorption to a similar extent. Beyond the proximal tubule there were similar increases in fractional and absolute fluid handling in both groups of rats. These results demonstrated that in DOCA-salt hypertension there was increased sensitivity to the natriuretic activity of atriopeptin III which appeared to result from an increased responsiveness of the proximal tubule.

Topics: Animals; Atrial Natriuretic Factor; Desoxycorticosterone; Hypertension; Kidney; Male; Natriuresis; Rats; Rats, Inbred Strains; Sodium Chloride

The biological actions of Atrial Natriuretic Peptide (ANP) make it potentially useful in the treatment of hypertension and heart failure. We review here the physiology of ANP, the effects of infusion in heart failure and hypertension and preliminary data suggesting that inhibition of endopeptidase 24.11, the enzyme degrading ANP, is an effective mechanism of raising circulating levels of endogenous ANP. Due to the rate of progress in this field we have restricted ourselves to recent work much of which is still available only in abstract form. For more complete accounts the reader is referred to recent reviews [9, 11, 14].

Topics: Atrial Natriuretic Factor; Heart Failure; Humans; Hypertension

To evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) in hypertension, hemodynamic effects of human ANP and antiserum against rat ANP were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous administration of human ANP caused greater hypotension associated with a decrease of cardiac output in SHR than in WKY, which suggests that SHR have enhanced responsiveness to exogenous ANP. The antiserum increased blood pressure and cardiac output, with the latter being significantly greater in SHR than in WKY. These results suggest that endogenous ANP counteract, in part, the maintenance of hypertension. In addition, hemodynamic and renal excretory effects of brain natriuretic peptide (BNP), a novel natriuretic peptide identified from porcine, were studied in SHR and WKY. BNP caused marked natriuresis and hypotension in a dose-dependent fashion, as observed with ANP. Not only ANP but also BNP may have a role in the regulation of blood pressure and water-electrolyte balance.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Humans; Hypertension; Molecular Sequence Data; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Swine

Atrial natriuretic peptide is a recently discovered cardiac hormone with natriuretic, vasodilatory and hypotensive activities. The role of this hormone in the pathophysiology of hypertension is of particular interest. In contrast to an earlier concept, a deficiency of the atrial peptide could not be found in animal models of hypertension or in patients. ANP plasma levels were elevated in SHR with accelerated hypertension, in salt-sensitive Dahl rats, in rats with DOCA-salt-hypertension and in animals with renovascular hypertension. Elevated ANP levels under these conditions can be explained by an expansion of the intravascular volume or by an elevated atrial wall stretch induced by the hypertension itself. In patients with primary hypertension, plasma levels of the peptide are raised in some patients and are normal in others. Plasma ANP levels correlate with age, blood pressure and signs of left ventricular hypertrophy. A negative correlation is described between ANP and renin. Measurement of plasma ANP levels does not allow a differentiation between primary and secondary forms of hypertension. Elevated ANP levels are also found in primary hyperaldosteronism and in renal failure. Stimulation of ANP secretion by physical exercise and dietary salt loading is maintained in hypertension. Infusion of 1-28-hANP leads to a reduction in systemic arterial pressure in normotensives and hypertensives. The natriuresis induced by exogenous ANP is more pronounced in hypertensives. Stimulation of endogenous ANP secretion does not prevent the rise in blood pressure possibly due to a reduction in ANP receptors in target tissues.

Topics: Acromegaly; Animals; Atrial Natriuretic Factor; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney Failure, Chronic; Male; Rats; Rats, Inbred Strains

The discovery of atrial natriuretic factor (ANF) constitutes a major advance in our knowledge of negative cell regulatory pathways leading to vasodilation. The biochemical mechanisms of the action of ANF at the cellular level appear to be mediated by the cGMP- particulate guanylate cyclase system. In the kidney, the main cGMP increasing effect of ANF occurs at the level of the glomeruli, but it appears that action of ANF at the lowest part of the distal tubule is required for its natriuretic activity. Although most current knowledge concerning ANF has been obtained with pharmacological doses of the hormone, it appears that endogenous manipulations of ANF, such as those occurring with postural change, are associated with physiological consequences including increases of cGMP, natriuresis, and diuresis. In both experimental and human hypertension, increased plasma levels of ANF are secondary to higher blood pressure. In hypertension, the administration of ANF leads to an exaggerated renal response. We propose as a hypothesis that an abnormality in the expression of a vasodilatory system, such as ANF-cGMP, may play a role in the pathogenesis of hypertension.

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Kidney

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Hypertension, Pulmonary

In response to acute exposure to moderate high-altitude hypoxia, mammals increase their blood hemoglobin concentration very rapidly by reducing their plasma volume. This phenomenon is caused not only by a redistribution of the body fluid volumes but also by a suppression of voluntary sodium and water intake as well as an inhibition of renal tubular sodium reabsorption with natriuresis and diuresis. This article reviews the role of the peripheral arterial chemoreceptors within the framework of the reflex mechanisms that might cause the changes in sodium and water metabolism in acute arterial hypoxia. The evidence that the peripheral arterial chemoreceptors do also influence sodium and water homeostasis in normoxia is presented. The interrelations between carotid body structure and arterial chemoreceptor reflex effects on the one hand and primary systemic hypertension on the other are discussed.

Topics: Animals; Arteries; Atrial Natriuretic Factor; Body Water; Chemoreceptor Cells; Homeostasis; Humans; Hypertension; Hypoxia; Models, Cardiovascular; Muscle, Smooth, Vascular; Reflex; Sodium

The development of the first semi-automatic blood pressure measuring instrument including optic and acoustic registration of systolic and diastolic blood pressure has led to a reliable assessment of arterial blood pressure during increasing ergometer exercise. There is a linear connection between workload intensity and systolic pressure. Intraarterially and noninvasively obtained values are identical with regard to systolic behavior. In principle, the intraarterially measured diastolic blood pressure, too, increases in healthy subjects, which, nevertheless, may often not be demonstrated in such a clear way due to artefacts occurring during blood pressure measuring. There are no significant differences between untrained and endurance-trained subjects at a given work load. Persons exhibiting a better performance capacity only reach higher maximal systolic values. The male and female subjects' regression lines significantly differ--the reason possibly being the woman's smaller muscle mass. Age-induced differences, too, are significant. Bodybuilders with extremely developed muscle mass do not show any significant differences with regard to blood pressure behavior during exercise. When establishing a relation to the relative muscle force the bodybuilders show blood pressure values even lower than normal values.

Topics: Animals; Arousal; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitors; Dopamine; Exercise Test; Heart Atria; Humans; Hypertension; Rats; Serotonin

Topics: Atrial Natriuretic Factor; Humans; Hyperaldosteronism; Hypertension; Natriuresis; Sodium, Dietary; Vasopressins; Water-Electrolyte Imbalance

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Homeostasis; Humans; Hypertension; Natriuresis; Neurosecretory Systems

Extensive examination in the mammalian brain for the presence of atrial natriuretic factors (ANF) has revealed both peptide and receptors specifically distributed throughout the central nervous system. High concentrations of ANF have been found in several hypothalamic nuclei, septal areas, the anteroventral third ventricular area (AV3V), and the median eminence, whereas moderate concentrations have been detected in the circumventricular organs and several brainstem nuclei. The receptors for ANF have been found in moderate to high concentrations in the olfactory lobe, AV3V region, and several circumventricular organs (subfornical organ, organum vasculosum of the lamina terminalis) as well as the nucleus tractus solitarius, median eminence, and choroid plexus. These findings suggest a role for ANF in modulating fluid and electrolyte balance, and blood pressure in this compartment, analogous to the proposed actions of this peptide hormone in the periphery. To determine whether ANF might function as a neuromodulator of blood pressure, we administered ANF via fourth ventricular injection into the brain of hypertensive (SHR) and normotensive rats (WKY). Atrial natriuretic factor caused a moderate and significant decrease in mean arterial blood pressure in both strains. The action of ANF appeared to be mediated by activating the central alpha 2-adrenergic nervous system, probably through the release of catecholamines. Further, a dependence on the secretion and action of an endogenous opioid was probably involved; heart rate was unaffected in these studies. Experiments from other laboratories indicate that central ANF may modulate the pressor effects of centrally acting angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Central Nervous System; Hypertension; Neurotransmitter Agents; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Ion Channels; Natriuresis; Natriuretic Agents; Potassium; Renin; Sodium

Topics: Animals; Atrial Natriuretic Factor; Endocrine Glands; Heart; Heart Diseases; Humans; Hypertension; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Second Messenger Systems

Much has been learned over the past 25 years concerning the role of the heart in hypertension. In a multiplicity of areas a great deal has been clarified but a number of issues remain unresolved. This personal overview outlines some of these challenging areas for investigation, including questions relating to the cardiogenic reflexes, mechanisms underlying total body autoregulation that may involve not only the adaptation of arterioles but also venoconstriction in hypertension, postcapillary constriction also involving the efferent glomerular arterioles, the mechanisms underlying the development and regression of hypertrophy as well as the function of the hypertrophied and "regressed hypertrophy" heart, and the precise hemodynamic actions of atrial natriuretic factor.

Topics: Atrial Natriuretic Factor; Cardiomegaly; Heart; Hemodynamics; Humans; Hypertension; Vascular Resistance

Studies were conducted to assess the effects of bolus injections and infusions of human atrial natriuretic factor (ANF) in control subjects and patients with mild essential hypertension, and to measure plasma immunoreactive ANF (irANF) concentration in a large group of patients with essential hypertension. The results are compared with those obtained by other groups on the measurements of plasma irANF in hypertensive patients. It appears that plasma irANF concentrations are not increased in patients with mild essential hypertension despite the evidence of increased preload and of atrial distention as reported by others. This suggests a hyporesponsiveness of the atria to release ANF.

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension; Rats; Research

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Hypertension; Kidney; Vasoconstriction

Topics: Animals; Atrial Natriuretic Factor; Biological Transport; Calcium; Cytosol; Dopamine; Humans; Hydrogen; Hypertension; Parathyroid Hormone; Sodium; Sodium Chloride

An explosion of research over the last seven years has led to the discovery and characterization of a peptide, originating in the heart's atria, that possesses impressive vasorelaxant and natriuretic properties. Although the several atrial peptides that have been isolated by researchers working in different laboratories vary in length, all contain the same core sequence. Cardionatrin I, a 28-amino acid peptide, is the likely active circulating hormone. In the atrial peptide's action on vascular smooth muscle, it appears especially to counter the effects of angiotensin II. The peptide's effects on renal hemodynamics and sodium excretion include a marked increase in glomerular filtration rate. Atrial hormone also induces impressive natriuresis in experimental animals, for which an increase in glomerular filtration rate may be a necessary component. Atrial hormone has been found to reduce arterial blood pressure in both animals and humans. In experimental animals, the peptide appears to lower blood pressure by different mechanisms in high- and low-renin forms of hypertension, and to lower pressure to a greater degree and with lower doses in the former as compared with the latter. In patients with essential hypertension, primary aldosteronism, congestive heart failure, renal failure, and perhaps ascitic cirrhosis, plasma ANH levels tend to be higher than they are in normotensive individuals. Atrial hormone causes marked and sustained suppression of renal renin secretion and, thus, of plasma renin levels. In addition, atrial hormone blocks aldosterone secretion and opposes the vasoconstrictive effects of angiotensin II and the sodium-retaining action of aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Hemodynamics; Homeostasis; Humans; Hypertension; Muscle, Smooth, Vascular; Renal Circulation; Renin; Renin-Angiotensin System; Sodium

Topics: Animals; Atrial Natriuretic Factor; Blood Volume; Heart Failure; Hemodynamics; Humans; Hypertension; Natriuresis; Norepinephrine; Renin-Angiotensin System; Vasodilation

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Natriuresis

The possible roles of a humoral sodium pump inhibitor and atrial natriuretic peptide in low renin hypertension are considered, relying heavily on data from a classical animal model of low renin hypertension, the reduced renal mass-saline model in the rat, and on data uncovered by a new literature survey of the two agents in various normotensive and hypertensive states. Based on these data, particularly those indicating both agents are released by volume expansion, our current view is that low renin hypertension is in part generated by the sodium pump inhibitor and is in part moderated by atrial natriuretic peptide. We suggest that the atrial natriuretic peptide compensates for increased volume due to reduced renal function and/or increased salt intake and that in low renin hypertension the compensation is not sufficient to return volume and pressure to normal. In this view, the sodium pump inhibitor is prohypertensive, via actions on blood vessels and heart, and atrial natriuretic peptide is antihypertensive, via actions on kidney and the cardiovascular system.

Topics: Animals; Atrial Natriuretic Factor; Heart Atria; Humans; Hypertension; Ion Channels; Natriuretic Agents; Renin; Sodium Chloride; Tissue Extracts

The atria and blood plasma of man and many mammals have been discovered to contain a regulatory atrial natriuretic factor (ANF) that comprises peptides of several species ranging 2500 to 3500 daltons in molecular mass. ANF receptors in various tissues have been localized, and the major functions of the factor, viz., vasodilator (hypotensive), diuretic, and natriuretic, have been elucidated. This has led investigators to modify their views on the regulation of extracellular fluid dynamics. In light of the new knowledge on ANF functions, targeted histologic studies of the atria and their endocrine system in disease are now presenting heightened interest.

Topics: Aging; Animals; Atrial Natriuretic Factor; Extracellular Space; Heart Atria; Humans; Hypertension; Muscle, Smooth, Vascular; Myocardial Infarction; Myocardium; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Tissue Distribution

A short and up-to-date review on the great advances made in the field of the atrial natriuretic factor (ANF) is presented. All the short active peptides (up to 33 AA) isolated after purification of atrial homogenates have the same core of 23 amino acids (Ser 103-ARG 125). The ANF liberated in the medium of cultures of rat atrial cardiocytes is the 26 amino acid Arg 101-Tyr 126. Cloning of the cDNA encoding for ANF and of the rat, mouse, and human ANF gene has been accomplished. ANF has a most potent and short-lasting diuretic and natriuretic effect that appears to be predominantly due to a significant increase in glomerular filtration rate. ANF inhibits the release of aldosterone both in vitro and in vivo. It produces a profound inhibition of vascular contraction induced by norepinephrine and angiotensin II. This vasorelaxation is followed by a prolonged refractory period. ANF administration corrects the hypertension in 2K-1C hypertensive rats and in spontaneously hypertensive rats. Specific high-density binding sites have been found in the brain, especially in the hypothalamus, subfornical organ, median eminence, area postrema, and nucleus tractus solitarius, all areas involved in the brain control of hypertension and in the regulation of salt and water. ANF has no effect on the known sodium transport mechanisms across cell membrane. It has a major effect on the stimulation of guanylate cyclase activity, especially in renal glomeruli. Specific radioimmunoassay procedures have been established and results of preliminary studies that establish clearly that ANF is a circulating hormone are presented.

Topics: Adrenal Glands; Amino Acid Sequence; Animals; Arteries; Atrial Natriuretic Factor; Blood Pressure; Heart Failure; Humans; Hypertension; Pituitary Gland, Posterior; Plasma Substitutes; Radioimmunoassay; Sodium

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular System; Humans; Hypertension; Kidney; Natriuresis; Renal Circulation

Topics: Animals; Atrial Natriuretic Factor; Biological Transport, Active; Blood Proteins; Calcium; Cardenolides; Digoxin; Female; Humans; Hypertension; Peptides; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium

The control of sodium balance plays a vital role in the regulation of both intravascular and extravascular fluid volume. The discovery and synthesis of the atrial natriuretic peptides has led to the suggestion that they may be an important hormone in the control of sodium and water balance. Studies in man have confirmed that, when injected, they are natriuretic and that the plasma level, as measured by radioimmunoassay, changes with physiological changes in extracellular volume particularly those that occur with alteration of salt intake, the levels of atrial peptide rising as salt intake is increased. A recent study with a low dose infusion of atrial peptides has shown an increase in sodium excretion at the same plasma levels as those found with saline infusion, confirming that the atrial peptides are a natriuretic hormone in man. These findings allow a better interpretation of the raised levels that are already being described in patients with heart failure, renal failure and high blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Blood Volume; Body Water; Humans; Hypertension; Natriuresis; Sodium; Water-Electrolyte Balance

Preliminary reports are that plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) are higher in essential hypertensive patients than in normotensive controls, and that the urinary response to injected alpha human atrial natriuretic peptide (alpha-hANP) is augmented in essential hypertension. Further, there are reports of positive relationships between IR-ANP levels and arterial pressure. Confirmation is needed, however, with larger numbers of patients and with careful matching of diet electrolytes, age and sex, body posture, time of day, and other factors which may alter release or plasma clearance of atrial peptides. If indeed IR-ANP levels are raised in essential hypertension, it is possible that increased demands on the atria as a consequence of altered left ventricular structure and function lead to augmented secretion of atrial peptides. Whether the observed minor increases in plasma IR-ANP could have biologic effects to oppose pressor systems, to sustain glomerular filtration rate, and to suppress vasoactive hormone secretion, is unclear since the threshold level of IR-ANP which has biologic actions in man, is unknown. Plasma IR-ANP levels are raised in primary aldosteronism, and fall with treatment. These early reports suggest that atrial peptides might play a role in the pathophysiology of primary aldosteronism and perhaps essential hypertension, but much more information is needed.

Topics: Atrial Natriuretic Factor; Epinephrine; Humans; Hypertension

Isolation, purification and determination of the amino acid sequences of biologically active peptides were performed in 1983-84 by several groups. By that time the existence of such a humoral diuretic/natriuretic factor had been proposed for many years. The main, and perhaps the only, circulating form of atrial natriuretic peptide (ANP) is a 28 amino acid peptide structure with a disulphide bridge. This peptide is distributed mainly peripherally in the right and left cardiac atria. Smaller amounts are found in neonatal cardiac ventricles as well as in autonomic ganglia. In the central nervous system, high concentrations are found in hypothalamus, while lower concentrations are found in midbrain and brain stem regions. The amino acid sequence of ANP in the brain may be shorter than the form originating from cardiac atria. A 1 126 amino acid prohormone is present in granulae of atrial myocytes. After atrial distention the circulating 28 amino acid form is cleaved off. The main actions of this hormone include a diuretic/natriuretic effect, relaxation of vascular smooth muscle, and inhibition of basal or stimulated aldosterone secretion from the adrenal cortex. In the central nervous system, ANP has antidipsogenic actions, decreases salt appetite and lowers blood pressure. ANP may be of pathophysiological importance in several cardiovascular disorders such as congestive heart failure, paroxysmal supraventricular tachycardia and possibly also arterial hypertension. ANP seems to be a circulating hormone as well as putative neurotransmitter with important regulatory actions on salt and water homeostasis as well as blood pressure regulation.

Topics: Adrenal Cortex; Animals; Atrial Natriuretic Factor; Brain; Brain Chemistry; Heart Failure; Humans; Hypertension; Kidney; Muscle, Smooth, Vascular; Myocardium; Tachycardia, Supraventricular

The hypothesis of a natriuretic factor-originally an intriguing possibility and now an experimentally documented reality-has occupied the minds of scientists for more than 30 years. It has attracted not only experts in salt and water metabolism but also those interested in hypertension, because of the well known link between sodium homeostasis and blood pressure regulation. There are at least two distinct types of natriuretic substances: one is an inhibitor of the Na+K+ATPase and has been proposed to contribute to a rise in blood pressure; the other, now isolated from atrial tissue, is vasodilatory, natriuretic, diuretic, and has been demonstrated to decrease blood pressure. Our knowledge of regulation and function of this ANP has increased rapidly since its detection. Its role in blood pressure regulation is now fairly well understood. As depicted in Fig. 1, both synthesis and release of ANP are induced by atrial and ventricular wall stretch. In hypertension, distension of the left atrium and ventricle may be of particular importance for ANP release. The endocrine function of myocardial cells is stimulated in response to wall stretch in the ventricle. ANP is synthesized and stored as a 126 amino acid prohormone. Enzymatic processing of this prohormone to the circulating forms ANP 1-98 and ANP 99-126 takes place within the myoendocrine cells. The biological effects of ANP 1-98 are as yet unknown. ANP 99-126 acts at multiple sites to reduce blood pressure. One may distinguish between acute and more chronic effects. The acute effects include shift of fluid to the extravascular compartment and vasorelaxation. This shift is indicated by the rapidly developing rise in haematocrit, which is observed in intact as well as in nephrectomized rats and therefore not due to diuresis alone. The reduction of blood volume in addition to an increase in venous capacitance may be responsible for the reduced cardiac output. The latter may cause a reflex activation of the sympathetic nervous system and an increase in peripheral resistance, thereby overriding the vasodilator effects of the peptide. ANP appears to have a 'de-pressor' effect rather than a direct vasodilator effect. A lowering of peripheral resistance in response to ANP is not observed in normotensives, but is readily seen in at least certain forms of hypertension associated with an increased vascular tone. This most likely explains the discrepancy in the haemodynamic responses to ANP in normotensives and hyperte

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Brain Chemistry; Hemodynamics; Humans; Hypertension

The atrial natriuretic factor (ANF) has pharmacological actions resulting in lower atrial and arterial pressures. Atrial distention stimulates ANF release, suggesting that ANF is an effector limb of a feedback loop for controlling cardiac filling pressure. To test this hypothesis it will be necessary to determine whether physiological atrial distention releases ANF in sufficient amounts to exert biological actions. Immunoblockade of endogenous ANF and attenuation of ANF release by atrial ablation inhibited volume-induced natriuresis in rats. Infusion of ANF in rats at doses mimicking those observed during experimental volume expansion produced a natriuresis sufficient to partly account for the volume-induced response. Infusion of ANF at doses expected to change plasma ANF levels minimally decreased arterial pressure in hypertensive rats over 7 days. In dogs, some studies suggest that increased plasma ANF levels following experimental changes in atrial pressure were not sufficient to exert acute cardiovascular or renal actions, whereas others support such a notion and indicate that ANF inhibited barostimulated renal renin release. This last action could alter arterial pressure in the long term by allowing sodium equilibrium at lower renal arterial pressure. Infusion of ANF in humans that produced plasma levels in the upper physiological range caused increased sodium excretion and decreased plasma renin activity. Although data are exiguous, justifying neither acceptance nor rejection of the hypothesis that ANF functions physiologically to regulate body fluid volume and arterial pressure, the current evidence slightly favors acceptance.

Topics: Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Dogs; Humans; Hypertension; Infusions, Parenteral; Natriuresis; Rats; Renin; Species Specificity

In assessing the role that atrial natriuretic peptide (ANP) might have in the homeostasis of fluid volume and blood pressure, it is important to define the physiological and pathophysiological conditions that determine its release into the circulation. There is substantial evidence that ANP is released through atrial distension under a variety of conditions. There are also some indications that ANP may be released through humoral factors, although it is not clear whether this is a result of direct action on the myocytes or simply a result of ensuing haemodynamic changes. There is no evidence to suggest that ANP can be released through stimulation of efferent fibres innervating the atria, but it may be released as a result of changes in myocardial work and oxygen consumption. Plasma levels of ANP are elevated in several disease states and that release appears to be a result of the haemodynamic disturbances in those conditions.

Topics: Atrial Function; Atrial Natriuretic Factor; Heart; Humans; Hypertension

Besides the classical modulators of aldosterone secretion, new factors influencing positively or negatively aldosterone secretion have been described. These new factors and the effect of related drugs constitutes the aim of this review. The effect of dopamine agonists and H2-receptor antagonists on aldosterone secretion in normal volunteers as well as in different clinical situations characterized by an increased production of aldosterone opens a new field of investigation for the therapy of aldosterone secretion alterations.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Dopamine; Histamine; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Pituitary Hormones; Potassium; Renin; Serotonin

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cricetinae; Dogs; Guinea Pigs; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Lung Diseases, Obstructive; Natriuresis; Rats

Following the discovery of the natriuretic effect of atrial extract, our laboratory attempted to dissect the possible physiological role of atrial natriuretic factor. Initial micropuncture experiments demonstrated that the reduction of tubular sodium reabsorption was localized in the medullary collecting duct, a nephron site in which sodium transport was known to be inhibited after acute hypervolemia. Partial removal of the endogenous source of atrial natriuretic factor was associated with a reduced renal response to hypervolemia, confirming that the factor is causally involved in acute sodium balance. In vitro incubation of atrial tissue was used to investigate mechanisms of release of atrial natriuretic factor. It was found that agonists known to activate the intracellular polyphosphoinositide system in other tissues were effective in releasing natriuretic activity from the atria into the incubation medium. To determine whether atrial natriuretic factor might play a role in hypertension, atrial natriuretic content was measured in spontaneously hypertensive rats and their normotensive controls. Hypertension was associated with increased content. Since the renal response to exogenous factor was not impaired in these animals, we suggested that the increased content might play a compensatory role. Our early studies thus indicated that atrial natriuretic factor was a previously unrecognized hormone involved in cardiovascular regulation.

Topics: Animals; Atrial Natriuretic Factor; Blood Volume; Homeostasis; Hypertension

Topics: Atrial Natriuretic Factor; Diuresis; Humans; Hypertension; Plasma Volume

The atriopeptins are newly discovered cardiac-derived peptides whose observed actions suggest a role in volume homeostasis and blood pressure regulation. Studies in animal models are underway to pinpoint pathogenetic mechanisms involved in the evolution of hypertension, some of which may well be shared by humans with "essential" hypertension. Preliminary observations indicate that circulating atriopeptin levels are altered in human disease. It is anticipated that exogenously administered atriopeptin may be a helpful pharmacological tool in the management of patients with volume overload and hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension

Topics: Atrial Natriuretic Factor; Endocrine Glands; Female; Heart; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Renin-Angiotensin System

Topics: Adenylyl Cyclases; Adrenal Cortex; Aldosterone; Amino Acid Sequence; Animals; Antihypertensive Agents; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Chemical Phenomena; Chemistry; Cricetinae; Diuresis; Guanylate Cyclase; Heart Atria; Heart Rate; Humans; Hypertension; Kidney; Mesocricetus; Muscle, Smooth; Myocardium; Natriuresis; Radioimmunoassay; Rats

Anesthetized beagle dogs received increasing doses of continuous infusions of a 26-amino-acid synthetic atrial natriuretic factor (ANF). Urinary sodium excretion rose in a dose-dependent manner to a maximum level similar to that seen after hydrochlorothiazide administration. Mean arterial blood pressure decreased, but only modestly, and not in a dose-dependent fashion. Dogs chronically retaining NaCl secondary to constriction of the thoracic inferior vena cava showed only modestly enhanced natriuresis when infused with similar levels of ANF. When ANF was infused directly into the renal artery of anesthetized beagles, a dose-dependent natriuresis and calciuresis were observed with maximal fractional sodium excretion averaging approximately 8%. Although glomerular filtration tended to increase, the average dose-related changes were not significant. Cyclic GMP excretion was increased during intra-renal-arterial infusion of ANF. Excretion of cyclic GMP by both the infused and noninfused kidneys was equal, which suggests that urinary cyclic GMP was not nephrogenous but derived from the elevated circulating levels. These and other data from rats dissociate changes in urinary cyclic GMP excretion and sodium excretion.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium; Cyclic GMP; Enzyme Activation; Furosemide; Glomerular Filtration Rate; Guanylate Cyclase; Hydrochlorothiazide; Hypertension; Kidney; Kidney Tubules; Muscle, Smooth, Vascular; Natriuresis; Rats; Rats, Inbred SHR; Vasodilation

Recent research has led to the discovery and characterization of a hormone secreted by the atria that has powerful vasodepressor and natriuretic properties. A series of atrial peptides varying only in length and exhibiting these activities have been isolated, so that it is not yet clear which of these is the active hormone. The factors that determine its secretion remain to be characterized although preliminary evidence suggests that sodium-volume loading and/or intraatrial distension may be centrally involved. Atrial hormone acts in four different ways to oppose or counter the actions of the renin angiotensin aldosterone system. Thus, it produces vasorelaxation, which is especially pronounced in angiotensin-preconstricted blood vessels; it blocks angiotensin-induced aldosterone secretion by the adrenal cortex; it inhibits renin secretion by the kidneys; and its natriuretic action opposes the sodium-retaining action of aldosterone. Accordingly, the atrial-natriuretic and vasorelaxant hormone may play a role complementary to the renin angiotensin-aldosterone system in the long-term regulation of sodium balance and arterial pressure. In this construction the renin system acts primarily to defend sodium balance and blood pressure, with the atrial hormone playing an increasingly active counterpart in situations involving sodium-volume surfeit and/or high blood pressure. The physiologic properties of the new atrial hormone already suggest a major role for it in sodium-volume, blood pressure homeostasis, and for understanding and treating hypertensive-cardiovascular diseases.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Circulation; Blood Pressure; Diet, Sodium-Restricted; Dogs; Hemodynamics; Homeostasis; Humans; Hypertension; Kidney; Muscle, Smooth, Vascular; Potassium; Rabbits; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; Sodium; Sodium Chloride

The atrial peptide hormone exhibits remarkable vasorelaxant, natriuretic and hypovolaemic actions, suggesting that it is part of a cardiovascular control mechanism which operates to regulate blood pressure, blood volume and sodium balance. In this endocrine control, the renin axis provides the primary defence against sodium volume depletion and hypotension while atrial hormone plays an increasingly active counter-role for coping with situations that involve a sodium-volume surfeit or rising blood volume or blood pressure levels. For this assignment, the atrial hormone acts in four different ways to counter or oppose the renin-angiotensin-aldosterone axis. Thus, it promptly reduces renin secretion, it relaxes angiotensin-constricted vessels, it blocks angiotensin-induced aldosterone synthesis, and its natriuresis opposes aldosterone-induced sodium retention. Another special action of atrial hormone seems to be rapidly adjust central blood volumes by promoting the rapid transfer of fluid to the extracellular spaces. This hypovolaemic action probably reflects an action on capillary fluid exchange. It is reflected by a prompt and sustained rise in haematocrit levels. A similar action on the glomerular capillaries may be involved in causing natriuresis. These effects serve to rapidly decompress blood volumes and thereby reduce cardiac work. More work is needed to define the afferent stimuli to the right and left heart which elicit atrial hormone release. The possible role(s) of this new hormonal system in hypertensive and oedematous cardiovascular disorders also remains to be defined.

Topics: Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Calcium; Humans; Hypertension; Muscle, Smooth, Vascular; Natriuresis; Renin-Angiotensin System; Sodium; Vasoconstriction; Water-Electrolyte Balance

Atriopeptins are biologically active peptides with potent natriuretic, diuretic, and vasorelaxant activities. Manipulation of an animal's salt and water intake influences the synthesis, storage, and release of atriopeptin. In addition to its direct effects on fluid and electrolyte balance, atriopeptin influences other volume regulatory hormones, including renin, aldosterone, and vasopressin. Atriopeptin, by its direct actions and its effects on hormone systems, provides a means for delicate hormonal control of fluid and electrolyte homeostasis.

Topics: Animals; Atrial Natriuretic Factor; Blood Volume; Deamino Arginine Vasopressin; Dogs; Hydroxydopamines; Hypertension; Myocardium; Oxidopamine; Rats; Rats, Inbred SHR; RNA, Messenger; Vasopressins; Water-Electrolyte Balance

Topics: Adrenal Cortex; Animals; Atrial Natriuretic Factor; Biological Transport; Blood Pressure; Heart Atria; Heart Failure; Humans; Hypertension; Immunoenzyme Techniques; Kidney; Kidney Diseases; Molecular Weight; Natriuresis; Radioimmunoassay; Rats; Renin

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Atrial Natriuretic Factor; Endorphins; Estradiol; Humans; Hypertension; Peptide Fragments; Renin-Angiotensin System; Sympathetic Nervous System

In less than three years since the rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats was reported the factor responsible for the diuretic, natriuretic, and vasodilating activity of the atrial homogenates was isolated, its chemical structure elucidated, and its total synthesis achieved. Also the cDNA and the gene encoding for the atrial natriuretic factor in mice, rats, and man have been cloned and the chromosomal site identified. The major effects of this hormone are vasodilatation, prevention and inhibition of the contraction induced by noradrenaline and angiotensin II, diuresis, and natriuresis associated in most instances with a pronounced increase in glomerular filtration rate and filtration fraction, inhibition of aldosterone secretion, and considerable stimulation of particulate guanylate cyclase activity. High density specific binding sites have been demonstrated in the zona glomerulosa of the adrenal cortex, in the renal glomeruli, and in the collecting ducts, and in the brain areas involved in the regulation of blood pressure and of sodium and water (AV3V region, subfornical organ, nucleus tractus solitarius, area postrema).

Topics: Adrenal Cortex; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Brain; Heart; Humans; Hypertension; Kidney; Muscle, Smooth, Vascular; Structure-Activity Relationship

The susceptibility of immature and adult animals to various environmental factors often differs because the response of the young organism can only involve those regulatory mechanisms that are available at the particular stage of development. Increased sensitivity to certain (e.g., hypertensive) stimuli may be limited to a relatively short age period that is usually characterized by the maturation of some important physiological functions. High salt intake seems to influence the animals especially during the weaning period and prepuberty, in the course of which profound developmental changes of circulation, electrolyte metabolism, and neurohumoral regulation have been demonstrated. Indeed, salt-dependent forms of experimental hypertension are more severe when they are induced in immature animals. Moreover, substantial differences in hemodynamics, distribution of body fluids, and involvement of pressor and natriuretic agents indicate that the mechanisms of salt hypertension need not be the same in immature and adult animals. For this reason, increased attention should be paid to developmental factors in the study of induced forms of experimental hypertension.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Hemodynamics; Hypertension; Rats; Rats, Inbred SHR; Sodium Chloride

To sum up, the endocrine analysis of human hypertension, tracing the renin system patterns, has provided a convincing body of data revealing and defining the biochemical heterogeneity of human hypertension. The heterogeneity, and the ability to differentiate it by the study of renin, embraces the major category that we call essential hypertension, which brackets at least 85% of all hypertension patients. This spectrum of biochemical heterogeneity is manifested physiologically by two different forms of vasoconstriction. One form is renin-mediated vasoconstriction, signified by the finding of a medium or high plasma renin activity and corrected by antirenin surgical or pharmacologic means. Toward the other end of the spectrum, revealed by the finding of low plasma renin, a sodium-volume-induced form of vasoconstriction operates. This appears to involve abnormal calcium metabolism and can also be characterized by measurable changes in serum ionized calcium values. With the development of newer and more specific antihypertensive agents with actions that appear to be rather specific against a particular vasoconstriction mechanism, new patterns of treatment are emerging that are preferable to the undiscriminating protocols of diuretic-oriented stepped care. The beta blockers or the CEIs can now be considered as the first pharmacological step against high- or medium-renin hypertensive states. The prescription of diuretics as the first step against the low-renin state can now be weighed against a more rational physiologic attack involving the probably safer, less troublesome, and more specific calcium-channel blocking drugs and also by the less potent alpha-adrenergic blockers. These latter two types of agents may exhibit finer marksmanship than do diuretics in opposing the etiology of low-renin hypertension, for there is growing reason to believe that sodium-volume-mediated vasoconstriction is related to abnormal calcium influx and possibly to abnormal alpha-adrenergic traffic.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Calcium; Enzyme Precursors; Humans; Hypertension; Hypertension, Renovascular; Renin; Renin-Angiotensin System; Vasoconstriction

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Chemical Phenomena; Chemistry; Humans; Hypertension; Rats

Topics: Animals; Atrial Natriuretic Factor; Dogs; Hemodynamics; Humans; Hypertension; Kidney; Natriuresis; Rats; Rats, Inbred SHR; Receptors, Cell Surface; Renal Circulation; Renin-Angiotensin System

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Glomerular Filtration Rate; Heart Diseases; Hemodynamics; Humans; Hypertension; Muscle, Smooth; Muscle, Smooth, Vascular; Renal Circulation; Renin-Angiotensin System

Topics: Amino Acid Sequence; Angiotensinogen; Apoproteins; Arteriosclerosis; Atrial Natriuretic Factor; Cloning, Molecular; DNA; Genetic Engineering; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type III; Hypertension; Myosins; Receptors, Cell Surface; Receptors, Lipoprotein; Sodium-Potassium-Exchanging ATPase

Topics: Adrenal Cortex; Animals; Atrial Natriuretic Factor; Blood Proteins; Cardiomegaly; Cardiotonic Agents; Chickens; Digoxin; Dogs; Guinea Pigs; Heart Atria; Humans; Hydroxysteroids; Hypertension; Hypothalamus; Kidney; Muscle Proteins; Natriuretic Agents; Proteins; Rabbits; Rats; Sheep; Sodium; Sodium-Potassium-Exchanging ATPase; Vasodilation

The search for natriuretic hormones or factors by studies of negative pressure breathing, atrial distension experiments, head-out water immersion, expansion of blood volume, Na+/K+-ATPase inhibitors and parabiosis experiments in Dahl rats has led to the finding that the atria are a peptide-secreting endocrine gland. This new natriuretic hormone has now been purified, sequenced and synthetized, and its cDNA and gene have been cloned. The native and synthetic hormones exert identical wide ranging effects (possibly through particulate guanylate cyclase stimulation and adenylate cyclase inhibition) on the kidney, blood vessels, adrenal cortex, and pituitary. Physiopathologic implications of the hormone in experimental hypertension, congestive heart failure, and expansion of blood volume are beginning to emerge.

Topics: Adrenal Glands; Animals; Atrial Function; Atrial Natriuretic Factor; Blood Vessels; Blood Volume; Cattle; Chickens; Cricetinae; Dogs; Guinea Pigs; Heart; Humans; Hypertension; Immersion; Kidney; Muscle Proteins; Natriuresis; Pituitary Gland; Radioimmunoassay; Rats; Receptors, Cell Surface; Rectum; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Homeostasis; Humans; Hypertension; Muscle Proteins; Saponins; Sodium-Potassium-Exchanging ATPase

Two independent series of biomedical investigations have led to the discovery that the atria are a peptide-secreting endocrine gland. The first is mainly morphological and starts with the finding that mammalian atrial but not ventricular cardiocytes contain "dense bodies". These "dense bodies" later called "specific granules" were found to be different from lysosomes, to be made up of proteins and to incorporate both 3H-leucine and 3-H-fucose in a pattern typical of peptide-secreting endocrine cells. The finding that rat atrial granulation varied with the sodium and water balance led to the crucial observation that atrial extracts have natriuretic and diuretic effects. In less than 4 years, this new natriuretic hormone has been purified, sequenced and synthetized, and its cDNA and gene have been cloned. The ANF gene has been assigned to the distal short arm of chromosome 1 in band 1P36 while the mouse gene is localized in chromosome 4. The native and synthetic hormones exert identical wide ranging effects (possibly through particulate guanylate cyclase stimulation and adenylate cyclase inhibition) on the kidney, blood vessels, adrenal cortex and pituitary. Physiopathologic implications of the hormone in experimental hypertension, congestive heart failure and expansion of blood volume are already beginning to emerge. On the other hand, the search for natriuretic hormones or factors by studies of negative pressure breathing, atrial distention experiments, head-out water immersion, expansion of blood volume, Na+/K-ATPase inhibition and parabiosis experiments in Dahl rats has provided a general framework within which to interpret this new cardiac function.

Topics: Adrenal Cortex; Animals; Atrial Natriuretic Factor; Blood Vessels; Blood Volume; Brain Chemistry; Cloning, Molecular; Diuresis; Genes; Heart; Heart Atria; Heart Failure; Humans; Hypertension; Kidney; Liver; Natriuresis; Pituitary Gland; Radioimmunoassay; Rats; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Structure-Activity Relationship

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Cattle; Digoxin; Dogs; Edema; Guinea Pigs; Humans; Hypertension; Hypothalamus; Kidney Failure, Chronic; Kidney Tubules; Muscle Proteins; Potassium; Rabbits; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

The evidence presented here indicates that atrial cardiocytes, apart from their contractile function, are bona fide endocrine cells which synthesize a peptide of known composition (152AA) through identified pathways [6,7]. Part of the peptide is released into the circulation where it can be measured by radio-immunoassay. A synthetic fragment (8-33AA) of the peptide is endowed with potent and variegated effects on several target tissues: massive diuresis and natriuresis of rapid onset and short duration, inhibition of the secretion of aldosterone from beef and rat zona glomerulosa and, to a lesser extent, of cortisol from beef zona fasciculata, vasodilatation and inhibition of the arterial contraction induced by catecholamines or angiotensin II. This peptide is a potent antihypertensive agent. The presence of receptors in the anterior and posterior pituitary, as well as the significant decrease of adenylate cyclase activity observed in both portions of the gland, indicate that the hormone may act at these levels as well. Thus, the heart is raised from the status of a pump to that of a putative endocrine integrator of cardiovascular homeostasis.

Topics: Adenylyl Cyclase Inhibitors; Adrenal Glands; Animals; Arteries; Atrial Natriuretic Factor; Blood Volume; Cattle; Cells, Cultured; Cyclic GMP; Endocrine Glands; Heart; Hypertension; Muscle Relaxation; Myocardium; Pituitary Gland; Radioimmunoassay; Rats

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Cyclic GMP; Double-Blind Method; Drug Combinations; Drug Interactions; Humans; Hypertension; Male; Middle Aged; Sildenafil Citrate; Tetrazoles; Valsartan

GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR).. Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment.. Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration.. Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypertension; Liraglutide; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Receptors, Glucagon; Sodium

To examine 24-h blood pressure (24BP), systemic haemodynamics and the effect of sodium intake on 24BP in obese patients before and after gastric bypass surgery [laparoscopic Roux-en-Y gastric bypass (LRYGB)], and to determine whether weight loss from LRYGB might be related to an increase in plasma concentrations of atrial natriuretic peptide.. Twelve hypertensive and 12 normotensive morbidly obese patients underwent LRYGB: 24BP, systemic haemodynamics and mid-regional pro-atrial natriuretic peptide (MRproANP) were assessed before, 6 weeks and 12 months after surgery. The effect of high versus low sodium intake on 24BP was evaluated before and 12 months after LRYGB.. Six weeks after LRYGB, the average weight loss was 20 kg, with a further 21 kg weight loss 1 year after surgery. In hypertensive patients, 24BP was significantly reduced at 6 weeks, but not 1 year after LRYGB. However, antihypertensive medications were successively reduced from baseline to 1 year after surgery. In normotensive patients, there was no change in 24BP 6 weeks after LRYGB, but a tendency towards a reduction 1 year after the operation. Plasma concentrations of MRproANP were subnormal prior to surgery in hypertensive patients and increased by 77% 1 year after the operation. In normotensive patients, preoperative concentrations were normal and increased only by 6%. High sodium intake induced plasma volume expansion, increased stroke volume and cardiac output, but no significant change in 24BP - neither before nor after LRYGB.. LRYGB resulted in a significant 24BP reduction and a substantial increase in MRproANP plasma concentrations in hypertensive, obese patients 6 weeks after surgery, suggesting a causal link between obesity-hypertension and altered release/degradation of cardiac natriuretic peptides.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Gastric Bypass; Humans; Hypertension; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Time Factors; Weight Loss

Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF.. The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality.. The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Atrial Natriuretic Factor; Diabetes Complications; Female; Furosemide; Heart Failure; Hospital Mortality; Humans; Hypertension; Japan; Length of Stay; Male; Prospective Studies; Registries; Sodium Potassium Chloride Symporter Inhibitors

Dysregulation of the expression/shuttling of the aquaporin-2 water channel (AQP2) and the epithelial sodium channel (ENaC) in renal collecting duct principal cells has been found in animal models of hypertension. We tested whether a similar dysregulation exists in essential hypertension.. We measured urinary excretion of AQP2 and ENaC β-subunit corrected for creatinine (u-AQP2(CR), u-ENaC(β-CR)), prostaglandin E2 (u-PGE2) and cyclic AMP (u-cAMP), fractional sodium excretion (FE(Na)), free water clearance (C(H2O)), as well as plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), and atrial and brain natriuretic peptide (ANP, BNP) in 21 patients with essential hypertension and 20 normotensive controls during 24-h urine collection (baseline), and after hypertonic saline infusion on a 4-day high sodium (HS) diet (300 mmol sodium/day) and a 4-day low sodium (LS) diet (30 mmol sodium/day).. At baseline, no differences in u-AQP2(CR) or u-ENaC(β-CR) were measured between patients and controls. U-AQP2(CR) increased significantly more after saline in patients than controls, whereas u-ENaC(β-CR) increased similarly. The saline caused exaggerated natriuretic increases in patients during HS intake. Neither baseline levels of u-PGE2, u-cAMP, AVP, PRC, Ang II, Aldo, ANP, and BNP nor changes after saline could explain the abnormal u-AQP2(CR) response.. No differences were found in u-AQP2(CR) and u-ENaC(β-CR) between patients and controls at baseline. However, in response to saline, u-AQP2(CR) was abnormally increased in patients, whereas the u-ENaC(β-CR) response was normal. The mechanism behind the abnormal AQP2 regulation is not clarified, but it does not seem to be AVP-dependent. Clinicaltrial.gov identifier: NCT00345124.

Topics: Adult; Aldosterone; Angiotensin II; Aquaporin 2; Atrial Natriuretic Factor; Cross-Over Studies; Cyclic AMP; Dinoprostone; Epithelial Sodium Channels; Female; Glomerular Filtration Rate; Humans; Hypertension; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain; Osmolar Concentration; Renin; Sodium; Sodium, Dietary; Vasopressins

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA) showed that an amlodipine-based regimen prevented more cardiovascular events than an atenolol-based regimen in patients at high risk of hypertension.The basis of this difference is partly unknown and may be due to their divergent effects on the remodelling process of hypertensive heart disease.. We measured plasma levels of aminoterminal propeptide of atrial natriuretic peptide (NT-proANP) and aminoterminal propeptide of B-type natriuretic peptide and serum levels of the aminoterminal propeptide of type I procollagen (PINP), aminoterminal propeptide of type III procollagen and type I collagen telopeptide in 93 patients randomized in the ASCOT study at baseline and after two and four years and compared them with echocardiographic parameters and blood pressure. NT-proANP decreased at two years by 22 (-484 - 153) pmol/l in the amlodipine-based regimen and increased by 109 (-297 - 1545) pmol/l in the atenolol-based regimen (P < 0.001), whereas no significant difference in NT-proBNP between the arms was found. PINP levels increased by 1.8 (-29 -31) microg/l in the amlodipine-based regimen and decreased by 4.7 (-27- 31) microg/I in the atenolol-based regimen, whereas no differences were found in other collagen markers between the arms. Major echocardiographic changes were not found.. Our results show that the two treatment regimens of ASCOT-BPLA had different effects on plasma natriuretic peptides and serological markers of collagen turnover, probably reflecting divergent effects in cardiac remodelling.

Topics: Amlodipine; Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Biomarkers; Collagen; Collagen Type I; Humans; Hypertension; Natriuretic Peptide, Brain; Peptide Fragments; Peptides; Procollagen; Ventricular Remodeling

The effect of salt restriction on blood pressure is under intense debate. We tested the effect of 100 mmol salt reduction on ambulatory blood pressure (ABP) in 46 Swedish individuals, 39 of whom completed the study, using a double-blind, placebo-controlled, cross-over design. Furthermore, we tested whether the basal plasma concentration of renin or N-terminal atrial natriuretic peptide (Nt-proANP) predict the degree of salt sensitivity.. Participants received all meals and drinks with a total daily NaCl content of 50 mmol during 8 weeks. In addition, NaCl capsules (100 mmol/day) and corresponding placebo capsules were administered for 4 weeks each in random order. ABP after high-salt intake (150 mmol/day) was compared with ABP after low-salt intake (50 mmol/day). Salt sensitivity was defined as the difference between 24-h systolic ABP at the high-salt versus the low-salt periods. Baseline renin and Nt-proANP were related to salt sensitivity.. Lowering of salt intake from 150 to 50 mmol/day induced significant blood pressure reductions (mean reduction, 95% confidence interval) in systolic and diastolic 24-h ABP (5.8, 3.4-8.2 and 2.6, 0.91-4.4 mmHg), daytime ABP (5.5, 2.9-8.1 and 2.3, 0.42-4.1 mmHg) and night-time ABP (6.4, 3.5-9.3 and 3.4, 1.4-5.5 mmHg). Baseline ln(renin) correlated inversely with salt sensitivity (r = -0.50, P = 0.001) whereas baseline ln(Nt-proANP) correlated directly (r = 0.33, P = 0.04).. Lowering of salt intake with 100 mmol/day induces clinically relevant ABP reductions. Renin and Nt-proANP, measured with individuals on their habitual diet, could be useful biomarkers to identify individuals with the greatest blood pressure-lowering benefit from reduced salt intake.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Renin; Sodium Chloride, Dietary

In essential hypertension (ESS) whole body and vascular nitric oxide (NO) synthesis is generally thought to be reduced. We therefore investigated the systemic and renal responses to acute treatment with N(G)-monomethyl-l-arginine (L-NMMA), a competitive NOS-inhibitor, in 12 patients with ESS and 18 healthy controls (CON) in a randomized, placebo-controlled study. Main effect parameters were renal hemodynamics (glomerular filtration rate [GFR] and renal plasma flow [RPF]), systemic blood pressure (BP), and fractional excretions of sodium (FE(Na)) and lithium (FE(Li)). Experiments were performed on two occasions for each subject studying the effects of either L-NMMA (3 mg/kg intravenously) or placebo. The patients with ESS were studied after at least 14 days off antihypertensive medication. Renal hemodynamics were assessed by the clearances of (125)I-hippuran (RPF) and (51)Cr-EDTA (GFR). The L-NMMA induced a significant increase in systemic BP and significant reductions in RPF, FE(Na), and FE(Li) in both groups. The increase in diastolic BP was significantly attenuated in ESS (ESS: 8% +/- 2% v CON: 14% +/- 2%, P < .05). The GFR and RPF were equally reduced by L-NMMA in both groups (RPF(ESS): -19% +/- 4% v RPF(CON): -15% +/- 3%, P = not significant [NS]). However, the reduction in FE(Na) was enhanced in ESS (ESS: -42% +/- 7% v CON: -25% +/- 3%, P < .01). The FE(Li) decreased equally in both groups (ESS: -17% +/- 2% v CON: -17% +/- 6%, P = NS). It is concluded that acute NO blockade in ESS is accompanied by a reduced systemic pressor response, an unchanged renal hemodynamic response, and an enhanced reduction in FE(Na). The results suggest that patients with essential hypertension are highly dependent on NO to maintain sodium excretion.

Topics: Administration, Oral; Adult; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Cyclic GMP; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Lithium; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Renal Circulation; Renin-Angiotensin System; Sodium; Sodium Chloride; Time Factors

In patients with pulmonary disease, it is often challenging to distinguish exacerbated pulmonary disease from congestive heart failure (CHF). The impact of B-type natriuretic peptide (BNP) measurements on the management of patients with pulmonary disease and acute dyspnea remains to be defined.. This study evaluated the subgroup of 226 patients with a history of pulmonary disease included in the BASEL Study. Patients were randomly assigned to a diagnostic strategy with (n = 119, BNP group) or without (n = 107, clinical group) the use of BNP levels provided by a rapid bedside assay. Time to discharge and total cost of treatment were recorded as the primary end points.. Baseline characteristics were similar in patients assigned to the BNP and control groups. Comorbidity was extensive, including coronary artery disease and hypertension in half of patients. The primary discharge diagnosis was CHF and exacerbated obstructive pulmonary disease in 39% and 33%, respectively. The use of BNP levels significantly reduced the need for hospital admission (81% vs 91%, P = .034). Median time to discharge was 9.0 days in the BNP group as compared with 12.0 days (P = .001) in the clinical group. Median total cost of treatment was $4841 in the BNP group as compared with $5671 in the clinical group (P = .008). Inhospital mortality was 8% in both groups.. CHF is a major cause of acute dyspnea in patients with a history of pulmonary disease. Used in conjunction with other clinical information, rapid measurement of BNP reduced time to discharge and total treatment cost of these patients.

Topics: Acute Disease; Aged; Asthma; Atrial Natriuretic Factor; Biomarkers; Confidence Intervals; Coronary Artery Disease; Dyspnea; Emergencies; Female; Heart Failure; Humans; Hypertension; Length of Stay; Male; Pneumonia; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), > or =90 and < or =109 mm Hg; systolic blood pressure (SBP), > or =150 and < or =180 mm Hg). After a single-blind 2- to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n=62) or to active treatment (n=61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (-8.00 mm Hg, P=0.002) and DBP (-5.38 mm Hg, P=0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (P<0.001) reductions in serum ACE activity and significant (P<0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P=0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dizziness; Double-Blind Method; Female; Headache; Humans; Hypertension; Male; Middle Aged; Neprilysin; Peptidyl-Dipeptidase A; Placebos; Thiazoles; Treatment Outcome

Exposure to water in hot springs containing thoron is thought to exercise beneficial effects on hypertension and diabetes mellitus. To put to a test this hypothesis we examined the time dependent changes in the levels of lipid peroxide, vasoactive- and diabetes associated substances in human blood in order to throw further light on the possible beneficial influence of thoron and thermal therapy on the mechanism of hypertension and diabetes mellitus. Every 2 days, nasal inhalation of vapor containing thoron was performed for 40 min. Blood samples were collected after each treatment at 1, 2, and 3 weeks after the first treatment. Results show that the treatment decreased the lipid peroxide levels. The finding suggests that the treatment contributes to the prevention of peroxidation reaction related to hypertension and diabetes mellitus. Moreover, the changes in vasoactive-associated substances indicate an increase in tissue perfusion, suggesting that the treatment plays a role in alleviating hypertension. The treatment decreased the total ketone body levels and the finding suggests that the treatment contributes to the prevention of diabetes mellitus related to the insulin deficiency.

Topics: 3-Hydroxybutyric Acid; Administration, Inhalation; Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Case-Control Studies; Diabetes Mellitus; Hot Springs; Hot Temperature; Humans; Hypertension; Ketone Bodies; Lipid Peroxidation; Middle Aged; Radon; Time Factors

Secretion of natriuretic peptides is related to cardiac wall stress and influenced by the renin-angiotensin system. Therefore, we investigated the influence of blood pressure (BP) reduction with losartan versus atenolol on N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP).. In 183 patients with hypertension and electrocardiographic left ventricular (LV) hypertrophy, enrolled in the LIFE Study, we measured BP and serum Nt-proANP and Nt-proBNP by immunoassay after 2 weeks of placebo treatment and after 1, 2, 4, 6, 12, 24, 36 and 48 months of randomized treatment with losartan- or atenolol-based antihypertensive regimens.. There was no significant difference in BP at any time point between the two treatment groups. In patients treated with losartan, median Nt-proANP decreased gradually throughout the study, reaching significance after 6 months of treatment (1125-1060 pmol/l, P < 0.001), and Nt-proBNP decreased within the first month (24.7-18.7 pmol/l, P < 0.01) and stayed reduced throughout the study. During losartan-based antihypertensive treatment, Nt-proANP and Nt-proBNP as a percentage of baseline values were correlated to reductions in systolic BP (r = 0.11, P < 0.01 and r = 0.10, P = 0.01) and diastolic BP (r = 0.17, P < 0.001 and r = 0.07, P = 0.09). In atenolol-treated patients, Nt-proANP (1100-1640 pmol/l, P < 0.001) and Nt-proBNP (20.0-37.7 pmol/l, P < 0.001) increased during the first month, and remained elevated throughout the study. During atenolol-based antihypertensive treatment, changes in Nt-proANP (r = -0.16, P < 0.001) and Nt-proBNP (r = -0.07, P = 0.08) were negatively related to change in heart rate.. Nt-proANP and Nt-proBNP were reduced in parallel with BP in losartan-treated patients whereas they increased in parallel with decreased heart rate in atenolol-treated patients.

Topics: Aged; Atenolol; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments

Delayed hypertension (HT) and renal dysfunction (RD) are observed after aortic operations accompanied by infra-renal aortic cross-clamping (AXC). Atrial natriuretic peptide (ANP) has effects on vasodilation and renal protection, and we examined the hypothesis that synthetic human alpha-ANP (hANP) improves the postoperative management for abdominal aortic aneurysm (AAA).. Fifty patients undergoing elective aneurysmectomy for infrarenal-AAA between 1998 and 2001 (M:F = 43:7, mean age 70.5 +/- 7.7 years) were randomly allocated to one of 2 groups; Group H (n = 24) received hANP immediately after operation (initial dose: 0.025 microg/kg/min), and Group C (n = 26) served as a control group.. All patients in Group C required nicardipine hydrochloride (4.41 +/- 1.68 mg/h) for prevention of postoperative HT, whereas only 6 patients in Group H required the increase in hANP dose due to HT (P < 0.0001). Maximum hANP dose was 0.035 +/- 0.019 microg/kg/min. Group H showed significantly smaller furosemide dosage in the initial 3 days (H vs. C; 9.2 +/- 11.0 vs. 58.8 +/- 41.5 mg, P < 0.0001), significantly lower peak-Crn (H vs. C; 1.16 +/- 0.53 vs. 2.58 +/- 1.42 mg/dL, P < 0.0001), and significantly lower plasma renin-activity (7.09 +/- 2.38 vs. 11.52 +/- 4.89 ng/mL/h, P = 0.0002) and aldosterone (51.6 +/- 12.7 vs. 81.2 +/- 34.2 pg/mL, P = 0.0002) on the first postoperative day than Group C did.. These results imply that renin-angiotensin system may play a role in the incidence of postoperative HT and RD, and suggest that hANP infusion is a simple, reliable, and effective method for management during the immediate period after AAA operations.

Topics: Aged; Aldosterone; Aortic Aneurysm, Abdominal; Atrial Natriuretic Factor; Chi-Square Distribution; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Postoperative Complications; Renin

Hypertension after craniotomy is frequent. To establish an association between vasoactive modulators and postoperative hypertension, we followed the arterial blood pressure and plasma concentrations of selected substances in patients undergoing craniotomy. Twelve consecutive patients scheduled for operation of a supratentorial brain tumor were anesthetized with thiopental, fentanyl, isoflurane, and pancuronium. None of the patients had a history of arterial hypertension or were hypertensive before the operation. Arterial blood pressure and heart rate measurements were obtained preoperatively, after incision, during closure, and four times in the 50-minute interval after stopping isoflurane. At the same time, plasma concentrations of norepinephrine, epinephrine, renin, aldosterone, atrial natriuretic peptide, endothelin, and cortisol were measured. Data are given as mean +/- SD (range). The postoperative concentrations of these substances were significantly higher than the baseline concentrations measured preoperatively. Six of the patients developed postoperative hypertension defined as a mean arterial pressure (MAP) > 20% more than the baseline MAP (group H), and six had normal blood pressure postoperatively (group N). The mean value of the maximal postoperative MAPs measured in groups H and N, respectively, was 118 +/- 16 mm Hg (range: 96-132) and 103 +/- 9 mm Hg (range: 92-115) (P =.01). Only renin levels were higher intraoperatively in group H when compared to group N. However, postoperative levels of catecholamines, aldosterone, renin, and endothelin levels were higher in group H patients. The results suggest that in addition to an increased discharge of the sympathetic system, activation of the renin-angiotensin aldosterone system may also play an important role in the development of postoperative hypertension after craniotomy.

Topics: Adult; Aged; Aldosterone; Anesthesia; Atrial Natriuretic Factor; Blood Pressure; Catecholamines; Craniotomy; Endothelins; Female; Heart Rate; Hormones; Humans; Hydrocortisone; Hypertension; Intraoperative Complications; Male; Middle Aged; Monitoring, Intraoperative; Postoperative Complications; Renin; Renin-Angiotensin System; Supratentorial Neoplasms; Sympathetic Nervous System

Recent studies have suggested a differential influence of mean pressure and pulse pressure on myocardial infarction and stroke, and differences among the major drugs in their efficacy at preventing these individual endpoints. We hypothesized that antihypertensive drugs have differing influences upon the pulse wave even when their effects on blood pressure are the same. We studied 30 untreated hypertensive patients, aged 28-55 years, who were rotated through six 6-week periods of daily treatment with amlodipine 5 mg, doxazosin 4 mg, lisinopril 10 mg, bisoprolol 5 mg, bendrofluazide 2.5 mg or placebo. The best drug was repeated at the end of the rotation. Blood pressure readings and radial pulse tonometry (by Sphygmocor) were performed at each visit, and blood was taken for measurement of levels of atrial natriuretic peptide and brain natriuretic peptide (BNP). The Sphygmocor derivation of the central aortic pulse wave was used to measure time for transmission of the reflected wave (T(R)) and the augmentation index (AI), which is the proportional increase in systolic pressure due to the reflected wave. There was a dissociation between the effects of the drugs on blood pressure and pulse wave analysis. Bisoprolol caused the greatest falls in blood pressure and T(R), but was the only drug to increase AI. This paradoxical response to bisoprolol was associated with a 3-fold increase in plasma BNP levels. There was a smaller elevation of BNP in women compared with men, as described previously, and this elevation also was associated with significantly higher values of AI. Other drugs reduced AI, and this was associated with a significant decrease in BNP by amlodipine. In conclusion, antihypertensive drugs differ in their short-term effects on augmentation of the systolic pulse wave and secretion of BNP from the heart, regarded as a sensitive measure of strain on cardiomyocytes. These differences may help to explain cause-specific differences in outcome in recent trials.

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Determination; Cross-Over Studies; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Pulsatile Flow; Radial Artery; Sex Factors

Previous studies have demonstrated that beta-blockade increases the levels of plasma atrial natriuretic peptide (ANP), but relationships between this effect and the antihypertensive action of beta-blockade remain unknown. In this study we investigated the amplitude and determinants of bisoprolol-induced ANP increase and the relationships between this increase and the antihypertensive effect of bisoprolol. Nineteen patients with mild to moderate hypertension were included in the study. In the first phase of the study (cross-over, placebo controlled, randomized phase), the effects of 10 mg bisoprolol on plasma ANP at rest and during exercise were compared to placebo. The antihypertensive action of bisoprolol was then evaluated after a 2-week period of treatment (10 mg/day) using ambulatory blood pressure monitoring. Bisoprolol significantly increased plasma ANP level at rest (from 30.6 +/- 20.5 to 42.8 +/- 35.6; P < 0.05) and also during exercise (from 54.7 +/- 44.3 to 119.1 +/- 159.9; pg/mL +/- SD; P < 0.05). Plasma ANP at rest was not significantly correlated with left ventricular mass. After the 15 days of treatment, the bisoprolol-induced daytime diastolic blood pressure reduction was significantly correlated to the initial bisoprolol-induced plasma ANP increase (r = 0.49, P = 0.035). These results suggest that the antihypertensive effect of beta-blocking agents could be partly mediated by an increase of ANP release.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Bisoprolol; Blood Pressure; Cross-Over Studies; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged

The aim of the present study was to investigate whether plasma concentration of proANP(1-30), the N-terminal fragment of the atrial natriuretic peptide prohormone, or 24-hour urinary excretion of urodilatin reflects the degree of salt sensitivity in hypertension-prone individuals. Plasma concentration of proANP(1-30) and urinary urodilatin excretion were determined at baseline, after 1 week on a low-salt diet (10 mmol/d) and after another week on a high-salt diet (240 mmol/d) in 30 healthy subjects with heredity for hypertension. Salt sensitivity was defined as the difference between mean arterial blood pressure after the high-salt diet and the mean arterial blood pressure after the low-salt diet. High- versus low-salt intake increased proANP(1-30) (668+/-330 versus 358+/-150 pmol/L; P<0.00001) and urodilatin (18.7+/-5.2 versus 16.0+/-8.3 pmol/24 h; P<0.05). ProANP(1-30) correlated with salt sensitivity at baseline (r=0.76, P<0.000001), after the low- (r=0.80, P<0.0000001) and high-salt diets (r=0.85, P<0.00000001). The increase in proANP(1-30) induced by changing from the low- to the high-salt diet was also directly related to salt sensitivity (r=0.78, P<0.000001). ProANP(1-30) was not related to urinary sodium excretion. Neither urodilatin nor the sodium-induced change in urodilatin correlated with salt sensitivity. However, urodilatin was related to the urinary sodium excretion at baseline (r=0.58, P<0.01) and after the high-salt diet (r=0.62, P<0.001). In conclusion, the close correlations between proANP(1-30) and salt sensitivity suggest that proANP(1-30) may serve as a marker for salt sensitivity and could be useful in identifying subjects who would benefit from dietary salt restriction to prevent development of hypertension.

Topics: Adult; Atrial Natriuretic Factor; Female; Humans; Hypertension; Male; Middle Aged; Peptide Fragments; Protein Precursors; Sodium Chloride, Dietary; Statistics as Topic

The aim of this study was to evaluate the medium-term effects of the selective AT1-blocker irbesartan on atrial natriuretic peptide (ANP) levels in patients with moderate essential hypertension. The drug was given orally in a daily dose of 300 mg for 30 days. Plasma ANP levels increased by 15.7% despite the drop in blood pressure and the slight decrease of atrial and ventricular diameters. These findings indicate that AT,-blockers like irbesartan exert part of their antihypertensive action by increasing ANP plasma levels.

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Humans; Hypertension; Irbesartan; Male; Middle Aged; Receptor, Angiotensin, Type 1; Tetrazoles

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Female; Humans; Hypertension; Lisinopril; Male; Middle Aged; Pyridines; Renin-Angiotensin System; Sodium, Dietary; Thiazepines; Treatment Outcome

The T594M polymorphism of the epithelial sodium channel is found in approximately 5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle's syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89+/-3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91+/-4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8+/-4/2 mm Hg (systolic, P<0.05; diastolic, P<0.01). On restarting amiloride, blood pressure was again controlled to 140/88+/-6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.

Topics: Aldosterone; Amiloride; Amino Acid Substitution; Atrial Natriuretic Factor; Black People; Blood Pressure; Diuretics; Epithelial Sodium Channels; Follow-Up Studies; Humans; Hypertension; Longitudinal Studies; Polymorphism, Genetic; Renin; Sodium Channels; Treatment Outcome

The aim of the present study was to evaluate the effects of the level of salt intake on endothelium-derived factors in a group of patients with essential hypertension. A group of 50 patients with essential hypertension who had never been treated for the condition were placed on a low-sodium (50 mmol/day), low-nitrate (400 micromol/day) diet, which was supplemented, in a single-blind fashion, with placebo tablets for the first 7 days and then with NaCl tablets (200 mmol/day) for a further 7 days (total sodium intake 250 mmol/day). At the end of both periods, 24-h ambulatory blood pressure monitoring was performed. In addition, plasma levels and 24-h urinary excretion of nitrites plus nitrates and cGMP were measured, along with plasma levels of endothelin. A high salt intake promoted significant decreases in plasma levels of nitrites plus nitrates (from 41.0+/-2.1 to 32.8+/-1.8 nmol/ml; P<0.001), 24-h urinary nitrate excretion (from 417+/-36 to 334+/-37 micromol/24 h; P=0.045) and plasma endothelin levels (from 5.6+/-0.3 to 4.6+/-0.3 pg/ml; P=0.007). The plasma concentration and 24-h urinary excretion of cGMP were not altered significantly by a high salt intake. We did not find any relationship between endothelium-derived products and 24-h mean blood pressure, at either low or high salt intakes, or between changes induced by the high-salt diet. A high salt intake also induced significant decreases in plasma renin activity, angiotensin II and aldosterone, and a significant increase in atrial natriuretic peptide. We conclude that a high salt intake decreases the plasma concentration and urinary excretion of nitrates and plasma levels of endothelin in patients with essential hypertension, suggesting that the level of salt intake may affect endothelial cell function. However, these alterations are not correlated with changes in blood pressure induced by the high salt intake.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Cyclic GMP; Diet, Sodium-Restricted; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Nitrates; Nitrites; Normal Distribution; Renin; Single-Blind Method; Sodium Chloride, Dietary; Statistics, Nonparametric

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P=0.008), ambulatory systolic blood pressure (P=0.004), and ambulatory mean arterial pressure (P=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Creatinine; Cyclic GMP; Double-Blind Method; Electrolytes; Female; Genetic Predisposition to Disease; Hemodynamics; Humans; Hypertension; Lisinopril; Male; Metalloendopeptidases; Middle Aged; Pyridines; Sodium, Dietary; Thiazepines

Since renal sympathetic nerves are involved in the regulation of sodium excretion, we investigated whether treatment with urapidil, an alpha1-adrenoceptor blocking agent which also lowers sympathetic activity, alters sodium excretory capacity in patients with essential hypertension.. A double-blind, randomized, parallel-group study.. Studies were carried out in 26 patients who were randomized to treatment with either placebo or urapidil for 8 weeks. Before and after treatment blood pressure, renal haemodynamics and various neurohormones were measured, as well as the response of these variables to a hypertonic saline infusion.. Urapidil had no effect on renal haemodynamics or neurohormones at rest However, as compared to placebo the saline-induced rises in renal plasma flow and glomerular filtration rate lasted longer during treatment with urapidil. Responses of renin, angiotensin II and catecholamines were not modified by urapidil. On the other hand, aldosterone was less suppressed while atrial natriuretic peptide was less stimulated following the saline load when patients had been treated with urapidil. Cumulative sodium excretion during a 3 h period from the moment of saline infusion was similar whether patients had been treated with placebo or with urapidil.. Our data show that urapidil interferes with renal haemodynamics after sodium loading but that any tendency to promote sodium output may be offset by changes in aldosterone and atrial natriuretic peptide. We conclude that urapidil, under the circumstances tested, does not affect the sodium excretory capacity of the kidney.

Topics: Adrenergic alpha-Antagonists; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Biomarkers; Catecholamines; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Piperazines; Renal Circulation; Renal Plasma Flow; Renin; Severity of Illness Index; Sodium

We examined the effects of the vasodilator peptide adrenomedullin (AM) infused intravenously into subjects with essential hypertension. Eight men 39 to 58 years old with uncomplicated hypertension (147/96+/-5/3 mm Hg at baseline) were studied in a placebo-controlled, crossover design. Each subject received intravenous AM in a low and a high dose (2.9 and 5.8 pmol. kg(-1). min(-1) for 2 hours each) or vehicle-control (Hemaccel) infusion in a random order on day 4 of a controlled metabolic diet (80 mmol/d Na(+), 100 mmol/d K(+)). Plasma AM reached pathophysiological levels during infusion (18+/-4 pmol/L in low dose, 34+/-9 pmol/L in high dose) with a concurrent rise in plasma cAMP (+8.4+/-1.2 pmol/L, P:<0. 05 compared with control). Compared with control, high-dose AM increased peak heart rate (+17.8+/-2.3 bpm, P<0.01), lowered systolic (-24.6+/-0.9 mm Hg; P<0.01) and diastolic (-21.9+/-1.4 mm Hg; P<0.01) blood pressure, and increased cardiac output (+1.0+/-0. 1 L/min in low dose, +2.9+/-0.2 L/min in high dose; P<0.01 for both). Despite a rise in plasma renin activity during high dose (P<0.05), aldosterone levels did not alter. Plasma norepinephrine levels increased 1295+/-222 pmol/L (P<0.001) and epinephrine increased 74+/-15 pmol/L (P<0.05) with high-dose AM compared with control. AM had no significant effect on urine volume and sodium excretion. In subjects with essential hypertension, the intravenous infusion of AM to achieve pathophysiological levels produced significant falls in arterial pressure, increased heart rate and cardiac output, and stimulated the sympathetic system and renin release without concurrent increase in aldosterone. Urinary parameters were unaltered. Although AM has potent hemodynamic and neurohumoral effects in subjects with essential hypertension, the threshold for urinary actions is set higher.

Topics: Adrenomedullin; Adult; Aldosterone; Atrial Natriuretic Factor; Creatinine; Cross-Over Studies; Cyclic AMP; Dose-Response Relationship, Drug; Epinephrine; Hemodynamics; Humans; Hydrocortisone; Hypertension; Infusions, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Peptide Fragments; Peptides; Potassium; Potassium, Dietary; Prolactin; Renin; Sodium; Sodium, Dietary

In order to explore the hypothesis of an atrial natriuretic factor (ANF) deficiency in prehypertension, we compared the response to sodium loading on ANF and renal function in subjects with positive and negative histories of hypertension.. Twenty-two offspring of hypertensive parents (OH) and 20 offspring of normotensive parents (ON) were studied after 4 days of low (50 mmol/day) or high (300 mmol/day) dietary sodium intake. The diets were allocated randomly. Blood pressure (BP), renal function, plasma concentration of ANF, cyclic guanosine monophosphate (cGMP), renin, angiotensin I and II, aldosterone, endothelin and catecholamines were determined during a clearance period of 90 min on both diets. Neurohormones were measured by radioimmunoassays. Renal function was determined by simultaneous measurements of 51Cr-ethylenediaminetetraacetate (a marker of glomerular filtration rate), lithium and sodium clearances.. Supine systolic and diastolic BPs were significantly elevated in OH, with both low and high dietary sodium intake. There was no difference in ANF and cGMP concentrations on the low sodium diet. Increasing sodium intake caused a similar increase in ANF in OH and ON but cGMP did not change significantly. As expected the activity of the renin-angiotensin-aldosterone system was decreased by enhancing sodium intake but with both low and high sodium intake plasma renin concentration was significantly higher in OH than in ON. Activation of the sympathetic nervous system with low sodium intake was indicated by a moderate increase in plasma concentrations of epinephrine and norepinephrine in both groups. The renal effects were characterized by significant increases in GFR, lithium and sodium clearances with increasing sodium intake. There were no differences between OH and ON. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly and in a similar way in both OH and ON.. These results indicate that the renal and neuroendocrine responses to dietary sodium loading are similar in both OH and ON. The only difference was a higher BP and an elevated plasma renin concentration on both dietary regimens in OH compared with ON. In particular, in OH and ON an identical increase in plasma ANF concentration in response to sodium loading was found. Thus, this study cannot support the hypothesis of a dysregulation of ANF in hypertension-prone humans.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Female; Genetic Predisposition to Disease; Glomerular Filtration Rate; Humans; Hypertension; Kidney Tubules; Male; Renin; Sodium, Dietary

Fifteen hypertensive patients (13 men) with left ventricular hypertrophy, mean age 69 6 5 years, having complete heart block and paced in the DDD mode, were studied by two-dimensional and Doppler echo in 100 and 200 ms atrioventricular delays. ANF plasma levels were measured at rest and at peak exercise, during pacing with the two different atrioventricular delays. ANF plasma levels were significantly higher at pacing with long atrioventricular delays (200 ms), at rest (152.47 6 12.38 pg/mL vs 119 6 12.38 pg/mL, P, 0.001) and at exercise (180.93 6 11.51 vs 123.67 6 16.24 pg/mL, P, 0.0001). ANF plasma levels were significantly increased at exercise, compared to those at rest during pacing with the two different atrioventricular delays, but we found a more pronounced increase of ANF levels (from 152.47 6 10.49 pg/mL to 180.93 6 11.51 pg/mL), when the atrioventricular delays was set to 200 ms (P, 0.0001). A significant decrease of isovolumic relaxation time (from 123.33 6 20.5 to 105.33 6 11.06 ms, P, 0.001) was observed, during pacing with the short atrioventricular delays. Moreover, the peak early (E) to peak atrial (A) velocity ratio (E/A) was declined (from 0.89 6 0.7 to 0.57 6 0.18, P, 0.05). We also noticed that patients with small left ventricles exhibit greater increase in ANF plasma levels during DDD pacing with long atrioventricular delays (r 5 20.792, P 5 0.000). In conclusion, left ventricular diastolic function of our patients seems to be improved during DDD pacing with short (100 ms) atrioventricular delays, as it was expressed by echocardiographic and hormonal measurements.

Topics: Activities of Daily Living; Aged; Atrial Natriuretic Factor; Atrioventricular Node; Cardiac Pacing, Artificial; Cardiac Volume; Diastole; Echocardiography; Echocardiography, Doppler; Exercise Test; Female; Heart Block; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardial Contraction; Physical Exertion; Rest; Ventricular Function, Left

This was a double-blind, randomized, two-center, active-controlled, prospective, parallel study designed to evaluate the effects of nebivolol at daily doses of 5 mg on lipid and carbohydrate metabolism and on blood pressure in comparison with atenolol at daily doses of 50 mg. Normometabolic subjects with mild-to-moderate essential hypertension were recruited for this study, which included a 4-week, single-blind placebo washout phase and a 12-week double-blind treatment phase. After 12 weeks of treatment, both drugs demonstrated a significant decrease from baseline in high-density lipoprotein (HDL) apolipoprotein A-I (HDL-apoA-I) (nebivolol, P <.02; atenolol, P <.05). A significant reduction in HDL cholesterol (HDL-C) from baseline was also observed with nebivolol (P <.05). There were no significant differences between the drugs for these parameters, and the ratio low-density lipoprotein cholesterol (LDL-C)-to-HDL-C did not change significantly after 12 weeks of active treatment with nebivolol or atenolol. There were no significant changes in total cholesterol, HDL (2) -C, HDL (3) -C, LDL-C, very-low-density lipoprotein cholesterol (VLDL-C), total triglycerides, HDL-triglycerides (TG), LDL-TG, VLDL-TG, total apoB, LDL-B, VLDL-B (including the ratio LDL-C-to-LDL-apoB), or Lp(a) during treatment with both drugs. No significant differences in plasma apoA-I and apoC-III as well as in apoA-I-, C-III-containing lipoprotein particles (including the apoC-III ratio) were observed between the drugs, neither before nor after each active treatment. There were no significant differences between the drugs or within each treatment group in plasma glucose, insulin, or C-peptide concentrations after a 2-hour oral glucose tolerance test. Mean clinic trough sitting systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 150/98 mm Hg at baseline to 141/90 mm Hg at termination for nebivolol and from 160/99 mm Hg at baseline to 145/88 mm Hg at termination for atenolol. No significant between-treatment differences were observed for the mean clinic trough sitting SBP/DBP. Both drugs significantly increased the atrial natriuretic factor (ANF) N-terminal plasma levels, whereas no changes were observed in ANF C-terminal plasma concentrations. A significant decrease (P <. 05) in the plasma adrenocorticotropic hormone levels was observed after administration of both drugs. A significant decrease (P <.05) in plasma cortisol levels was observed only aft

Topics: Adrenocorticotropic Hormone; Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Benzopyrans; Blood Pressure; Double-Blind Method; Ethanolamines; Female; Heart Rate; Humans; Hydrocortisone; Hypertension; Lipids; Male; Middle Aged; Nebivolol; Time Factors

Adrenomedullin (ADM), secreted by the failing human heart, is a newly discovered potent endogenous vasorelaxing and natriuretic peptide that may play a role in cardiorenal regulation. No data are available on ADM in heart-transplant recipients (Htx) and the aim of this study was to determine the short- and long-term responses of ADM after heart transplantation.. Circulating ADM and its relationship with parameters of cardiovascular hemodynamics, humoral factors and renal function were determined in normal subjects and Htx early (1, 2, 4, 8, 15 and 30 days) and late (32 +/- 16 months) after transplantation. Additionally, ADM was obtained in matched hypertensive and renal-transplant patients (n = 9 in each group).. Plasma ADM, elevated in heart failure patients, further increased transiently at day 1 after transplantation (from 37.9 +/- 15.9 to 125.8 +/- 15.3 pmol/l, P < 0.01) and, although decreasing thereafter, remained elevated until the 30th day after transplantation (52.1 +/- 25.2 pmol/l). Late after transplantation. ADM concentrations were still increased compared to normal values (31.3 +/- 5.3 vs. 19.4 +/- 2.7 pmol/l, P < 0.001). ADM positively correlated with endothelin, atrial natriuretic peptide (ANP) and cyclosporine. ADM was also correlated with increased diastolic (r = 0.68, P < 0.04) and systolic (r = 0.66, P < 0.05) blood pressure in late Htx. No relationship was observed between ADM and left ventricular mass index, aldosterone and creatinine. ADM elevation was similar in hypertensive, renal-transplant patients and in Htx.. Circulating ADM is increased after heart transplantation, in relation to hypertension, endothelin, cyclosporine and ANP. In view of ADM's biological properties, these results might suggest a compensatory role for ADM against further development of vasoconstriction and fluid retention states after heart transplantation.

Topics: Adrenomedullin; Analysis of Variance; Atrial Natriuretic Factor; Cyclosporine; Endothelins; Heart Transplantation; Humans; Hypertension; Kidney Transplantation; Middle Aged; Peptides; Postoperative Period; Vasodilator Agents

To determine the relationship between endothelin-1 (ET-1), human atrial natriuretic peptide (hANP), plasma-renin activity (PRA) and 24-h urinary excretion of aldosterone (U-Ald) in pregnancy-induced hypertension (PIH).. Plasma hANP (pg/ml), ET-1 (pg/ml), PRA (ng/ml per h) and U-Ald (microg/24 h) were measured and 24 h ambulatory mean arterial pressure (MAP) was monitored in 178 normotensive subjects (NT) and 79 gravidas with PIH at the 8th, 18th, 23rd, 28th, 32nd and 36th weeks.. The PIH group had higher MAP than the NT group from the 23rd week (91.64 +/- 8.76 versus 83.48 +/- 4.36 mmHg, P< 0.01) until the end of the pregnancy. ET-1 levels (pg/ml) in both groups were identical at the beginning of pregnancy and different in the 23rd week [(NT versus PIH) (35.11 +/- 17.42 and 40.2 +/- 19.51, respectively, P < 0.05)] and the 36th week (37.36 +/- 18.07 and 42.7 +/- 16.43, P< 0.05). hANP levels (pg/ml) in the NT group decreased insignificantly from the 8th till the 32nd week, then increased to 101.94 +/- 17.4 in the 36th (P< 0.001 versus any other week). In the PIH group, hANP increased from 104.8 +/- 26.8 pg/ml at the 8th week to 161.3 +/- 28.6 pg/ml at the 36th week (P< 0.0001). hANP correlated with MAP in the NT group (r = 0.252, P< 0.0005) but not the PIH group. U-Ald in the NT group increased from 23.52 +/- 6.83 microg/24 h at the 8th week to 54.07 +/- 19.62 microg/24 h at the 36th week (P < 0.0001) and in the PIH group it increased from 27.90 +/- 11.6 to 53.66 +/- 20.4 microg/24 h (P< 0.0001). In the PIH group, PRA was lower compared with the NT group from the 8th (2.99 +/- 1.26 versus 4.10 +/- 1.82 ng/ml per h, P< 0.05) until the 36th week (3.34 +/- 2.16 versus 4.46 +/- 2.13 ng/ml per h). In the forced multiple regression analysis model with hANP as a dependent variable, a value of P< 0.003 was found with PRA, U-Ald and MAP, which indicates an interaction between the two vasoactive and homeostatic systems: the renin-angiotensin-aldosterone system and hANP.. In PIH, elevated hANP might be important as a counterbalance to the presence of the active vasopressors and sodium retention. By inhibiting renin release, enhancing the transcapillary fluid migration and with its action as vasodilator, it acts as a corrective factor of the imbalance between the contracted circulating fluid volume and the vasoconstricted vascular bed.

Topics: Adolescent; Adult; Aldosterone; Atrial Natriuretic Factor; Endothelin-1; Female; Humans; Hypertension; Longitudinal Studies; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies; Regression Analysis; Renin; Time Factors

The effects of a long-term therapy with quinapril on plasma renin activity, plasma aldosterone, atrial natriuretic peptide and left ventricular mass were analysed in patients with mild to moderate systemic hypertension. Fifteen patients (4 women) were treated for one year with quinapril 10 or 20 mg once daily, reducing hereby the systolic and diastolic blood pressure from 167.5 +/- 11.3 to 141 +/- 6.7 mmHg p < 0.001 and from 105.3 +/- 5 to 90 +/- 7 mmHg respectively, within the first two weeks. Blood pressure remained stable during the following 52 weeks. After 6 and 52 weeks of therapy, as expected, we observed an increase of plasma renin activity, plasma aldosterone decrease from 262.6 +/- 88.1 to 178.8 +/- 79.9 p = 0.01 and to 170.3 +/- 64.3 ng/ml p = 0.006 respectively. Atrial natriuretic peptide levels were not significantly altered. After 52 weeks of treatment left ventricular mass index decreased from 107.9 +/- 16.2 to 90.1 +/- 13.4 g/m2 p = 0.0001. It is concluded that treatment with quinapril for 1 year in addition to controlling blood pressure also reduced left ventricular mass probably by a favourable effect on renin-angiotensin-aldosterone system.

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Female; Heart Ventricles; Humans; Hypertension; Isoquinolines; Male; Quinapril; Renin-Angiotensin System; Single-Blind Method; Tetrahydroisoquinolines

Responses of endocrine systems to acute and chronic salt loading were examined in normotensive and hypertensive subjects. In the acute salt load study, isotonic saline (20 ml/kg for 1 h) was intravenously infused in 10 normotensive subjects and 12 patients with essential hypertension. Plasma noradrenaline was suppressed by saline infusion in the normotensive subjects (-19%, p < 0.05), but was not suppressed in the hypertensive patients (-5%, NS). Plasma brain natriuretic peptide concentration was significantly increased in the hypertensive patients (+15%, p<0.05), while it was unchanged in the normotensive subjects. In the chronic salt load study, 9 normotensive subjects and 30 patients with essential hypertension underwent two 7-d periods of 30 and 260 mmol/d sodium intake. On the basis of the blood pressure change, 17 hypertensive patients were classified as salt-resistant and 13 as salt-sensitive. The salt-sensitive hypertensive patients had suppressed plasma renin activity even during low-salt intake. During high salt intake, the plasma noradrenaline concentration failed to decrease in the salt-sensitive hypertensive patients (-6%, NS), whereas it fell significantly in the normotensive subjects (-27%, p < 0.05) and the salt-resistant hypertensive patients (-33%, p < 0.01). The high-salt intake also increased plasma concentrations of brain natriuretic peptide as well as atrial natriuretic peptide in all groups. In the salt-sensitive hypertensive patients, there was a positive correlation between the increase in blood pressure and that in atrial natriuretic peptide (r= 0.84, p< 0.01). These data indicate that brain natriuretic peptide is involved in chronic changes in body fluid volume. In patients with essential hypertension, acute volume expansion also evokes the response of brain natriuretic peptide. Salt-sensitive hypertension seems to be characterized by blunted response of the sympathetic nervous system. In addition, an increase in atrial natriuretic peptide is likely to play an important role in mechanisms counteracting salt-induced elevation of blood pressure.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Norepinephrine; Sodium Chloride; Sodium, Dietary; Water-Electrolyte Balance

Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone.. Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12+/-2%; P=0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (P=0.6) after pretreatment with both placebo (13+/-1%, P=0.006) and enalapril (17+/-6%, P=0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ETA antagonist BQ-123 (100 nmol/min), and both combined. Thiorphan caused local forearm vasoconstriction (13+/-1%, P=0.0001); BQ-123 caused local vasodilatation (33+/-3%, P=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32+/-1%, P=0.0001) similar to BQ-123 alone (P=0.98). In a fourth study, 6 hypertensive patients (blood pressure >160/100 mm Hg) received intra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progressive forearm vasoconstriction (10+/-2%, P=0.0001).. Inhibition of local NEP causes vasoconstriction in forearm resistance vessels of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorphan and its absence during concomitant ETA receptor blockade suggest that it is mediated by endothelin-1 and not angiotensin II. These findings may help to explain the failure of systemic NEP inhibition to lower blood pressure.

Topics: Adult; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Coronary Vessels; Cross-Over Studies; Cyclohexanecarboxylic Acids; Enalapril; Endothelin-1; Humans; Hypertension; Injections, Intra-Arterial; Male; Middle Aged; Myocardium; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Renin; Single-Blind Method; Thiorphan; Vasoconstriction

Both environmental and genetic factors are implicated in the pathogenesis of essential hypertension. The defect of the ANP precursor gene leading to the decrease of ANP synthesis are a cause of the development of sodium-sensitive hypertension in animals. Recent findings in African-Americans who are a model of sodium-sensitive population, reveal a strong association between Sma I polymorphism at intron 2 (the polymorphic site is identical for Hpa II restriction enzyme) or both Sma I and Sca I polymorphism at exon 3 of ANP precursor gene and essential hypertension. The aim of our study was to optimize the methods for Sma I and Sca I analysis in the ANP precursor gene (PCR followed by digestion with restriction enzymes) and to determine the frequencies of Sma I or Sca I genotypes and alleles in patients with sodium-sensitive (SS) or sodium-nonsensitive (SR) hypertension. The Sma I heterozygous mutation (WM genotype) were detected in 4 (8.9%) SS patients and in 2 (10%) patients in SR group. The frequency of Sca I M allele (allele with mutation) was significantly higher in SS group as compared to sodium-nonsensitive hypertensives. Our results suggest that, in contrast to Black hypertensives, in Caucasians with essential hypertension the Sma I polymorphism is very rare and the Sca I polymorphism of ANP precursor gene is associated with sodium-sensitivity of blood pressure.

Topics: Adult; Atrial Natriuretic Factor; DNA Restriction Enzymes; Female; Genotype; Humans; Hypertension; Introns; Male; Nucleic Acid Precursors; Polymorphism, Genetic; Sodium, Dietary

Plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) are high in patients with hypertension and congestive heart failure. The present study examined changes in plasma ANP and BNP concentrations during 1 year of monotherapy with enalapril in elderly hypertensive patients with left ventricular (LV) hypertrophy. Eight elderly hypertensive patients with LV hypertrophy were treated with enalapril for 1 year, during which time serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of ANP and BNP. Enalapril maintained systolic and diastolic blood pressure in the normal range for over 1 year. Treatment significantly reduced posterior wall thickness at 6 months, and more so at 1 year, and tended to reduce septal wall thickness and LV mass index at 1 year. LV ejection fraction was slightly but significantly increased at 1 year. Plasma ANP and BNP, which were markedly elevated at study entry, both decreased after 1 year of enalapril. These results suggest that 1 year of treatment with enalapril caused both a modest regression of LV hypertrophy and a modest improvement in LV systolic function in our selected group of elderly hypertensive patients. The drug reduced elevated plasma ANP and BNP levels but did not alter BUN and serum creatinine levels. Enalapril appears to be useful for the treatment of elderly hypertensive patients with LV hypertrophy.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Electrocardiography; Enalapril; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Renin; Systole; Ventricular Function, Left

The purpose of this study was to investigate the effect of exercise on plasma concentrations of adrenomedullin, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) in patients with essential hypertension (n = 15) and in normotensive controls (n = 10). Exercise consisted of two fixed workloads, 40 and 80 watts of work load using a supine bicycle ergometer. Plasma levels of all three peptides at rest were significantly higher in hypertensives than in controls. Plasma concentrations of ANP increased with exercise in both groups and had greater increments in hypertensive patients than in normotensives. Plasma concentrations of BNP increased only in patients with hypertension and the levels of increase correlated with basal plasma BNP levels (r = 0.94, p < 0.001) and with left ventricular mass (r = 0.62, p < 0.01) determined by echocardiography. In contrast, plasma adrenomedullin did not change with exercise in either group. These results suggest that secretion patterns of these peptides are regulated by different mechanisms and that the amount and kind of peptides mobilized by exercise may depend on the underlying diseases or pathophysiologic condition.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Exercise; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides; Reference Values

The effects of 10 weeks of treatment with atenolol (n = 9) or the converting enzyme inhibitor zofenopril (n = 25) on plasma atrial natriuretic peptide (ANP) were studied in 34 essential hypertensive patients. After 4 weeks on placebo, pretreatment ANP, 56 +/- 7 pg/ml, was slightly but not significantly higher than that of 29 controls (41 +/- 4) and correlated with age (r = 0.44), ECG score for left ventricular hypertrophy (LVH) (r = 0.51) and serum creatinine (r = 0.67), and negatively with creatinine clearance (r = -0.39). Atenolol reduced blood pressure (BP) by 0 +/- 6/8 +/- 2 mm Hg (ns/P < 0.01), and zofenopril by 14 +/- 4/6 +/- 2 (P < 0.01/P < 0.01), not significantly different between the two agents. Heart rate was decreased by atenolol (-16 +/- 4 bpm, P < 0.01) but not by zofenopril (+1 +/- 2 bpm, ns). Atenolol increased ANP in all patients but one (delta = +42 +/- 9 pg/ml, P < 0.01), while zofenopril did not change it significantly (-6 +/- 6 pg/ml), due to 15 patients exhibiting decreases and 10 increases in plasma ANP. The effect of atenolol on ANP positively correlated with duration of hypertension (r = 0.74), ECG score for LVH (r = 0.73) and serum creatinine (r = 0.68). Individual changes in ANP by zofenopril negatively correlated with pretreatment ANP (r = -0.69), ECG score for LVH (r = -0.44) and serum creatinine (r = -0.41). No correlations were found between BP, heart rate or their changes by treatment and the effect of either agent on plasma ANP. Multiple linear regression showed that the change in ANP was explained by the therapeutic agent used, the pretreatment plasma level of ANP, and the ECG score for LVH (F = 12.5, P < 0.001, r2 = 0.56). We conclude that the effect of antihypertensives on plasma ANP is independent of their action on BP, but dependent on an interaction between the type of drug employed and those clinical characteristics of the patient that reflect pre-existing hypertensive target organ damage.

Topics: Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Blood Pressure; Captopril; Double-Blind Method; Drug Interactions; Hemodynamics; Humans; Hypertension

To investigate the possible role played by endogenous dopamine as a modulator of renal sodium (Na+) reabsorption after a combined Na+ and volume load.. A randomized placebo-controlled study.. Ten healthy volunteers and four hypertensive patients were subjected to intravenous infusions of 21 0.9% saline (308 mmol Na+) administered from 1000 to 1300 h after oral administration of placebo or of carbidopa, a dopamine decarboxylase inhibitor.. Studies on control subjects after placebo showed that natriuresis occurred during the 6 h after commencement of the saline infusion, with falls in plasma albumin concentration, plasma renin activity and plasma aldosterone concentration; in comparison with results of mock infusion (6 mmol Na+) there was no change in the urinary excretion of dopamine and noradrenaline (In their free or conjugated forms). There was, however, a marked surge in excretion of urinary conjugated dopamine and in the dopamine: noradrenaline ratio from 1300 to 1600 h, after either type of infusion. Administration of carbidopa before the saline infusion resulted in a marked decrease in excretion of urinary free dopamine, but had no effect on the surge in excretion of urinary conjugated dopamine. Saline infusion decreased proximal fractional Na+ reabsorption. Administration of carbidopa delayed but did not prevent this decrease. The effects of saline infusion and of carbidopa on the urinary excretion of dopamine and noradrenaline from hypertensive patients were similar to those observed with the healthy volunteers.. These findings indicate that volume expansion by intravenous saline infusion has no appreciable effect on the urinary free dopamine excretion from normal or hypertensive humans; with any apparent increase, it is important to exclude the possibility of conversion of conjugates to free dopamine in vitro. Furthermore, that carbidopa administration did not inhibit the afternoon surge of conjugated dopamine suggests that administration of carbidopa is deficient as a tool to investigate the functional role of the renal dopamine system.

Topics: Adolescent; Adult; Aldosterone; Aromatic Amino Acid Decarboxylase Inhibitors; Atrial Natriuretic Factor; Carbidopa; Dopamine; Enzyme Inhibitors; Female; Humans; Hypertension; Infusions, Intravenous; Isotonic Solutions; Male; Middle Aged; Natriuresis; Norepinephrine; Renin; Serum Albumin; Sodium Chloride

Using digitized M-mode echocardiograms, we evaluated the relationship between plasma atrial natriuretic factor (ANF) and morphofunctional characteristics of the left ventricle (LV) in 24 mild hypertensive men, never treated, with normal renal function. For each subject we collected a blood sample for plasma ANF evaluation and, immediately after, we recorded the LV echocardiogram. All the patients had normal LV diastolic diameter and systolic function; LV hypertrophy was present in 10 patients, 7 of whom had left atrial enlargement, and 13 patients had impaired LV diastolic function. ANF was similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement, whereas ANF was significantly (P < .01) higher in patients with LV diastolic dysfunction than in patients with normal diastolic function. ANF was inversely correlated with both indices of diastolic function (peak lengthening rate and peak wall thinning rate), whereas it did not correlate with blood pressure, heart rate, end-systolic wall stress, and other LV parameters. In conclusion, from our results, ANF level in never-treated mild hypertensives is related neither to the degree of LV hypertrophy nor to the afterload, expressed as blood pressure or end-systolic wall stress, whereas it is mainly influenced by LV diastolic function: the diastolic impairment induces an increase in ANF level, probably through an increased atrial stretch.

Topics: Adult; Atrial Natriuretic Factor; Echocardiography; Humans; Hypertension; Kidney Function Tests; Male; Regression Analysis; Ventricular Function, Left

This study compared the effects of 1 year of monotherapy with a calcium-channel antagonist (nilvadipine; NIL), an angiotensin-converting enzyme (ACE) inhibitor (temocapril; TEM), or a new vasodilator (cadralazine; CAD) on left ventricular (LV) hypertrophy in essential hypertension. Furthermore, to elucidate the mechanism responsible for regression of LV hypertrophy after treatment, LV mass index (LVMI) by echocardiography, plasma renin activity (PRA), aldosterone (PAC), norepinephrine, and atrial natriuretic peptide (ANP) concentration were measured before and after treatment. Thirty-six patients were randomly assigned to the NIL, TEM, or CAD groups. Blood pressure (BP) before treatment was 174 +/- 10/104 +/- 7, 173 +/- 18/103 +/- 8, and 171 +/- 16/103 +/- 7 mm Hg (mean +/- SD) in NIL, TEM, and CAD groups, respectively. BP was lower after treatment with each of the three test drugs than after the placebo period, and there were no differences in BP reduction among three groups. LVMI, in NIL and TEM, was reduced from 129 +/- 48 to 115 +/- 39 g/m2 and from 117 +/- 39 to 88 +/- 20 g/m2 (p < 0.05 and p < 0.01, respectively), whereas, in the CAD group, it was increased (110 +/- 30 to 138 +/- 27 g/m2; p < 0.01). In the CAD group, PAC decreased and ANP increased significantly. The change in LVMI correlated with that in BP for TEM and with that in ANP in all patients. These data indicated that LV volume overload as well as LV pressure overload may contribute to LV hypertrophy and that monotherapy with CAD is not desirable from the point of view of LV mass reduction in essential hypertension.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Calcium Channel Blockers; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nifedipine; Norepinephrine; Pyridazines; Renin; Thiazepines; Vasodilator Agents

We have studied an insertion/deletion (I/D) dimorphism located in the second intron of the human atrial natriuretic factor (ANF) gene among 232 United Arab Emirates (UAE) nationals (112 normotensives and 120 hypertensives) from the Abu Dhabi Emirate, with a view to evaluating the value of this marker in relation to hypertension. Our findings show that genotype frequencies of this I/D marker occur in Hardy-Weinberg proportions (respective genotype frequencies in the overall sample population are: II, 51%; ID, 42%; DD, 7%). No association, however, was evidenced between this dimorphic site and clinical diagnosis of essential hypertension. This suggests that: 1) this I/D dimorphism is not a useful marker to study the relationship between the ANF gene and hypertension in the UAE; and 2) variations of the ANF gene that may be in linkage disequilibrium with this marker do not play a major role in the determination of hypertension in this Arab population.

Topics: Alleles; Arabs; Atrial Natriuretic Factor; Case-Control Studies; DNA; Female; Genetic Markers; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; United Arab Emirates

Topics: Atrial Natriuretic Factor; Deoxyribonuclease HpaII; DNA; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; White People

Obesity increases the risk of developing hypertension by two-to fourfold, with more that one third of all cases of hypertension attributable to obesity. The present study tested the role of atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2) and neuropeptide Y (NPY) in pathogenesis of obesity hypertension. The plasma concentrations of ANP, ET-1,2 and NPY were determined in the peripheral venous blood by radioimmunoassay in 27 obese hypertensive patients (group I), in 24 obese normotensive patients (group II), and in 35 normal subjects (group III).. Mean plasma ANP was significantly higher in obese than in normal subjects. ANP levels were higher in patients group I than in those group II and I. In patients of group I plasma ANP concentrations correlated with III BMI and mean blood pressure. Plasma levels of ET-1,2 and NPY were similar in patients group I, II and III.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Catecholamines; Endothelin-1; Endothelin-2; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Obesity; Peptides

Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56 +/- 0.62 L/min) was greater than that for BNP (3.4 +/- 0.23 L/min, P <.001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%; P <.001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels; P <.001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure-lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure.

Topics: Atrial Natriuretic Factor; Hemodynamics; Hormones; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins

The renin-angiotensin-aldosterone system plays a major role in renovascular hypertension, but the relationship between renin release and the renal fractional extraction of atrial natriuretic peptide (ANP) in this condition is not well defined. We measured ANP levels in the renal veins and aortas of 49 untreated hypertensive patients studied under standardized conditions immediately before renal angiography. Twenty-one patients had renal artery stenosis, 13 of which were unilateral and 8 bilateral. Five of the 13 patients with unilateral renal artery stenosis had an elevated renin ratio (> or = 1.5). Patients with renal artery stenosis were older (P < .01) and had higher systolic pressures (P < .05) than patients with essential hypertension. Arterial levels of ANP were significantly higher in patients with unilateral or bilateral renal artery stenosis than in patients with essential hypertension (P < .05). Patients with hypertension and left ventricular hypertrophy had significantly higher arterial ANP levels than those with no hypertrophy (40 versus 26 pmol/L, P < .05), but in patients with renal artery stenosis, arterial ANP levels were similar in those with or without hypertrophy. Renal venous ANP levels were significantly higher in stenotic than in normal kidneys. Moreover, in unilateral renal artery stenosis, stenotic kidneys of patients with an elevated renin ratio (stenotic kidney/contralateral kidney > or = 1.5) had a significantly higher renal venous ANP level than stenotic kidneys of patients with normal renin ratio (30 versus 17 pmol/L, P < .05). However, the median fractional extraction of ANP was similar, around 0.50 (range, 0 to 0,83), in normal kidneys of hypertensive patients and in stenotic and contralateral kidneys of patients with renal artery stenosis. A significant inverse correlation between arterial ANP and renal venous active plasma renin concentration was found for normal kidneys (r= -.62, P < .01) of hypertensive patients without hypertrophy. However, for stenotic kidneys, no such relationship was apparent. A significant correlation between arterial ANP and the arteriovenous difference of ANP (r = +.92, P < .001) was found. This relationship was similar for normal and stenotic kidneys. In conclusion, an inverse relationship between arterial ANP and renal venous active plasma renin concentration exists in normal kidneys of essential hypertensive patients without left ventricular hypertrophy. Furthermore, data of ANP extraction thro

Topics: Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Female; Humans; Hypertension; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Kidney; Male; Middle Aged; Radiography; Renal Artery; Renal Veins; Renin

To evaluate the behavior of active kallikrein excretion in salt-sensitive and salt-resistant hypertensive patients during changes in sodium-chloride (NaCl) intake, 61 male, nonobese, nondiabetic outpatients affected by uncomplicated essential hypertension were given a diet that contained 140 mmol NaCl per day for 2 wk. Patients then received either a low- (20 mmol NaCl/day) or a high- (320 mmol NaCl/day) sodium diet for 2 wk, according to a randomized, double-blind, cross-over protocol. Hypertensive patients were classified as salt sensitive when their diastolic blood pressure rose by at least 10 mm Hg after the high-sodium diet, and decreased by at least 10 mm Hg after the low-sodium diet, considering as baseline blood pressure values those that were taken at the end of the 140 mmol NaCl/day intake period. The remaining patients were classified as salt resistant or, when diastolic blood pressure increased by 10 mm Hg or more after low-sodium intake, as counter-regulating. Twenty-three patients were therefore classified as salt sensitive, 28 as salt resistant, and 10 as counter-regulating. The baseline active kallikrein excretion was significantly lower (P < 0.0001) in salt-sensitive (0.62 +/- 0.31 U/24 h) patients than in salt-resistant (1.39 +/- 0.44 U/24 h) and counter-regulating patients (1.27 +/- 0.38 U/24 h). Surprisingly, the kallikrein response to changes in sodium intake was similar in all subgroups, although enzyme excretion was always at the lowest level in salt-sensitive hypertensive patients. This latter group also showed the highest plasma atrial natriuretic peptide levels (28.2 +/- 8.5 fmol/mL, P < 0.0001 versus salt-resistant and counter-regulating patients), and the greatest peptide increment with sodium load (P < 0.0001 versus salt-resistant and counter-regulating patients). Counter-regulating patients showed the steepest increase in plasma renin activity (from 0.24 +/- 0.18 to 0.83 +/- 0.21 ng/L per s, P < 0.001) and decrease of plasma atrial natriuretic peptide (from 26.1 +/- 6.3 to 6.8 +/- 3.1 fmol/mL, P < 0.001) when switched from a high to a low-sodium intake. In conclusion, salt-sensitive hypertensive patients excrete less active kallikrein than do salt-resistant and counter-regulating patients, but maintain a normal enzyme response to changes in dietary sodium intake. The exaggerated response of atrial natriuretic peptide to high-sodium intake that was observed in the same patients could be compensating for an impaired renal capab

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Humans; Hypertension; Kallikreins; Male; Middle Aged; Renin; Reproducibility of Results; Sodium; Sodium Chloride, Dietary

The amount of, and response of the kidneys to, endogenous natriuretic factor(s) could be important in the pathogenesis of essential hypertension. Searching for possible disturbance(s) related to atrial natriuretic factor (ANF) and its second messenger, cyclic guanosine monophosphate (c-GMP), we assessed plasma immunoreactive (ir) ANF and c-GMP, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary c-GMP, absolute and fractional (FE) excretions of sodium (Na) and chloride (Cl) before and during infusions of low ANF doses or vehicle (V) in 7 normotensive sons of essential hypertensive parents (SEH) compared with 7 sons of normotensive parents (SN). Each subject was infused at 2-week intervals in a single-blind randomized sequence with 4 different solutions: V only or ANF 0.004, 0.008 and 0.016 microgram/kg/min, infused over 90 min. Plasma irANF was lower in SEH than in SN (p < 0.001) during vehicle infusion. Basal plasma c-GMP levels were, on all 4 different study days lower (p < 0.05 to < 0.01) in SEH in SN. Response of plasma c-GMP to infused ANF was also slightly decreased in SEH (p < 0.05 to < 0.01). BP, ERPF and GFR did not differ between SEH and SN and were unchanged during the 4 infusions. Urinary c-GMP excretion, FENa and FECl increased dose-dependently during ANF (p < 0.05 to < 0.0001) but not V infusions. These findings indicate that at the stage of pre-hypertension a disturbance in the ANF-c-GMP regulatory pathway may occur, which is expressed primarily at the circulatory rather than the renal excretory level.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Kidney; Male; Renal Plasma Flow, Effective

Neuropeptide Y (NPY) has been recently characterized as a circulating vasoconstrictor peptide which is co-stored with noradrenaline in sympathetic neurons. To investigate the role of NPY concentration in hypertension we measured the circulating NPY, endothelin-1,2 (ET-1,2), atrial natriuretic peptide (ANP), aldosterone, plasma renin activity (PRA) and noradrenaline (NA) in patients with stable mild to moderate primary hypertension. Circulating levels of NPY, ET-1,2, ANP, aldosterone and PRA were measured with radioimmunoassay, NA by double-isotope radioenzymatic assay. There were significant increase in concentrations NPY, ET-1,2, ANP and NA in patients with moderate primary hypertension, and significant positive correlations between the plasma levels of NPY, ET-1,2 and NA.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Renin

In order to evaluate the effect of atrial natriuretic peptide (ANP) infusion on plasma and urinary digitalis-like substance (DLS) levels, 18 essential hypertensive males (mean age 45.6 +/- 3.8 y) were studied. After 1 week on a normal NaCl intake (120 mmol/24h), patients were randomly double-blindly assigned to receive either ANP (99-126) (0.3 microgram/kg/min) (number of patients = 10) or its vehicle (50 ml isotonic saline) (8 patients) over a period of 60 min, in supine position. Plasma and urinary DLS levels were measured at time -60, 0, 30, 60, 120, 180, and 240 min (infusion time from 0-60 min). During ANP infusion, plasma DLS levels decreased significantly (from 25.2 +/- 6.8 pg/ml at time 0 to 12.5 +/- 5.6 pg/ml at 60 min, p < 0.01), while urinary DLS excretion increased (from 60.5 +/- 26.1 pg/ml at time 0 to 246.3 +/- 34.2 pg/ml at 30 min, p < 0.0001). and 402.3 +/- 44.1 pg/ml at 60 min, p < 0.0001). After 3 h from the end of ANP infusion, both plasma and urinary DLS returned to baseline levels (20.5 +/- 14.4 pg/ml and 84.5 +/- 34.2 pg/ml, respectively). Taken together, our data show that ANP infusion significantly increases urinary DLS excretion, while decreasing its circulating levels. This phenomenon could explain the different response of ANP and DLS to some stimuli, such as acute volume expansion. In fact, the rapid increment of plasma ANP due to an acute increase of extracellular fluid volume might simultaneously inhibit the increase in circulating DLS levels by promoting the urinary excretion of this substance.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cardenolides; Digoxin; Enzyme Inhibitors; Heart Rate; Humans; Hypertension; Male; Middle Aged; Saponins; Sodium

1. Responses of adrenomedullin to acute and chronic salt loading were examined in normotensive and hypertensive subjects. 2. In the acute salt load study, isotonic saline (50 ml/kg for 1 h) was intravenously infused into nine normotensive subjects and 11 patients with essential hypertension. Plasma adrenomedullin was higher in hypertensive than in normotensive subjects but was unchanged by saline infusion in either the normotensive (before infusion, 2.4 +/- 0.2 fmol/ml; after infusion, 2.4 +/- 0.1 fmol/ml) or hypertensive (before infusion, 3.0 +/- 0.1 fmol/ml; after infusion, 2.9 +/- 0.2 fmol/ml) group, while renin was suppressed and atrial natriuretic peptide was markedly increased. Plasma endothelin was not affected either. 3. In the chronic salt load study, seven normotensive subjects and 23 patients with essential hypertension underwent two 7-day periods of 30 and 260 mmol/day sodium intake. Depending on the blood pressure change, 13 hypertensive subjects were classified as salt-resistant and 10 as salt-sensitive. Salt-sensitive hypertensive subjects had suppressed plasma renin activity even during low salt intake. Plasma adrenomedullin or endothelin were not affected by the salt intake changes in any group; however, the high salt intake increased atrial natriuretic peptide in all groups. 4. These data indicate that the circulating level of adrenomedullin is not changed by either acute or chronic salt loading in normotensive subjects and patients with essential hypertension.

Topics: Adrenomedullin; Adult; Aged; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Body Fluids; Drug Administration Schedule; Endothelins; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Peptides; Renin; Sodium Chloride; Sodium Chloride, Dietary

Many factors have been reported to stimulate the release of brain natriuretic peptide (BNP) as well as atrial natriuretic peptide (ANP). In hypertensive patients, however, little is known about whether these factors differ from those in normotensive subjects or if they are influenced by antihypertensive treatment. We measured the plasma concentrations of BNP and ANP in 12 hypertensive patients and examined the chronic effects of beta-adrenoceptor blockade on BNP secretion during exercise with a bicycle ergometer. The exercise raised both plasma BNP and ANP with concomitant increases in systolic blood pressure, heart rate (HR) and plasma norepinephrine (NE) and epinephrine (Epi) before and after treatment. Before treatment, the changes in ANP and BNP correlated with that in HR (p < 0.05). After treatment 4 wk of treatment, the change in ANP correlated with those in NE and Epi as well as HR. Multivariate regression analysis indicated that only NE was a significant stimulus for ANP secretion during the treatment period. As for BNP, HR was the only significant stimulant for its secretion both before and after treatment. In essential hypertension, beta-adrenergic receptor blockade affected the factors stimulating exercise-induced ANP release but not those stimulating BNP release. BNP release, therefore, seems to be stimulated by similar but distinct factors from those that stimulate ANP release.

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Bisoprolol; Blood Pressure; Body Mass Index; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Physical Exertion; Regression Analysis

Recently carperitide (synthetic human-atrial natriuretic peptide) in known to be useful for the care of acute heart failure. Stretch of the atrial wall has been suggested to be on one of the important factors involved in peptide release. The 8 patients were undertaken cardiac surgery. Carperitide was infused intravenously during postoperative period in these patients and the effects of carperitide were examined. Blood pressure (BP), central venous pressure (CVP), mean pulmonary arterial pressure (PA), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) were monitored by Swan-Ganz catheter, and urinary volume per body weight (UV/kg) were measured. The variables were determined before and after the intravenous infusion of carperitide at 0.1 to 0.2 microgram/kg/min. BP, CVP, PA, PCWP, SVR, and PVR were decreased, and CI and UV/kg were increased after administration of carperitide. These results suggest that carperitide is the useful agent for the postoperative care of cardiovascular surgery especially in the point of decreasing BP and increasing urination.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Coronary Artery Bypass; Diuretics; Heart Valve Prosthesis; Humans; Hypertension; Male; Peptide Fragments; Postoperative Care; Postoperative Complications

The etiology of late hypertension (LH) in pregnant women is still unknown. The purpose of this study was to measure the circulatory levels of endothelin-1,2 (ET-1,2), 6-keto-PGF1-alfa as a major metabolite of prostacyclin, and atrial natriuretic peptide (ANP) in the serum of pregnant women with LH, and in the serum of control healty pregnant women, and control healthy nonpregnant women.. The mean level of ET-1,2 among pregnant women with LH did not show any significant difference compared to control group. Serum 6-keto-PGF1-alfa levels was significantly higher (p < 0.001) in healthy pregnant women than in those of the pregnant women with LH and of healthy nonpregnant women. Serum ANP was significantly higher (p < 0.01) in the pregnant women with LH compared to healthy pregnant women and healthy nonpregnant women (p < 0.001). Among the women with LH there was no correlation between ET-1,2, 6-keto-PGF1-alfa and ANP.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atrial Natriuretic Factor; Endothelins; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular

Water immersion (WI) is followed by hypoxemia and haemodilution, and induces alterations in renal haemodynamics (increase of tubular sodium load). These facts justified the performance of studies which aimed to assess the influence of WI on EPO secretion. Serum EPO and atrial natriuretic peptide (ANP) concentration and plasma renin activity (PRA) were estimated in 18 patients with essential hypertension (EH) and in 9 healthy subjects (HS) before, after two hours of WI and two hours after discontinued WI. WI was followed by a significant increase of plasma volume and decrease of PRA which were of similar magnitude in both examined groups. Patients with EH showed significantly higher basal levels of serum EPO (66.7 +/- 11.4 mU/ml in EH vs 20.0 +/- 3.4 mU/ml in HS) and ANP (110.6 +/- 15.4 pg/ml in EH vs 75.6 +/- 8.2 pg/ml in HS). WI was followed by significant increase of both EPO (by 34.0 +/- 8.9 mU/ml in EH and 17.0 +/- 5.4 mU/ml in HS) and ANP (by 106.9 +/- 19.2 pg/ml in EH and 149.4 +/- 16.9 pg/ml in HS). Only in EH a significant correlation was found between serum EPO level and MAP and post-WI natriuresis respectively.. 1. Patients with EH are characterized by elevated basal serum levels of ANP and EPO. 2. Participation of the renin-angiotensin system and ANP in the regulation of EPO secretion could not be proven both in normotensive and hypertensive patients. 3. Involvement of EPO in the pathogenesis of EH seems to be likely.

Topics: Adult; Aged; Atrial Natriuretic Factor; Erythropoietin; Female; Humans; Hypertension; Immersion; Male; Middle Aged; Potassium; Renin; Renin-Angiotensin System; Sodium

To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM).. After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks -6, -4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations.. At week 12, the mean daily dose of enalapril was 35 +/- 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 +/- 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = -0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group.. In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.

Topics: Albuminuria; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Furosemide; Glycated Hemoglobin; Humans; Hypertension; Indapamide; Nifedipine; Placebos; Potassium; Regression Analysis; Renin; Sodium; Time Factors

Blood pressure responses to 1 week of low (20 mmol sodium/day) and high (300 mmol sodium/day) salt intake were investigated in a double-blind, randomized study in 46 white, nonobese subjects with essential hypertension (13 women, 33 men; mean age 45.3 +/- 2.2 years, age range 25 to 80 years). The individuals were classified as salt-sensitive when mean arterial blood pressure rose by at least 5 mm Hg during high salt intake, as salt-resistant when mean arterial blood pressure changed by less than 5 mm Hg, and as "counter-regulators" when mean arterial blood pressure fell by at least 5 mm Hg during the high salt diet. Mean arterial blood pressure of all subjects taken together increased from 101.9 +/- 1.4 mm Hg during salt restriction to 103.7 +/- 1.5 mm Hg (P < .05) during salt loading. Eleven subjects (23.9%) were classified as salt-sensitive, 27 (58.7%) as salt-resistant, and 8 (17.4%) as counter-regulators. Multiple regression analysis revealed that age, but not baseline blood pressure, sex, body mass index, or family history of hypertension contributed significantly to the change in blood pressure following the diets. Ten of the 11 salt-sensitive subjects were older than the median age of 45 years. In salt-sensitive, as compared to salt-resistant, hypertensive subjects, creatinine clearance was lower and plasma renin activity was suppressed at baseline as well as during low and high salt intake. In contrast, plasma concentrations of norepinephrine and atrial natriuretic peptide were elevated in salt-sensitive subjects. These differences between the groups appeared, at least partially, to be age-related.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Mass Index; Creatinine; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Regression Analysis; Renin; Sodium

To determine the major stimuli for the release of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), we measured their plasma concentrations in 14 normal subjects and 19 patients with essential hypertension during exercise with a bicycle ergometer. The plasma levels of both hormones at baseline were significantly higher in the hypertensive group than in the controls (p < 0.05). The exercise raised both the plasma BNP and ANP, with concomitant increases in systolic blood pressure (SBP), heart rate (HR) and plasma norepinephrine (NE) or epinephrine (Epi) in each group. In the controls the change in ANP correlated with those in SBP, HR and NE (p < 0.05), and similarly the change in BNP with those in SBP, HR, NE and Epi (p < 0.05). In multivariate regression analysis only NE was found to be a significant stimulus for ANP secretion, whereas SBP or Epi was related to BNP release. In the hypertensives the change in ANP correlated with those in HR and NE, but on multivariate regression analysis the change in ANP correlated only with that in HR. The change in BNP in the hypertensives correlated only with that in HR. These findings indicate that in normal subjects the exercise-induced release of BNP and ANP is more sensitive to a similar but slightly different sympathetic stimulus, whereas in hypertensives the major stimulus for the release of both hormones is heart rate, indicating that the mediators for BNP or ANP release are altered by some factors involved in hypertension.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Exercise Test; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Regression Analysis

To evaluate the antihypertensive efficacy of sinorphan, an orally active inhibitor of neutral endopeptidase EC 3.4.24.11.. The ability of sinorphan (100 mg twice a day) to lower blood pressure was compared with that of the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg twice a day) using a randomized-sequence, double-blind crossover design in 16 patients with essential hypertension. Each treatment was administered for 4 weeks and treatments were separated by a 3-week placebo period. At the end of the last phase of treatment sinorphan was combined with captopril for a further 4-week period. The changes in systolic (SBP) and diastolic blood pressure (DBP) were monitored using repeated ambulatory blood pressure monitoring.. When given as monotherapy for 4 weeks, neither sinorphan nor captopril significantly reduced the 24-h or the 14-h daytime mean SBP or DBP. However, a significant decrease in DBP was observed during the first 6 h after the morning administration of captopril. With sinorphan only a significant decrease in night-time SBP was found. With the combined therapy of sinorphan and captopril, significant decreases both in SBP and in DBP were observed, which were sustained over 24 h. After 4 weeks of sinorphan alone or in combination with captopril, no change in plasma atrial natriuretic peptide level was found. However, urinary cyclic GMP excretion increased transiently after administration of the neutral endopeptidase inhibitor.. Neutral endopeptidase inhibition with sinorphan has a limited effect on blood pressure in hypertensive patients when given alone. However, simultaneous neutral endopeptidase and ACE inhibition induces a synergistic effect, and might therefore represent an interesting new therapeutic approach to the treatment of essential hypertension.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cross-Over Studies; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Neprilysin; Protease Inhibitors; Thiorphan

Although atrial natriuretic peptide (ANP) levels are often elevated in low-renin hypertensives, the renal and hormonal effects of ANP infusion have never been evaluated in these patients. To address this topic, 27 lean nondiabetic men affected by uncomplicated essential hypertension were studied. Low-renin patients (n = 9, age 42 +/- 3 years) were defined as those individuals in balance on a low NaCl intake (10 mmol NaCl/day for 1 week) who had a plasma renin activity <0.30 ng angiotensin I/l/s, in both the supine and the upright positions. The remaining hypertensives (n = 18, age 41 +/- 4 years) were classified into the normal-renin group. Six age-matched healthy men (age 40 +/- 2 years) served as controls. After plasma renin activity determinations, both patients and controls were replaced on a normal NaCl intake (120 mmol NaCl/day). After 1 week, either ANP (99-126), at a dose (0.7 pmol/kg/min for 3 h) which is known to induce changes in plasma ANP confined to the range of normality, or its vehicle were infused at 1-week intervals, according to a randomized double-blind crossover design. At time 0, low-renin patients had significantly higher (p < 0.05) levels of plasma ANP (12.4 +/- 2.5 fmol/ml) than normal-renin patients (7.2 +/- 2.4 fmol/ ml) and normotensives (7.4 +/- 3.3 fmol/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Cross-Over Studies; Double-Blind Method; Glomerular Filtration Rate; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Natriuresis; Renin; Sodium, Dietary

To determine the effects of prior exercise and naloxone on haemodynamics, muscle sympathetic nerve activity, pituitary hormones and ambulatory blood pressure.. We studied 14 mild hypertensive and 14 normotensive subjects on two days. After baseline measurements, subjects were randomly allocated to vehicle or naloxone (0.4 mg/kg) 30 min before 45 min treadmill exercise.. In both groups blood pressure, stroke volume, and calf and total peripheral resistances were lower 1 h after exercise, whereas sympathetic activity was unchanged. In normotensive subjects naloxone abolished this calf vasodilation without altering muscle sympathetic nerve activity, and attenuated these haemodynamic aftereffects of exercise, implying a peripheral opioidergic mechanism. Naloxone had no haemodynamic effect in hypertensive subjects. In normotensives there was an inverse relationship between changes in blood pressure and sympathetic activity after vehicle and exercise. This was transformed by naloxone into a positive relationship (r = 0.69, P < 0.02) similar to that observed in hypertensives after vehicle and exercise. Naloxone did not alter the latter positive relationship. Naloxone altered exercise-induced changes in prolactin and luteinizing hormone, but only in normotensive males. In both groups ambulatory blood pressures and heart rates over 2 h after subjects left the laboratory were higher than the values recorded at baseline or 1 h after exercise, and were unaffected by naloxone.. The depressor effect of exercise is due to peripheral vasodilation, occurs in the absence of sympathetic withdrawal and is short-lived. Endogenous opioids, activated by running, participate in the haemodynamic, sympathoneural and pituitary hormone aftereffects of exercise in normotensive subjects, whereas in hypertensives these aftereffects of exercise are achieved through non-opioidergic mechanisms. These observations are consistent with the concept that activation of endogenous opioid systems by exercise is impaired in mild hypertension.

Topics: Adrenergic Fibers; Adult; Atrial Natriuretic Factor; Blood Pressure; Exercise; Female; Hemodynamics; Humans; Hypertension; Male; Muscle, Skeletal; Naloxone; Norepinephrine; Plasma Volume

Effects of nicardipine on endocrine functions were evaluated in 10 surgical patients who received surgeries under total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK). Plasma levels of norepinephrine (NE), epinephrine (E), plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (hANP) were measured following nicardipine injection during 30 minutes of intraoperative hypertension. When the systemic blood pressure exceeded 160 mmHg systolic and 95 mmHg diastolic for five minutes, 0.5 mg approximately 10 mg of nicardipine was administered for 30 minutes to maintain the systolic blood pressure below 160 mmHg. Following the injection of nicardipine a significant reduction by 20% in the mean systolic and diastolic pressure was observed. Mean heart rate increased by 5%, but the increase was not significant. Plasma NE increased significantly 1.7 time from the control level at 15 minute following the injection. Plasma levels of E, PRA, aldosterone and hANP showed no significant changes.

Topics: Adult; Aged; Aldosterone; Anesthesia, Intravenous; Atrial Natriuretic Factor; Catecholamines; Droperidol; Female; Fentanyl; Humans; Hypertension; Intraoperative Complications; Ketamine; Male; Middle Aged; Nicardipine; Renin

Ambulatory blood pressure monitoring (ABPM) has been shown to be more representative of blood pressure (BP) levels than casual BP measurements in adult patients treated by haemodialysis (HD). In this study we compared ABPM using the oscillometric SpaceLabs 90207 monitor with casual BP measurements in 35 paediatric patients [17 treated by peritoneal dialysis (PD) and 18 by HD]. Heart rate and plasma concentrations of atrial natriuretic peptide were also measured. No correlations were found between ABPM and causal BP measurements, except for systolic day-time BP in PD patients (r = 0.63). Seventy percent of PD and 33% of HD patients were regarded as hypertensive when evaluated by ABPM, while casual BP measurements demonstrated hypertension in 47% (P < 0.05) of PD patients and in 44% (NS) of HD patients. One-third of patients were reclassified by ABPM either from normotensive to hypertensive (7/19) or from hypertensive to normotensive (5/16). BP assessed by ABPM was higher in PD than in HD patients. The physiological decline of BP at night was significant and more pronounced in PD than in HD patients. In HD patients day-time BP did not differ between the 1st and the 2nd interdialytic day, but increased in the night hours before the following dialysis session. A positive correlation was found between day-time BP and pre-dialysis plasma atrial natriuretic peptide in both treatment groups. In conclusion this study demonstrates that casual BP recordings are not representative of average BP in dialysed paediatric patients. ABPM is useful in the diagnosis and treatment of hypertension in children with end-stage renal disease.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Child; Circadian Rhythm; Female; Heart Rate; Humans; Hypertension; Male; Peritoneal Dialysis; Renal Dialysis

Secretion of brain natriuretic peptide (BNP), a cardiac hormone, is accelerated via hypertrophied ventricles in experimental hypertension. The present study examined whether regression of left ventricular (LV) hypertrophy by long-term treatment with an angiotensin-converting enzyme inhibitor (ACEI) affects plasma BNP concentration in patients with essential hypertension.. Thirty-one hypertensive patients with LV hypertrophy were treated with ACEI (16 with enalapril; 15 with lisinopril) for 1 year. Serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of BNP and atrial natriuretic peptide (ANP).. ACEI therapy significantly reduced LV mass index at 6 months, and more so at 1 year. Septal and posterior wall thicknesses were also reduced. Plasma BNP and ANP were markedly elevated at study entry, but only BNP levels correlated with LV mass index. Both peptide levels declined after 6 months, and this decline was enhanced at 1 year. There was a close relation between BNP decline and LV mass index reduction overall and with enalapril and lisinopril separately. Changes in ANP and in LV mass index were not related.. Long-term ACEI therapy can reduce elevated plasma BNP. In this study, changes in BNP reflected the magnitude of regression of LVH. Plasma BNP may be a useful marker for LVH during antihypertensive therapy in patients with essential hypertension and LVH.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Lisinopril; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Treatment Outcome

The effects on blood pressure (BP) and heart rate (HR), at rest and during bicycle exercise, of the vascular selective calcium antagonist felodipine, the cardio-selective beta-blocker metoprolol, and of the two drugs in combination, were assessed in a double-blind, three-way cross-over study comprising 23 patients with essential, mild to moderate hypertension. All three treatment regimens were given to each patient in randomised order for 4 weeks after a 4 week placebo run-in period. Felodipine 10-20 mg daily, metoprolol 100-200 mg daily and the combination of felodipine 10-20 mg plus metoprolol 100 mg daily were all effective antihypertensive treatments both at rest and during exercise. The two drugs seemed to have additive effects and the effect on BP of the combination was greater than that of either drug given as monotherapy. The mean sitting BP was 148/103 mmHg at randomisation, after 4 weeks of placebo treatment, and 134/88, 134/94 and 121/84 mmHg, respectively, after 4 weeks' treatment with felodipine, metoprolol and the combination. Maximal exercise capacity was similar irrespective of treatment regimen, and the normal response to exercise BP and HR was maintained during all active treatments. Changes observed in volume regulatory hormones (PRA, aldosterone and ANP) were consistent with a direct tubular natriuretic-diuretic effect of felodipine and of beta-blocker attenuated release of renin. All treatment regimens were well tolerated and adverse events reported were usually mild and transient.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Exercise; Exercise Test; Felodipine; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Renin

Two groups of subjects (uraemic and control) were studied. The uraemic group consisted of 30 patients treated by HD (haemodialysis). The mean age was x +/- SD-35.4 +/- 8.4 years, duration of haemodialysis treatment 42.8 +/- 12.1 months, cuprophan dialyzers and acetate containing solution--35 mEq/l--were used, duration of HD-4 hours 3 times weekly, predialysis serum creatinine was 1060 +/- 218 mumol/l (12.8 +/- 2.5 mg%). The control group comprised 23 healthy subjects (mean age 33.0 +/- 8.0 years, serum creatinine level 88.4 +/- 14 mumol/l (1.0 +/- 0.16 mg%). In all examined subjects the following experimental protocol was used. Blood pressure (BP) was determined at about 8 a.m. after an overnight rest. Then blood samples were withdrawn for estimation of ANP, AVP, sodium and potassium, protein, osmolality and creatinine concentrations. Between 8 and 12 a.m. all examined uraemic subjects were dialysed. After each hour of dialysis BP was measured and blood samples were taken. ANP (Peninsula Lab. Kids.) and AVP (DRG) were measured using RIA method, and other biochemical parameters using routine methods. Plasma creatinine and plasma ANP levels significantly decreased, but AVP significantly increased after HD.. 1. In all uraemic subjects, plasma ANP and AVP levels were significantly higher than in control subjects; 2. During haemodialysis with ultrafiltration a significant increase AVP level and decrease ANP level was observed; 3. A significant correlation between ANP concentration and blood pressure may suggest participation of above mentioned hormone in pathogenesis of hypertension in patients with uraemia; 4. It's possible, in pathogenesis plasma AVP increase takes part plasma ANP decrease, too.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Vasopressins

It is generally accepted that the development of left ventricular hypertrophy (LVH) represents a multifactorial phenomenon that also involves neurohormonal mechanisms. This finding may account for the ability of angiotensin-converting enzyme inhibitors to induce faster and more complete reversal of LVH than that observed with other antihypertensive treatments. The sympathetic system is also involved in the genesis of hypertension-induced LVH. We assessed the effects of satisfactory long-term treatment with rilmenidine, a new oxazoline with a potent antihypertensive action, on cardiovascular structural abnormalities and cardiac endocrine function in hypertensive patients with left ventricular hypertrophy. Eleven patients underwent M-mode and two-dimensional Doppler echocardiography, peripheral pulsed Doppler flowmetry, determination of plasma atrial natriuretic factor [(ANF) pg/ml] and renin activity, and 24-h urine electrolyte excretion under control conditions, after 4 weeks of blood pressure normalization, after 1 year of satisfactory antihypertensive treatment and, finally, 4 weeks after therapy withdrawal. I.VH (g/m2 body surface area) was reversed after 1-year treatment (from 152 +/- 5 to 131 +/- 4, p < 0.05). One-year treatment induced an improvement in brachial artery compliance (cm4/dyne.10(7)) (from 0.92 +/- 0.06 to 1.16 +/- 0.08, p < 0.05) that persisted after withdrawal of treatment (1.17 +/- 0.06, p < 0.05). Plasma renin activity and urinary electrolyte excretion did not change throughout the study, whereas ANF remained unchanged after blood pressure normalization (48.4 +/- 6.2 versus 44.7 +/- 2.9, NS), fell after reversal of LVH (28.6 +/- 3.4, p < 0.05), and remained significantly lower than under control conditions after therapy withdrawal (27.5 +/- 2.9, p < 0.05). These results demonstrate that a satisfactory long-term antihypertensive treatment with rilmenidine is able to reverse cardiovascular structural changes and to restore cardiac endocrine function.

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Drug Administration Schedule; Electrolytes; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Oxazoles; Renin; Rilmenidine

Thirty men with essential hypertension were examined at three different levels of sodium intake, containing 135, 44 and 290 mmol sodium per day, respectively. Ten patients who increased their 24 hour mean ambulatory blood pressure 10% or more when going from low to high sodium intake were defined as salt sensitive, the others as salt resistant. The casual and 24 hour ambulatory blood pressure measurements defined partly different patients as salt sensitive. In multiple regression analysis, salt sensitivity was associated with an increase in diuresis during low sodium intake, demonstrating a dissociation between water and sodium excretion during salt depletion in the salt sensitive group. The change 24 hour ambulatory blood pressure during salt repletion was positively correlated to the increase in the atrial natriuretic peptide (p < 0.01), and inversely correlated to the plasma concentration of atrial natriuretic peptide after salt depletion (p < 0.01). No difference in plasma norepinephrine, renin, aldosterone, plasma volume, blood volume or 24 hour sodium excretion was found between salt sensitive and salt resistant subjects. We conclude that salt sensitivity is difficult to describe as an entity, but seems to be associated with lower levels of atrial natriuretic peptide and a different response to salt depletion.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Catecholamines; Circadian Rhythm; Diuresis; Humans; Hypertension; Male; Middle Aged; Natriuresis; Prospective Studies; Renin; Sodium Chloride, Dietary

The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.

Topics: Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Rate; Humans; Hypertension; Male; Methionine; Middle Aged; Neprilysin

We tested the hypothesis that overactivity of the renal and systemic renin-angiotensin system is important to the pathogenesis of hypertension in autosomal dominant polycystic kidney disease (ADPKD). Up to 21 normotensive subjects with ADPKD and creatinine clearance > 70 ml/min/1.73 m2 were compared to 12 unaffected controls from the same families. Blood pressure, serum chemistry, sodium excretion, plasma renin and serum aldosterone and atrial natriuretic peptide (ANP) levels were measured at baseline, after acute sodium depletion, and after chronic higher sodium intake with and without enalapril. Effective renal plasma flow was measured by paraaminohippurate clearance in the higher sodium state, before and during an intravenous infusion of angiotensin II at 3 ng/kg/min. This was to test whether, by analogy to non-modulating essential hypertension, renal blood flow would fall to a lesser extent in the ADPKD subjects. The groups were comparable at baseline apart from a higher supine mean arterial pressure in the ADPKD group (median 91 vs. 81 mm Hg, P = 0.002). There were no significant differences between ADPKD and control subjects in blood pressure or hormonal response to sodium depletion. During chronically higher sodium intake, serum ANP was significantly higher (median 130 vs. 81 ng/liter, P = 0.0006) and plasma renin tended to be higher (median 20.5 vs. 13.5, P = 0.08) in ADPKD than in control subjects. The ADPKD group had a higher renal vascular resistance (median 7420 vs. 5915 dyn.sec.cm-5, P = 0.009) before angiotensin, but tended to have a lower percentage rise in resistance during angiotensin (median 31.5 vs. 46, P = 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Models, Biological; Polycystic Kidney, Autosomal Dominant; Renal Circulation; Renal Plasma Flow, Effective; Renin-Angiotensin System; Sodium, Dietary; Vascular Resistance

To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity.. We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system.. We assessed plasma beta-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 micrograms/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction.. At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring.. Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Topics: Adult; Atrial Natriuretic Factor; beta-Endorphin; Disease Susceptibility; Dynorphins; Endorphins; Enkephalin, Methionine; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male; Naloxone; Norepinephrine; Opioid Peptides; Physical Exertion; Radioimmunoassay

To assess the efficacy and safety of different doses of the alpha-1 blocker terazosin on long-term therapy, 12 essential hypertensives (7 males, 5 females, aged 27-61) were investigated. The study was conducted according to the Latin square design and each patient underwent 4 periods of treatment with 2, 5, 10 mg/day terazosin and placebo, in a double-blind, randomized order. Each treatment lasted 4 weeks. In comparison to placebo, a fall in diastolic pressure was observed already with the 2 mg/daily dose, with a decrease > 10 mmHg in 7 patients (responders). Body weight increased in a dose dependent manner, while atrial natriuretic peptide, serum glucose and insulin during oral glucose tolerance test, total cholesterol, HDL and LDL cholesterol, triglycerides were unaffected. It is concluded that terazosin is effective and safe in essential hypertensives already at 2 mg daily dose. Further reduction in blood pressure at higher doses is likely to be counteracted by salt and water retention.

Topics: Adrenergic alpha-Antagonists; Adult; Atrial Natriuretic Factor; Blood Glucose; Double-Blind Method; Female; Humans; Hypertension; Insulin Resistance; Lipids; Male; Middle Aged; Prazosin

To examine the changes in plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and blood pressure in patients with essential hypertension on a low, normal and high sodium intake.. Twelve patients with mild-to-moderate essential hypertension were studied. Plasma, urinary and blood pressure measurements were made with the patients on their usual sodium intake, then on the fifth day of a low (10 mmol/day) and on the fifth day of a high (350 mmol/day) sodium intake, the sequence being allocated randomly.. Plasma levels of BNP and ANP increased significantly on the high sodium intake compared with when the patients were on their normal diet. The mean blood pressure on the high sodium intake was not significantly different from that with the patients on their normal diet. In contrast, plasma BNP and ANP decreased on the low sodium intake, but were not significantly different compared with when the patients were on their normal diet. However, there was a significant reduction in the mean blood pressure on the low sodium intake compared with when the patients were on their normal diet. Compared with the normal diet, BNP and ANP plasma levels showed similar percentage decreases on the low sodium intake and similar percentage increases on the high sodium intake.. These findings suggest that BNP and ANP are released in response to a common stimulus during changes in dietary sodium intake. The changes in plasma BNP and ANP observed with sodium restriction and sodium loading indicate the potential importance of BNP and ANP as a dual peptide system contributing to the maintenance of sodium balance and blood pressure regulation in patients with essential hypertension, during changes in dietary sodium intake.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Sodium

To examine whether the effect of atrial natriuretic peptide (ANP) on renal glomerular and tubular segmental handling of sodium in patients with essential hypertension is pressure dependent.. Part 1. The renal effects of a low-dose continuous infusion (10 ng kg-1 min-1) with ANP for 1 h were compared in 10 untreated essential hypertensives (EH) and 13 normotensive control subjects (CS). Part 2. The hypertensives were studied on another day with ANP infusion during preceding acute BP reduction with sodium nitroprusside infusion (NP). The results were compared with those obtained during infusion with ANP+placebo (Part 1).. Lithium clearance was used to estimate the proximal tubular reabsorption of sodium.. Part 1. Atrial natriuretic peptide caused an exaggerated increase in urinary sodium excretion (+102 vs. +38%: P < 0.05), fractional excretion of sodium (+80 vs. +37%: P < 0.05), and urinary output (+56 vs. +8.3%; P < 0.05) in EH compared with CS. Glomerular filtration rate and filtration fraction increased to the same degree in both groups. Absolute lithium clearance (CLi) increased and FELi tended to increase (P = 0.061) in EH, but these were unchanged in CS. The increase in plasma cyclic guanosine 5'-phosphate (cGMP) and urinary excretion of cGMP and the decrease in plasma aldosterone during ANP infusion were the same in the two groups. Part 2. During NP infusion the natriuresis caused by ANP in EH was reduced (+51 vs. +99%; P < 0.05). The relative changes in GFR, CLi, and FELi during ANP infusion were not affected by the preceding BP reduction with NP. Mean arterial pressure was reduced from 122 to 101 mmHg during NP infusion. The relative increase in sodium excretion in EH was significantly correlated to mean arterial pressure.. Low-dose ANP infusion causes an exaggerated natriuresis in untreated essential hypertensives due to a more pronounced reduction in tubular reabsorption. After BP reduction, the natriuresis induced by ANP in essential hypertensives is decreased, probably due to a less pronounced reduction in tubular reabsorption beyond the proximal tubules. We suggest that the enhanced natriuretic response to ANP in EH in secondary in some degree to the elevated systemic pressure.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Female; Humans; Hypertension; Infusions, Intravenous; Kidney; Kidney Function Tests; Male; Middle Aged; Natriuresis; Nitroprusside

A strong influence of urinary kallikrein excretion on the salt sensitivity of blood pressure has been recently suggested in normotensive patients. To evaluate the relationship between kallikrein and salt sensitivity in essential hypertension, active kallikrein excretion, plasma renin activity, atrial natriuretic peptide and aldosterone levels were evaluated in 37 male hypertensives (mean age 43.3 +/- 4.7 years) after two weeks on a normal NaCl diet (120 mmol NaCl per day). After kallikrein determination, salt sensitivity was assessed in a randomized cross-over double-blind fashion by evaluating the blood pressure response to a high (240 mmol NaCl per day for two weeks) and a low (40 mmol NaCl per day for 2 weeks) NaCl intake. Blood pressure changes were evaluated considering as baseline blood pressure the measurement taken at the end of the 2 weeks under normal NaCl intake. Patients were classified as salt sensitive when a diastolic blood pressure change of 10 mm Hg or more occurred after both periods of low and high NaCl intake. At the end of the assessment of salt sensitivity, 19 hypertensive patients (mean age 43.0 +/- 4.6 years) were resistant. The urinary excretion of active kallikrein was significantly lower (P < 0.0001) in salt sensitive (0.51 +/- 0.36 U/24 hr) than in salt resistant patients (1.28 +/- 0.48 U/24 hr). Also, plasma atrial natriuretic peptide levels were higher in salt sensitive than in salt resistant hypertensives (P < 0.02), and a significant correlation between urinary kallikrein and plasma atrial natriuretic peptide was demonstrated in salt sensitive hypertensives (r = -0.691, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Double-Blind Method; Humans; Hypertension; Kallikreins; Male; Middle Aged; Sodium Chloride, Dietary

In patients with essential hypertension, left ventricular hypertrophy (LVH) increases the risk for cardiovascular morbidity and mortality. Thus its reversal represents one of the principal end-points of antihypertensive treatment. We assessed the cardiovascular effects of 1-year antihypertensive treatment with rilmenidine (1 or 2 mg/day orally), a new oxazoline with a potent antihypertensive action that acts selectively through imidazoline-preferring receptors. In 11 hypertensive patients (mean age, 49 +/- 2 years) with LVH, we measured systemic hemodynamics, large artery compliance, cardiac anatomy, and endocrine function. Patients underwent M-mode and 2-dimensional echocardiography as well as Doppler and peripheral pulsed Doppler flowmetry, determination of plasma atrial natriuretic factor (ANF) levels and renin activity (PRA), and of 24-hour urinary electrolyte and creatinine excretion in control conditions (systolic/diastolic blood pressure, 148 +/- 3/102 +/- 1 mm Hg), 4 weeks after blood pressure normalization (131 +/- 2/84 +/- 2 mm Hg; p < 0.01), after 1 year of satisfactory antihypertensive treatment (142 +/- 3/90 +/- 1 mm Hg; p < 0.01) and, finally, 1 month after therapy withdrawal (155 +/- 3/106 +/- 2 mm Hg; difference not significant [NS]). One-year of rilmenidine treatment induced an improvement in brachial artery compliance (from 0.92 +/- 0.06 to 1.16 +/- 0.08 cm4/dyne; p < 0.05), which persisted after withdrawal of treatment (1.17 +/- 0.06 cm4/dyne; p < 0.05). LVH was reversed after 1 year of rilmenidine treatment (from 152 +/- 5 to 131 +/- 4 g/m2 body surface area; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Echocardiography; Female; Forearm; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Oxazoles; Renin; Rilmenidine; Vascular Resistance

To evaluate the influence of atrial natriuretic factor (ANF) infusion on circulating prorenin, 20 essential hypertensive males, aged between 40 and 60 years, were studied. After 2 weeks under normal sodium intake (120 mmol NaCl per day), patients were randomly assigned to receive either ANF (0.01 fmol/Kg/min) (n.12 patients) or its vehicle (50 mL of isotonic saline) (n.8 patients) over a period of 60 minutes. Blood samples for plasma renin activity (PRA), prorenin and aldosterone (PAC) were taken at time -60, 0, 20, 40, 60, 120, 180, 240 minutes (infusion time: from 0 to 60 minutes). PRA and PAC decreased during the ANF infusion (PRA: from 0.33 +/- 0.05 ng/L/s at time 0 to 0.10 +/- 0.06 ng/L/s at 60 minutes, p < 0.0001; PAC: from 389.2 +/- 99.8 pmol/L at time 0 to 148.7 +/- 44.3 pmol/L at 60 minutes, p < 0.0001), while returned immediately to baseline levels after the infusion was stopped (PRA: 0.37 +/- 0.11 ng/L/s at 180 minutes, PAC: 251.6 +/- 72.1 pmol/L at time 180 minutes). On the contrary, plasma prorenin increased during ANF infusion (from 1.66 +/- 0.58 ng/L/s at time 0 to 2.44 +/- 0.72 ng/L/s at 60 minutes, p < 0.05), and returned to baseline levels after the end of the infusion (1.86 +/- 0.83 ng/L/s at 180 minutes). These data indicate that ANF infusion may alter only the circulating levels of active renin, without affecting plasma prorenin secretion.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Enzyme Precursors; Heart Rate; Humans; Hypertension; Male; Middle Aged; Renin; Sodium

The role of cardiac extrinsic innervation in the regulation of sodium balance and blood pressure is controversial.. We performed a double-blind study of endocrine and blood pressure responses to 5 days of low- (LS, 10 mmol/d) and 5 days of high- (350 mmol/d) sodium intake in 12 cardiac transplant recipients, 12 matched healthy subjects, and 12 matched subjects with untreated essential hypertension. In transplant recipients on low sodium, supine blood pressure was 137/94 +/- 8/4 (mean +/- SEM) mm Hg and plasma atrial natriuretic peptide (ANP) was 59.3 +/- 6.3 pg/mL; on high sodium, blood pressure was 148/97 +/- 5/3 mmHg (P < .05 for systolic pressure versus LS), and ANP was 94.3 +/- 10.6 pg/mL (P < .01 versus LS), respectively. Plasma ANP for those on each diet was significantly higher in the cardiac transplant recipients than in healthy or hypertensive controls; relative changes in plasma ANP in changing from low- to high-sodium diet were similar in each group. Urinary sodium excretion by the fifth day of each diet was similar in each group. Suppression of plasma renin activity and aldosterone by high-sodium diet was blunted in cardiac transplant recipients compared with healthy subjects (respectively, plasma renin activity: 1.41 +/- 0.30 versus 0.68 +/- 0.21 ng.mL-1 x h-1, P < .05; aldosterone: 391 +/- 35 versus 166 +/- 21 pmol/L, P < .05).. These results suggest that extensive denervation of the heart does not result in major abnormalities in regulation of large changes in sodium intake and that intact cardiac innervation is not required for plasma ANP responses to altered sodium intake. Blood pressure after cardiac transplantation is sensitive to reduced sodium intake.

Topics: Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Female; Heart; Heart Transplantation; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Sodium; Sodium, Dietary; Sympathetic Nervous System; Vagus Nerve; Water-Electrolyte Balance

To evaluate the influence of salt-sensitivity on the plasma insulin and glucose response to infusion of ANP, we studied 22 men with essential hypertension, who were between 40 and 60 years old. After 1 month under normal Na+ intake (120 mmol Na+ per day), patients were randomly assigned to receive either ANP (0.04 micrograms.kg-1.min-1) (n = 15) or vehicle (50 ml saline) (n = 7) over a 60-min period, while in the supine position. Plasma insulin and glucose were measured at time -60, 0, 20, 40, 60, 120, 180, 240 min. Ten days after ANP infusion, blood pressure sensitivity to changes in dietary salt intake was assessed according to a randomized double-blind crossover protocol. Patients were classified into two groups either salt-sensitive (n = 8) or salt-resistant (n = 7). Our results showed that plasma insulin and glucose did not change during ANP infusion in both groups. However, both plasma insulin (from 75.6 +/- 45.1 pmol/l at 60 min to 121.2 +2- 48.6 pmol/l at 240 min, p < 0.05 vs time 0) and glucose levels (from 4.86 +/- 0.73 mmol/l at 60 min to 6.56 +/- 1.03 mmol/l at 240 min, p < 0.01 vs time 0) rose after discontinuation of ANP in salt-sensitive patients, but did not change at all in salt-resistant patients. In conclusion, this randomized vehicle-controlled study demonstrates that plasma insulin and glucose levels increase in salt-sensitive hypertensive patients after the infusion of ANP. The increase of plasma insulin levels observed after ANP discontinuation, if occurring under physiologic conditions, could influence the blood pressure sensitivity to dietary Na+ intake.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Double-Blind Method; Heart Rate; Humans; Hyperglycemia; Hyperinsulinism; Hypertension; Infusions, Intravenous; Insulin; Male; Middle Aged; Sodium Chloride, Dietary

Plasma concentrations of atrial natriuretic factor (ANF) have been reported to be unchanged or increased in patients with essential hypertension. Head out of water immersion (HOI) in a thermoneutral bath induces diuresis and natriuresis, an increase in plasma ANF, and reductions in plasma renin activity and aldosterone concentrations. HOI was used in this study to stimulate the secretion of ANF, and compare its release in patients with essential hypertension (EH) (n = 14) and normotensive subjects (n = 13). Renal function changes induced by HOI were also monitored. HOI that lasted 2 h was compared with a control-seated period in each subject. Blood pressure was significantly reduced (P < .05) in normotensive controls from 112 +/- 3/74 +/- 2 to 100 +/- 3/61 +/- 2 mm Hg, and in patients with EH from 137 +/- 4/93 +/- 3 to 123 +/- 3/78 +/- 2 mm Hg. Plasma levels of ANF increased significantly (P < .05) in both groups from 5.9 +/- 1.3 to 16.3 +/- 3 pmol/L in normotensive controls and from 6.0 +/- 0.9 to 13.2 +/- 2.5 pmol/L in patients with EH. Plasma cyclic guanosine monophosphate concentrations increased more (P < .05) in the patients with EH (3.9 +/- 0.4 to 6.1 +/- 0.5 nmol/L) than in controls (3.4 +/- 0.3 to 4.8 +/- 0.4 nmol/L), whereas plasma renin activity levels decreased in controls (2.29 +/- 0.58 to 1.63 +/- 0.55 ng/mL/h) and to a greater degree in patients with EH (1.62 +/- 0.52 to 0.77 +/- 0.19 ng/mL/h, P < .05) by HOI.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Cell Count; Blood Pressure; Cyclic GMP; Heart Rate; Hormones; Humans; Hypertension; Immersion; Kidney; Kidney Function Tests; Male; Middle Aged; Natriuresis; Renal Circulation

Fourteen subjects with untreated essential hypertension were subjected to 2-h water immersion (WI) study. They were then randomly assigned to two distinct oral antihypertensive regimens with either calcium-channel blocker nifedipine (group 1, n = 7) or the angiotensin-converting enzyme (ACE) inhibitor lisinopril (group 2, n = 7). Three months later, a WI study identical to the first was repeated in the same hypertensive subjects. In group 1, treatment with nifedipine gastrointestinal therapeutic system (30 mg daily) significantly enhanced the natriuretic response to volume expansion by WI (peak value 405 +/- 82 mumol/min during WI plus nifedipine vs. 291 +/- 52 mumol/min during WI alone, p < 0.05). In group 2, treatment with lisinopril (20 mg daily) was associated with a blunted natriuretic response to volume expansion by WI (peak value 189 +/- 54 mumol/min during WI plus lisinopril vs. 320 +/- 53 mumol/min during WI alone; p < 0.025). A significant direct correlation between urinary sodium excretion (delta UNa V) and mean arterial pressure (delta MAP) was noted during WI plus nifedipine. Each long-term drug treatment was associated with a decrease in BP and hormonal changes of the same magnitude. Our data suggest that calcium antagonists could act as "diuretic agents" capable of counteracting the antinatriuretic effect of reduced renal perfusion pressure.

Topics: Adult; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Calcium Channel Blockers; Dipeptides; Extracellular Space; Female; Hemodynamics; Humans; Hypertension; Immersion; Lisinopril; Male; Middle Aged; Natriuresis; Nifedipine; Potassium; Renin

Recent studies showed that supplementation of a large dose of fish oil is effective in lowering blood pressure. Whether supplementation of a low dose of fish oil is also effective in lowering blood pressure is controversial. The present study evaluates the hemodynamic and humoral effects of low-dose dietary fish oil supplementation in patients with mild hypertension. Eleven patients with mild hypertension were given 3 g/day of n-3 polyunsaturated fatty acids for 6 week. Twenty-four hour blood pressure monitoring and humoral parameters were recorded before and during fish oil treatment. In five patients, blood pressure response to angiotensin II (AII) infusion (1, 2, 3, 6, 9 ng/kg/min) was also recorded before and during treatment. Casual mean arterial pressure was unchanged (111 +/- 1 mm Hg v 109 +/- 3 mm Hg; P = NS). Average 24-h mean arterial pressure (MAP) also did not change during fish oil treatment (98 +/- 2 mm Hg v 99 +/- 3 mm Hg; P = NS). Fish oil supplementation did not attenuate the vascular reactivity to AII infusion. Maximal MAP following AII infusion (9 ng/kg/min) was 128 +/- 5 mm Hg before and 129 +/- 7 mm Hg during fish oil treatment (P = NS). Plasma levels of norepinephrine, renin activity, aldosterone, and atrial natriuretic peptide remained unchanged during treatment. Plasma levels of total cholesterol slightly increased from 200 +/- 10 mg/dL to 211 +/- 9 mg/dL (P < .05), but plasma levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitors; Female; Fish Oils; Hemodynamics; Humans; Hypertension; Lipids; Male; Middle Aged; Neurotransmitter Agents; Norepinephrine; Renin

The paper presents concentrations of atrial sodium-uretic hormone (AH) in the plasma of hypertensive subjects during a hypertensive crisis and in stable blood pressure, in healthy subjects (12, 19 and 7 females, respectively). AH levels were the highest in hypertensives in the crisis. Mean AH concentrations in the crisis and short after the pressure normalization did not differ much. Mechanisms of these phenomena are discussed, relations between AH levels, clinical and hemodynamic characteristics of hypertensive crises are considered.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Female; Hemodynamics; Humans; Hypertension; Middle Aged

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Drug Resistance; Humans; Hypertension; Kallikreins; Male; Middle Aged; Sodium Chloride, Dietary

Topics: Adult; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Female; Humans; Hypertension; Indans; Male; Middle Aged; Neprilysin; Propionates

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Double-Blind Method; Humans; Hypertension; Indans; Male; Methionine; Middle Aged; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Posture; Propionates; Time Factors

Blood pressure responses to 1 week of low-salt (20 mmol sodium/d) and high-salt (300 mmol sodium/d) intake were investigated in a single-blind randomized study in 163 white, nonobese normotensive subjects (65 women and 98 men; mean age, 38 +/- 1.2 years). The individuals were classified as salt sensitive when mean arterial blood pressure rose by at least 5 mm Hg during high-salt intake, as salt resistant when mean arterial blood pressure changed by less than 5 mm Hg, and as "counterregulator" when mean arterial blood pressure fell by at least 5 mm Hg during the high-salt diet. Reexamination of 31 subjects showed that this approach to the testing of salt sensitivity was reliable and reproducible. Thirty subjects (18.4%) were classified as salt sensitive, 108 (66.3%) as salt resistant, and 25 (15.3%) as counterregulators. Multiple regression analysis revealed that age, body weight, and family history of hypertension contributed significantly to the change in blood pressure after the diets. Salt sensitivity was more frequent in older subjects and in those with a positive family history of hypertension. An increase in blood pressure after salt restriction was more likely in younger individuals and in those with a negative family history of hypertension. Plasma renin activity and plasma aldosterone concentrations were lower in salt-sensitive compared with salt-resistant and counterregulating subjects. The rise in plasma renin activity during salt restriction was most pronounced in counterregulating subjects. Plasma norepinephrine concentrations were not different among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Family Health; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Renin; Reproducibility of Results; Single-Blind Method; Sodium Chloride; Sodium, Dietary

To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension.. Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies.. Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-four-hour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic GMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides.. Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Heart Rate; Humans; Hypertension; Indans; Kidney; Male; Middle Aged; Natriuresis; Neprilysin; Propionates; Time Factors

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Guanosine Monophosphate; Heart Rate; Humans; Hypertension; Male; Methionine; Middle Aged; Natriuresis; Neprilysin; Norepinephrine; Renin-Angiotensin System; Sodium; Sympathetic Nervous System; Time Factors

To investigate a possible involvement of endogenous erythropoietin (EPO) in the salt sensitivity of blood pressure in essential hypertensive (EHT) patients, plasma EPO concentrations were measured during different salt intakes in 14 patients with EHT. All patients were given low salt (34 mmol NaCl/day) and high salt (342 mmol NaCl/day) diet of 7 days each. The plasma EPO concentrations were significantly higher on the high salt diet than those of low salt diet (23.5 +/- 1.9 v 18.7 +/- 1.8 mIU/ml, mean +/- SD, P < .05). The percentage change of plasma EPO concentration with salt loading correlated positively with hematocrit (Ht) at high salt diet (r = -0.62, P < .02) and tended to be correlated with plasma hemoglobin at high salt diet (r = 0.52, P < .10). These results suggest that the secretion of EPO is increased in response to hemodilution caused by the salt loading and the increased EPO concentration in plasma which may contribute to the increase in blood pressure through an expansion of total blood volume due to an enhanced red cell generation in combination with salt and water retentions.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Osmolar Concentration; Renin; Sodium Chloride

Effects of caffeine on ambulatory blood pressure, heart rate, renin-angiotensin system, and ANP were studied in patients treated for mild to moderate hypertension in a randomized, double-blind, placebo-controlled, cross-over trial comparing 2 weeks of caffeine-free diet with 2 weeks of regular coffee use. Twenty-three patients (13 men; aged 28-74 years) with treated, mild to moderate essential hypertension and a regular intake of 3-4 cups of coffee daily completed the study. Mean 24-h, day- or night-time ambulatory blood pressure and heart rate were not different between regimens. Nor were there any effects on the renin-angiotensin system while ANP was significantly increased during caffeine intake. Compliance of the dietary regimen was excellent as assessed by serum caffeine concentration measurements. We conclude that habitual coffee drinking did not influence the 24-h blood pressure profiles or cardiovascular hormones in treated hypertensives.

Topics: Adult; Aged; Ambulatory Care; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Determination; Caffeine; Coffee; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System

Abnormalities in the response of atrial natriuretic factor (ANF) to volume expansion have been reported in hypertensive-prone animals and men as well as in hypertensive patients undergoing ACE-inhibition. To investigate some of the mechanisms affecting ANF release in borderline hypertensive patients (BHT) we have studied 16 subjects by assessing their neuro-humoral and hemodynamic response to a two-hour isotonic i.v. NaCl infusion carried out during short-term administration of either placebo or captopril. ACE-inhibition increased baseline venous distensibility (VV30:1.4 vs 1.6 ml/100 ml; p < .05) and reduced the prompt (45') ANF response to saline loading (10.3 +/- 13 vs 42.7 +/- 15%; p < .05)) without affecting the overall ANF release (120':92 +/- 25 vs 65.8 +/- 20%; NS)). A significant pressor increase in response to NaCl loading was observed exclusively after ACE-inhibition (SBP: 5.2 +/- 2 vs 2.4 +/- 1%; p < .05--DBP: 7.1 +/- 3 vs 2 +/- 3%; p < .025) and occurred along with a peripheral arterial and venous constriction and with an increase in plasma levels of an endogeneous Na+/K+ATPase inhibitor (8.8 +/- 4 vs -2 +/- 4%; p < .05). We conclude that the ANF response to saline infusion is delayed by ACE-inhibition in borderline hypertensives. The abnormalities observed in ANF response could follow the changes in peripheral venous distensibility and contribute to the pressor and neuro-humoral derangements described in borderline hypertensives during volume expansion.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Captopril; Humans; Hypertension; Renin; Sodium Chloride; Vascular Resistance; Vasodilation

We investigated whether short-term changes in serum insulin would effect a reduction of arterial pressure in subjects with therapy-resistant essential hypertension. Six patients were examined twice with a 3 week's interval in a single-blind cross-over design with euglycemic insulin clamps (A and B). A reduction of endogenous serum insulin was achieved by continuous infusion of 50 microgram octreoid (a somatostatin analogue) per hour. During clamp A low dose insulin infusion (5 mU/m2/min) was given, whereas during clamp B insulin was infused at a rate of 60 mU/m2/min. Preceding each clamp a standard drug therapy was given for one week (50 mg atenolol+ 30 mg furosemide per day). During clamp A plasma insulin was reduced from 21.4 +/- 7.5 to 10.8 +/- 1.2 mU/l (p < 0.01) whereas plasma insulin rose during clamp B from 20.0 +/- 7.5 to 99.0 +/- 17.2 mU/l (p < 0.001). The mean arterial blood pressure did not decrease during clamp A (low dose insulin infusion). There was an increased natriuresis during the high-insulin clamp (70 vs. 38 mmol, p = 0.13), but no difference in arterial pressure between the clamps. The results do not support the notion that high insulin levels contribute to hypertension in therapy resistant hypertensive patients by any direct and immediate mechanism.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; C-Peptide; Drug Resistance; Humans; Hypertension; Insulin; Male; Middle Aged; Natriuresis; Octreotide; Renin

The effect of three calcium entry blockers--verapamil, nifedipine and felodipine--on diuresis, natriuresis, the renin-aldosterone axis, and atrial natriuretic peptide (ANP) levels was studied in 30 previously untreated patients with mild to moderate essential hypertension. All three blockers produced significant antihypertensive effects after 2 and after 24 h. Heart rate tended to decrease, but did not change significantly after verapamil, but increased significantly 1-2 h after nifedipine and felodipine. Plasma renin activity (PRA) did not change significantly with any treatment, and plasma aldosterone decreased with all three agents. ANP levels did not change significantly after verapamil, but increased significantly after nifedipine and felodipine. There was a significant positive correlation between the maximal change in ANP level and urinary sodium after nifedipine and felodipine. The increase in urinary sodium after verapamil was not significant. The role of the direct renal effect of calcium entry blockers in their persistent natriuretic action is discussed, as well as their short-term enhancement of ANP levels, which may account for the initial diuretic and natriuretic effects seen with this class of dihydropiridines.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Diuretics; Felodipine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuresis; Nifedipine; Renin; Renin-Angiotensin System; Verapamil

To evaluate the influence of salt sensitivity on the blood pressure response to oral indomethacin treatment, we studied 35 hospitalized essential hypertensive patients (24 men and 11 women, aged from 40 to 55 years). During a normal NaCl intake (120 mmol Na+ per day), patients were assigned to receive in a randomized double-blind fashion either 200 mg indomethacin (25 patients) or placebo (10 patients) for 5 days. Two weeks after the interruption of indomethacin treatment, during which the normal NaCl intake was continued, salt sensitivity was assessed by giving each patient a high (220 mmol Na+ per day for 10 days) and then a low (20 mmol Na+ per day for 10 days) NaCl diet. Blood pressure changes were evaluated, and the measurement taken at the end of the 2 weeks under normal sodium intake was considered baseline blood pressure. Patients were classified as salt sensitive when a diastolic blood pressure change of 10 mm Hg or more occurred after both low and high periods of sodium intake. In salt-resistant patients treated with indomethacin (n = 12, nine men and three women, mean age 50.5 +/- 3.7 years), neither blood pressure (systolic blood pressure from 150.8 +/- 11.2 to 154.6 +/- 9.3 mm Hg, NS; diastolic blood pressure from 99.3 +/- 2.1 to 101.1 +/- 4.4 mm Hg, NS) nor the urinary Na+ excretion (from 108.1 +/- 20.9 to 97.9 +/- 9.1 mmol/24 hr, NS) was significantly affected by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclooxygenase Inhibitors; Diastole; Double-Blind Method; Drug Resistance; Female; Humans; Hypertension; Indomethacin; Male; Middle Aged; Sodium Chloride; Systole

The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dioxolanes; Dipeptides; Double-Blind Method; Epinephrine; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuresis; Neprilysin; Norepinephrine; Renin-Angiotensin System

Candoxatril (UK79,300) is an orally available inhibitor of the neutral endopeptidase (E.C.3.4.24.11) which degrades atrial natriuretic factor (ANF). This study was designed to establish initial safety and efficacy data in essential hypertension for this novel class of drug.. A prospective, double-blind, placebo-controlled, single-dose comparison of candoxatril with placebo in a crossover manner. Three doses of candoxatril (10, 50 and 200 mg) were used, with four subjects at each dose level.. The Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow, UK (a hospital clinical research unit).. Twelve patients with untreated essential hypertension. Diastolic blood pressure was greater than 95 mmHg on three separate occasions before entry to the study.. Candoxatril or matching placebo was administered orally in the fasting state. Serial measurements of urinary volume and electrolyte excretion were taken (on each hour, urine volume was replaced with an equivalent volume of water by mouth). Blood pressure and heart rate were recorded for 12 h after drug administration and serial blood samples were taken for measurement of plasma ANF and neurohormone concentrations.. Urine volume and electrolyte concentration; blood pressure; heart rate; plasma atrial natriuretic factor.. Plasma ANF concentrations rose significantly in all patients within 2 h of candoxatril administration compared with placebo although peak and integrated ANF levels were similar at all three doses. A significant natriuresis was only seen after 200 mg candoxatril, with a greater cumulative urine sodium excretion over 12 h compared with placebo; this was associated with a greater diuresis over 12 h compared with placebo. After a single oral dose of candoxatril, blood pressure and heart rate remained unchanged.. Candoxatril in a single dose caused no adverse effects in essential hypertension. The drug caused a rise in basal ANF levels at all doses, but natriuresis was only seen with the highest dose used. No change in blood pressure was recorded after acute dosing, and the results of chronic studies with this compound are awaited. Oral inhibitors of ANF degradation may have therapeutic potential in cardiovascular disorders.

Topics: Administration, Oral; Adult; Analysis of Variance; Antihypertensive Agents; Atrial Natriuretic Factor; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Indans; Male; Natriuresis; Neprilysin; Propionates

(1) To compare urinary guanosine 3',5' cyclic monophosphate (cyclic GMP) excretion between normotensive subjects and essential hypertensive patients; (2) to determine the influence of changes in sodium intake on urinary cyclic GMP excretion in response to the neutral endopeptidase inhibitor candoxatril in essential hypertensives.. (1) Twenty-five normotensive subjects and 25 patients with established essential hypertension not on treatment; (2) Single oral dose of candoxatril in eight patients with essential hypertension after equilibration on a low- or high-sodium diet in a placebo-controlled, double-blind, randomized, crossover study.. Blood pressure was measured by ultrasound sphygmomanometry. Atrial natriuretic peptide (ANP) and urinary cyclic GMP were measured by radioimmunoassay. Group comparisons were made using unpaired t-tests and two-way analysis of variance.. Plasma ANP was significantly raised in patients with essential hypertension compared with the normotensive group, but there was no difference in urinary cyclic GMP excretion. Plasma ANP increased significantly on the high- compared with low-sodium diet. After candoxatril, there were significant diet-related increases in plasma ANP and urinary sodium excretion up to 6 h after drug administration. There were similar increases in urinary cyclic GMP excretion on both diets, but there were no consistent differences in this excretion between the low- and high-sodium diets.. These observations not only point to the importance of ANP-cyclic GMP coupling as a determinant of the natriuretic response to endopeptidase inhibition, but also suggest that the excretion of urinary cyclic GMP can be influenced by other factors in addition to circulating ANP.

Topics: Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Hypertension; Indans; Male; Middle Aged; Natriuresis; Neprilysin; Propionates; Sodium, Dietary

To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension.. Double-blind, placebo-controlled, parallel-group study of 28 days' duration.. Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK).. Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period.. Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules.. Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment.. When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo.. Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Female; Humans; Hypertension; Indans; Male; Middle Aged; Neprilysin; Propionates

The effects of manidipine (10 mg/day for 7 days) on the renal hemodynamics and vasoactive humoral factors were examined in 6 adults with diabetes mellitus (DM). Mean duration of DM was 9 +/- 2 years; serum creatinine concentration was 0.9 +/- 0.04 mg/dL. Plasma endothelin-1 (ET-1) concentration was 5.4 +/- 0.7 pg/mL before manidipine, compared with 1.9 +/- 0.2 pg/mL in 14 controls (p = 0.03%). Systolic and mean blood pressure decreased significantly during treatment without changes in glomerular filtration rate, renal plasma flow, or filtration fraction. Renal vascular resistance tended to decrease and fractional excretion of sodium significantly increased from 1.35 +/- 0.27% to 2.06 +/- 0.47 (p = 2.96%). ET-1 significantly decreased from 5.4 +/- 0.7 pg/mL to 3.5 +/- 0.6 (p = 2.95%), while plasma angiotensin II, atrial natriuretic factor, urinary excretion rate of ET-1, and albumin excretion rate did not change. Manidipine lowers blood pressure without adversely affecting renal function in diabetic patients. Manidipine, which lowers ET-1, may protect from progressive renal injury in diabetics.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Dihydropyridines; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Renal Circulation

The purpose of this study was to assess the effects of the calcium entry blocker nicardipine and alpha human atrial natriuretic peptide (hANP) on antihypertensive and diuretic activity in hypertensive surgical patients. The site of the diuretic actions of these drugs along the nephron were also investigated by measuring the excretion rate of inorganic phosphate (PO4). Hypertension during gastrectomy was treated by increasing the concentration of enflurane, by nicardipine infusion (0.5-2.0 micrograms.kg-1 x min-1), or by hANP infusion (0.05-0.2 microgram.kg-1 x min-1) under general anaesthesia. Enflurane, nicardipine and hANP all decreased arterial pressure to the same extent. Urine flow, Na and PO4 excretion increased following the administration of nicardipine or hANP. Fractional distal reabsorption of sodium was suppressed from 89.7 +/- 2.8% to 82.1 +/- 5.0% by the hANP, but not by the nicardipine infusion. Creatinine clearance was increased by hANP infusion, but did not change in the nicardipine group. It is concluded that nicardipine and hANP can be used safely for the treatment of hypertension during surgery. Both drugs induced phosphaturic diuresis, but the site of action of the two drugs on the nephron may be different. Phosphate reabsorption is considered to occur largely in the renal proximal tubule, so that its appearance in the urine in increased quantities without the change of renal circulation in the nicardipine group suggests a proximal tubular action of this drug. However, the site of action of hANP in the kidney was not determined because GFR increased and distal sodium reabsorption was suppressed due to the drug infusion.

Topics: Absorption; Adult; Aged; Anesthesia, Inhalation; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Enflurane; Female; Gastrectomy; Humans; Hypertension; Infusions, Intravenous; Intraoperative Complications; Kidney Tubules; Male; Middle Aged; Nephrons; Nicardipine; Phosphates; Sodium

In this pilot study we investigated the effects of a 4-h infusion of atrial natriuretic peptide (8-33 Met ANP) on hemodynamic, renal, and hormonal parameters in 12 patients with hypertension. Either 8-33 ANP in 5% mannitol (0.7 microgram/min [eight patients] and 1.05 micrograms/min [four patients]) or placebo (5% mannitol) was infused for 4 h on 2 consecutive days in a randomized double-blind crossover design. The plasma levels of ANP were not significantly different between the two doses of ANP and therefore the results from the two doses were combined. Plasma ANP increased from 61 +/- 24 pg/mL to 291 +/- 55 pg/mL after 2 h and to 288 +/- 40 pg/mL after 4 h. ANP caused a significant lowering of systolic blood pressure after 2 h of infusion from 148 +/- 5 mm Hg to 142 +/- 5 mm Hg (P less than .05) and to 128 +/- 6 after 4 h (P less than .01). Two hours after discontinuation of the infusion, systolic blood pressure was 126 +/- 6 and 135 +/- 7 mm Hg 4 h after the end of the infusion. Diastolic blood pressure did not change. Heart rate increased from 69 +/- 3 beats/min to 74 +/- 3 beats/min after 4 h and to 78 +/- 4 beats/min 2 h after termination of the infusion. Cardiac output did not change significantly. Urinary sodium and chloride increased significantly but creatinine clearance did not change. Plasma aldosterone decreased after 2 h of ANP infusion from 9.8 +/- 1.7 ng/dL to 6.7 +/- 0.9 ng/dL (P less than .01) and to 6.5 +/- 1.2 ng/dL after 4 h (P less than .05). Plasma renin activity decreased from 0.81 +/- 0.1 ng angiotensin I/mL/h to 0.57 +/- 0.1 after 2 h of infusion (P less than .05). There were no significant changes in plasma catecholamines or arginine vasopressin. Two patients developed severe hypotension and bradycardia and one of them had a sinus pause of 7.4 sec associated with loss of consciousness. Neither of these two patients had a significant increase in plasma catecholamines in response to the severe hypotension, suggesting that ANP may have inhibited their sympathetic response and increased their sensitivity to vagal cardioinhibitory reflexes. In conclusion, infusion of ANP in hypertensive patients causes prolonged lowering of systolic blood pressure with no change in diastolic pressure and cardiac output.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Bradycardia; Diuresis; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Hypotension; Infusions, Intravenous; Male; Middle Aged; Renin

The effects of long-term sodium restriction on plasma atrial natriuretic factor (ANF) concentrations, and the role of baseline plasma ANF concentration as an indicator of changes in haemodynamics and left ventricular hypertrophy during this treatment were studied in 40 middle-aged previously untreated mildly to moderately hypertensive men and women in a 6-month controlled randomized study. The main emphasis of the treatment programme was to reduce daily sodium intake to less than 70 mmol. Mean sodium excretion decreased from 148 +/- 74 mmol 24 h-1 to 79 +/- 71 mmol 24 h-1 in the treatment group, but remained unchanged in the control group (173 +/- 68 mmol 24 h-1 vs. 186 +/- 62 mmol 24 h-1; P less than 0.01 for the difference in changes between the groups). Mean plasma ANF concentrations in the treatment group were 52.4 +/- 20.7 (median 50) pg ml-1 at baseline and 38.7 +/- 26.3 (median 42) pg ml-1 at 6 months, and the corresponding values in the control group were 55.5 +/- 20.5 (median 50) pg ml-1 and 46.1 +/- 32.4 (median 50) pg ml-1, respectively (P = NS for the difference in changes). The ANF concentration decreased from 70 +/- 14 pg ml-1 to 32 +/- 26 pg ml-1 in treated subjects with a high baseline plasma ANF concentration (greater than 50 pg ml-1), but increased from 37 +/- 11 pg ml-1 to 45 +/- 27 pg ml-1 in subjects with a low baseline plasma ANF concentration (less than or equal to 50 pg ml-1) (difference in changes P less than 0.001). Compared with treated subjects with low baseline plasma ANF levels and with controls, treated subjects with high baseline plasma ANF levels showed a decrease (P less than 0.05) in interventricular septal and left posterior wall thicknesses, in relative wall thickness, and in peripheral resistance. These results suggest that in mildly to moderately hypertensive subjects long-term sodium restriction decreases high plasma ANF concentrations concomitantly with regression of concentric left ventricular hypertrophy, probably as a result of changes in haemodynamics.

Topics: Adult; Atrial Natriuretic Factor; Cardiomegaly; Diet, Sodium-Restricted; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Time Factors; Vascular Resistance

Various beta-blockers possessing similar antihypertensive potency have been found to differ widely with regard to their influence on blood pressure-regulating factors such as cardiac output and plasma levels of renin or norepinephrine. Recently, beta-blocker-induced stimulation of circulating atrial natriuretic factor (ANF) was reported. Blood pressure is determined not only by levels of vasoconstrictive factors but also by tissue reactivity. To investigate these aspects, we assessed the cardiovascular responsiveness to norepinephrine and angiotensin II, plasma levels of catecholamines, angiotensin II, ANF and aldosterone and the body sodium-blood volume state of 15 patients with essential hypertension (mean age +/- s.e.m., 42 +/- 3 years) and 12 normal control subjects (41 +/- 5 years), first on placebo and then after 4 weeks of intervention with carteolol, a non-selective beta-adrenergic antagonist with intrinsic sympathomimetic activity. Compared with placebo, carteolol decreased resting plasma norepinephrine in both groups while plasma norepinephrine-blood pressure response curves were shifted to the left, their slopes increased and norepinephrine pressor doses decreased (P less than 0.05 to less than 0.001). Chronotropic responses to isoproterenol were abolished but negative chronotropic responses to a norepinephrine-induced 20 mmHg rise in diastolic blood pressure were unaltered. Plasma norepinephrine clearance in the supine position was slightly decreased in hypertensive and unchanged in normal subjects. Supine and upright blood pressure was lowered (P less than 0.05 to 0.001) in the hypertensive while upright systolic blood pressure only decreased in the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Carteolol; Female; Humans; Hypertension; Isoproterenol; Male; Norepinephrine; Receptors, Adrenergic, beta; Single-Blind Method

Circulating organ-specific autoantibodies are serological markers of destruction or impairment of the relevant endocrine tissue cells and may be associated with abnormal hormone levels with or without clinical evidence of overt disease. We sought organ-specific cardiac antibodies in patients with autoimmune polyendocrinopathy because of increasing evidence that the heart has endocrine characteristics (secretion of atrial natriuretic peptide [ANP] and other peptide hormones). Serum samples from 166 patients with polyendocrinopathy, 80 with autoimmunity confined to one gland, and 200 healthy blood donors were tested for these antibodies by means of immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. Organ-specific cardiac antibodies were detected in significantly more of the patients with autoimmune polyendocrinopathy (28 [17%]) than of those with autoimmunity confined to one gland (1 [1%]) or of normal subjects (7 [3.5%]; p = 0.0001). Among the patients with autoimmune polyendocrinopathy, the prevalence of systemic hypertension was higher in those with cardiac autoantibodies than in those without (5/28 [18%] vs 2/80 [3%]; p = 0.01); the same was true for a family history of hypertension (11 [42%] vs 5 [7%]; p = 0.0001). There were no significant differences in mean basal or stimulated ANP concentrations between patients with or without antibodies or between patients and controls. 5 of the 22 antibody-positive patients had ANP concentrations outside the normal range, but these disturbances were not associated with systemic hypertension or a family history of the disorder. Patients with autoimmune polyendocrinopathy can have organ-specific cardiac antibodies, which may represent novel serological markers for an autoimmune form of systemic hypertension in the absence of overt cardiac disease.

Topics: Adult; Aged; Atrial Natriuretic Factor; Autoantibodies; Autoimmune Diseases; Biomarkers; Coronary Disease; Diabetes Mellitus, Type 1; Family Health; Female; Humans; Hypertension; Immunoglobulin G; Male; Middle Aged; Myocardium; Organ Specificity; Thyroid Diseases

The rate of erythrocyte Li-Na countertransport and cellular Na+ and K+ contents have been determined in normotensive (NT) and hypertensive (HT, essential hypertension) subjects in the presence and absence of atrial natriuretic peptide (ANP). The rate of Li-Na countertransport was significantly higher in erythrocytes of HT subjects, while the Na+ and K+ contents were not different between the NT and HT groups. We found that ANP (10(-9) and 10(-7) M) had no effect on either the rate of Li-Na countertransport or the cellular Na+ and K+ contents. Since ANP does not influence erythrocyte Na pump and Na-K-Cl cotransport, our results suggest that the Na transport systems of human erythrocytes do not respond to ANP and this lack of response in Li-Na countertransport is independent of the status of hypertension. These findings are consistent with the view that the rate of Li-Na countertransport of erythrocytes may serve as a useful genetic marker for essential hypertension in Chinese. However, the erythrocyte transport systems cannot provide further differentiation utilizing ANP response for essential hypertension.

Topics: Adult; Antiporters; Atrial Natriuretic Factor; Biomarkers; Carrier Proteins; China; Erythrocytes; Humans; Hypertension; Middle Aged; Potassium

In a randomized study in 26 elderly patients with mild essential hypertension, acute effects of alpha- and beta-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an alpha 1-adrenergic blocker), atenolol (a cardioselective beta-adrenergic blocker), or carteolol (a nonselective beta-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise, but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by beta-blockers, especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an alpha-blocker and a nonselective beta-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.

Topics: Aged; Atenolol; Atrial Natriuretic Factor; Carteolol; Exercise; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Prazosin; Ventricular Function, Left

A number of studies show that atrial natriuretic peptide (ANP) raises renal sodium excretion with a concomitant increase in glomerular filtration rate (GFR) in both experimental animals and normal humans. Studies using indirect evaluation of GFR have provided less consistent results in hypertensive patients. We studied the effects of intravenously administered (iv) alpha-human ANP on GFR in patients with hypertension by a radionuclide technique using technetium 99m diethylenetriaminepenta-acetic acid. In six patients (ANP group), GFR was determined under control conditions, during iv ANP (initial bolus of 0.5 micrograms/kg followed by a 21-min maintenance infusion at 0.05 micrograms.kg-1.min-1) and during a recovery phase. In six other patients (control group), GFR was determined under control conditions, during saline iv infusion and during recovery. The two groups did not differ with respect to age, sex, basal blood pressure, heart rate or GFR. In the ANP group, the infusion of the peptide induced a significant decrease of mean blood pressure (from 133 +/- 5 to 120 +/- 5 mmHg, P less than 0.01), no change in heart rate and a significant increase in GFR (from 104 +/- 4 to 125 +/- 5 ml/min, P less than 0.01). During recovery, blood pressure, heart rate and GFR were not different from the values recorded under control conditions. No changes in blood pressure, heart rate or GFR (from 106 +/- 5 to 108 +/- 5 ml/min, n.s.) were detected during saline infusion in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Radioisotope Renography; Sensitivity and Specificity; Technetium Tc 99m Pentetate

The short-term effects of atenolol and nifedipine on plasma levels of atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) were studied in two groups of patients with uncomplicated essential hypertension. Urinary catecholamines, and sodium and potassium excretion were also studied. A group of 20 patients with hypertension, after a wash-out period of at least 10 days, was randomly subdivided into two protocol therapy subgroups. One group (six men and four women) received atenolol (100 mg/d), and the other group (six men and four women) received nifedipine (30 mg/d). Circulating plasma levels of ANP, PRA, and PA were determined by radioimmunoassay, and other variables were determined by routine laboratory techniques before therapy and at day 3 and day 7 after the treatment began. Arterial blood pressure and heart rate were monitored during the study. Both drugs reduced arterial blood pressure (P less than .001) significantly. The atenolol therapy decreased heart rate (P less than .001), increased plasma ANP levels and urinary catecholamine excretion, and decreased PRA and circulating PA levels. Nifedipine treatment did not modify plasma ANP values, whereas it increased PRA and PA circulating levels and urinary catecholamine excretion. No differences were shown for urinary volume, urinary sodium, and potassium excretions during the two different treatments. These findings suggest that the increased plasma ANP levels could contribute to the antihypertensive effects of the beta-adrenoreceptor blockers, by a reduction in PRA and PA levels and a vasodilatative effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atenolol; Atrial Natriuretic Factor; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Renin

Urinary excretion of sodium and calcium was examined in hypertensive (n = 8) and normotensive (n = 7) subjects following infusion of 2% saline at a rate of 11 mL/min for 90 min. The urinary sodium excretion was 204 +/- 38 (mean +/- SEM) muEq/min in normotensives and 233 +/- 28 muEq/min in hypertensives before infusion of saline and increased maximally to 499 +/- 114 muEq/min (P less than .05) and to 928 +/- 68 muEq/min (P less than .01), respectively, after saline infusion. In normotensives, urinary calcium excretion did not change significantly; however, in hypertensives excretion increased markedly (P less than .01) from 6.1 +/- 0.7 muEq/min to 12.3 +/- 1.6 muEq/min. Plasma atrial natriuretic peptide (ANP) levels increased significantly (P less than .05) in both groups. Serum ionized calcium and plasma parathyroid hormone (PTH) levels did not change significantly. The increments of urinary sodium and calcium and of plasma ANP, as well as the preinfusion plasma PTH level, were significantly (P less than .05) higher in hypertensives than in normotensives. The present study showed that exaggerated natriuresis was accompanied by hypercalcinuria and an enhanced rise in plasma ANP in hypertensives. Basal levels of plasma PTH were elevated in hypertensives. The calcium deficiency may be attributable to a close relationship between urinary sodium and calcium, and causally related to the disturbance of sodium and volume homeostasis in hypertension, which results in exaggerated natriuresis.

Topics: Adult; Atrial Natriuretic Factor; Blood Proteins; Calcium; Female; Homeostasis; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Parathyroid Hormone; Renin-Angiotensin System; Sodium; Sodium Chloride

To elucidate the effect of natriuretic and antinatriuretic factors on the excretion of an intravenous sodium load, we observed the natriuretic responses of 12 patients with essential hypertension (EHT) and 7 age- and sex-matched normotensive (NT) subjects following the intravenous administration of 1500 mL of normal saline over a 3 h period. After saline infusion, both groups showed increases in urinary sodium excretion (UNaV). The increases in glomerular filtration rate (GFR), atrial natriuretic peptide (ANP) and urinary dopamine excretion (UDAV) and the suppression of plasma renin activity (PRA) were similar in both groups. However, no significant change in blood pressure (BP) was seen in either group. Since significant negative linear correlations between the basal level of PRA and percent change in UNaV or GFR were seen only in EHT, we observed the influence of suppressing the renin-angiotensin system with a converting enzyme inhibitor. After a 7 day treatment with enalapril, GFR and UNaV in EHT after saline infusion were comparable to data obtained in the absence of enalapril, despite a reduction in preexpansion BP. Furthermore, a significant positive correlation between the basal BP and the percent increase in UNaV was seen among EHT after enalapril treatment. These results suggest that the state of the renin-angiotensin system is important in renal sodium excretion in EHT.

Topics: Adult; Aging; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatine; Dopamine; Enalapril; Female; Glomerular Filtration Rate; Hematocrit; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Natriuresis; Norepinephrine; Prostaglandins; Regional Blood Flow; Renin; Renin-Angiotensin System; Sodium Chloride; Water-Electrolyte Balance

Sixteen patients with severe hypertension were treated for 1 year with extended release nifedipine, during which time serial changes in left ventricular mass index and associated alterations in left ventricular systolic function, left ventricular filling, plasma renin activity, atrial natriuretic peptide and catecholamines were evaluated. Mean seated blood pressure (+/- SE) was significantly reduced from 200 +/- 8/122 +/- 3 to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. After 6 months, left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thickness were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001), respectively. The prevalence of left ventricular hypertrophy decreased from 63% to 25%. Left ventricular fractional shortening increased from 34 +/- 2% to 41 +/- 3% (p less than 0.05) and the relation between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction, the peak velocity of early filling increased from 57 +/- 3 to 63 +/- 4 cm/s (p = 0.07), peak velocity of late filling did not change and the ratio of late to early peak left ventricular filling velocity significantly decreased (p less than 0.05). Plasma atrial natriuretic peptide levels, markedly elevated at entry, decreased from 70 +/- 15 to 41 +/- 8 pg/ml at 1 year (p less than 0.05). Plasma renin activity and catecholamine levels were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Cardiomegaly; Chlorthalidone; Delayed-Action Preparations; Echocardiography; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Norepinephrine; Renin; Time Factors; Ventricular Function, Left

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Captopril; Humans; Hypertension; Nifedipine

The effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin (rHuEPO) on blood pressure was evaluated in 20 patients with renal failure on continuous ambulatory peritoneal dialysis. The two groups of patients were commenced on a 16-week course of twice weekly rHuEPO by either the subcutaneous (10 patients) or the intraperitoneal route (10 patients). One patient in the latter group was subsequently excluded because of operation and transfusion. The hemoglobulin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl after subcutaneous rHuEPO treatment (p less than 0.01) at an average dose of 84 +/- 9 U/kg body weight/week. For the intraperitoneal group, despite a higher average rHuEPO dosage (133 +/- 7 U/kg body weight/week), the hemoglobin level was not significantly altered (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p less than 0.05). During the 16-week period of rHuEPO therapy, an increase in antihypertensive therapy was required more frequently in patients in the intraperitoneal group but the difference between groups failed to reach statistical significance. There was no conclusive evidence that the rise in hematocrit was an independent precipitant of hypertension. Patients who were hypertensive prior to rHuEPO therapy appeared most susceptible to the pressor effects in that 8 of 11 treated hypertensive patients required more intensive antihypertensive treatment during EPO administration whereas none of the untreated patients developed hypertension during the study (Fisher's exact test, p = 0.007). Plasma levels of the vasoactive hormones, atrial natriuretic peptide (ANP), plasma renin activity (PRA), and endothelin (ET) remained unchanged during both subcutaneous and intraperitoneal rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Endothelins; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Injections, Intraperitoneal; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renin; Time Factors

To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine.. Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days' duration.. Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake, patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter, patients continued to receive nifedipine GITS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied.. Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal.. Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Topics: Aged; Aldosterone; Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Delayed-Action Preparations; Diuresis; Female; Humans; Hypertension; Male; Middle Aged; Natriuresis; Nifedipine; Pulse; Renin; Single-Blind Method; Sodium

1. We examined the effects of metoclopramide (MCP: 10 mg i.v.) on plasma atrial natriuretic peptide (ANP) and aldosterone concentrations (PAC) and the effect of ANP on MCP-induced PAC in four patients with primary glomerular diseases and seven patients with essential hypertension. 2. MCP injection caused no significant changes in plasma ANP. MCP produced a marked increase in PAC without a significant change in plasma renin activity. 3. The increase in PAC induced by MCP injection was markedly attenuated when preceded by the infusion of ANP (25 ng/kg per min). 4. These results suggest that the dopaminergic D2 mechanism is not involved in the regulation of ANP secretion and that ANP modulates the dopaminergic regulation of aldosterone secretion.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Female; Glomerulonephritis; Heart Rate; Humans; Hypertension; Male; Metoclopramide; Middle Aged

Cromakalim, a novel potassium channel-activating drug, was administered for a 3-day period in eight untreated hospitalized patients with established hypertension. The fixed and single dose of 1.5 mg/day produced a significant reduction in systolic and diastolic blood pressure with a small increase in heart rate. Glomerular filtration rate was unchanged and effective renal plasma flow was slightly increased with a concomitant small decrease in filtration fraction and in renal vascular resistance. No significant change was observed in urinary prostaglandin (PG)E2, PGF2 alpha, and thromboxane B2, while 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) rose from 189 +/- 6 to 368 +/- 115 ng/day. The renal excretion of 6-keto-PGF1 alpha correlates with the modification observed in renal plasma flow, suggesting a compensatory role for prostacylin in preserving renal hemodynamics during antihypertensive therapy with cromakalim.

Topics: Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Benzopyrans; Blood Pressure; Chlorides; Cromakalim; Dinoprost; Dinoprostone; Eicosanoids; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Potassium; Prostaglandins; Pyrroles; Regional Blood Flow; Renin-Angiotensin System; Sodium; Thromboxane B2; Time Factors; Vascular Resistance

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.

Topics: Adult; Aldosterone; Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Creatine; Heart Rate; Hematocrit; Humans; Hypertension; Indans; Middle Aged; Neprilysin; Potassium; Propionates; Renin; Sodium; Sodium, Dietary

In order to evaluate the effects of atrial natriuretic factor (ANF) infusion on plasma insulin (IRI) in hypertension, 32 essential hypertensives (aged 40 to 62 years) were studied. After 1 week of pharmacologic washout under normal sodium intake (120 mEq of Na+/day), patients were randomly assigned to receive either ANF (0.04 micrograms/kg/min) or its vehicle (50 mL of isotonic saline) over a 60-min period in supine position. Plasma IRI and glucose were measured at -60, 0, 20, 40, 60, 120, 180, and 240 min (infusion time: from 0 to 60 min). Plasma levels of IRI and glucose did not change significantly during ANF infusion. On the contrary, after ANF discontinuation plasma IRI rose from levels of 13.5 +/- 6.4 microU/mL at 60 min to values of 20.1 +/- 11.3 microU/mL at 240 min (P less than .0001 v time 0). Plasma glucose showed a similar behavior, increasing from values of 100.4 +/- 5.0 mg/dL at 60 min to values of 120.0 +/- 5.1 mg/dL at 240 min (P less than .02 v time 0). Our findings suggest that ANF did not influence insulin release in hypertensives. The increase of plasma glucose and IRI observed after ANF discontinuation could be due to the relapse of sympathetic activity, suppressed during ANF infusion.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Insulin; Male; Middle Aged; Potassium; Sodium

The effects of chlorthalidone (mean dose 25 mg/day), metoprolol (mean dose 200 mg/day) or their combination (logroton) on blood pressure, lipids, lipoproteins and circulating atrial natriuretic factor (ANF) were evaluated in a controlled trial of 42-week duration in 33 hypertensive patients. There was a significant reduction in mean arterial pressure after chlorthalidone and metoprolol treatments. This effect was more pronounced with the chlorthalidone/metoprolol combination (logroton). There were no significant changes in mean ANF levels after any drug regimen, although a tendency to increase was observed after six weeks of treatment with metoprolol. Both chlorthalidone and metoprolol as monotherapy increased the total triglycerides. This effect was less pronounced with logroton. During metoprolol treatment, HDL cholesterol decreased significantly, whereas VLDL-C increased. When combined drug therapy was administered, the unfavorable effects on HDL-C were partially blunted and VLDL-C returned to baseline. LDL-cholesterol did not change significantly during any drug regimen nor did the ratio of LDL-C/HDL-C. Logroton significantly increased the VLDL apo B levels in patients who had received chlorthalidone as monotherapy but had no effect in patients already treated with metoprolol. Neither treatment had a significant influence on the ratio of LDL-C/B. There were no serious adverse events reported throughout the study. It is concluded that logroton may be an effective combination therapy that produces less adverse effects on lipid and lipoprotein metabolism than chlorthalidone or metoprolol monotherapies.

Topics: Atrial Natriuretic Factor; Blood Pressure; Chlorthalidone; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Double-Blind Method; Drug Combinations; Female; Humans; Hypertension; Lipids; Lipoproteins; Male; Metoprolol; Single-Blind Method

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Dietary Carbohydrates; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Renin

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Cyclic GMP; Dopamine; Glomerular Filtration Rate; Glomerulonephritis; Heart Rate; Humans; Hypertension; Kidney; Middle Aged; Proteinuria; Urination

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Topics: Atenolol; Atrial Natriuretic Factor; Blood Pressure; Diltiazem; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Heart Conduction System; Heart Rate; Humans; Hypertension

The effects of ketanserin, 40 mg/day (KE40) and 80 mg/day (KE80) on mean arterial pressure, lipids, lipoproteins, and circulating atrial natriuretic factor (ANF) were investigated in a 24-week controlled study in 29 patients suffering from mild to moderate hypertension. A significant decrease in mean arterial pressure (MAP) was observed after 18 weeks of therapy, accompanied by a 64% (P less than .05) and 80% (P less than .02) increase in circulating ANF levels with KE40 and KE80, respectively. There were no significant changes in mean total cholesterol, triglycerides, or cholesterol of the high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL) fractions. There was a significant increase in the mean apo B levels and consequently a slight but statistically significant decrease in the ratio of LDL C/B. It is concluded that both doses of KE are effective for monotherapy of mild to moderate essential hypertension. The drug sharply increases circulating ANF levels without significantly altering the plasma lipids. In contrast, by increasing the apolipoprotein B content of the LDL fraction, the beneficial cardiovascular effect of a lowered blood pressure may be partly blunted.

Topics: Atrial Natriuretic Factor; Blood Pressure; Clinical Trials as Topic; Drug Evaluation; Humans; Hypertension; Ketanserin; Lipids; Lipoproteins; Random Allocation

Eighteen patients with non-insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double-blind, randomised, cross-over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.

Topics: Aged; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Renin

The antihypertensive effect of the calcium-antagonist verapamil was investigated in two groups of patients, adult hypertensives (AH, less than 65 years of age) and elderly hypertensives (EH, greater than 65 years of age), who were treated with 240 mg p.o. sustained-release (SR) verapamil for 4 months. Arterial blood pressure was significantly reduced in both groups: the responders' rate was 65% in the AH group and 82% in the EG group. The heart rate was slightly but not significantly reduced. An improvement in cardiac haemodynamics was observed [cardiac index (CI), from 3.00 +/- 0.51 to 3.25 +/- 0.83 ml min-1 m-2 in AH and from 2.35 +/- 1.08 to 3.04 +/- 0.86 ml min-1 m-2 in EG]. We also evaluated the plasma concentrations of atrial natriuretic peptide (ANP) before and after treatment; ANP levels increased significantly only in the EH group. No serious side effects occurred. In conclusion, verapamil SR provided effective and well-tolerated antihypertensive treatment in both adult and elderly patients.

Topics: Age Factors; Aged; Atrial Natriuretic Factor; Blood Pressure; Delayed-Action Preparations; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Time Factors; Verapamil

In a double-blind, placebo-controlled cross-over study, the plasma atrial natriuretic peptide (ANP) levels of nine young and ten elderly hypertensive patients were compared after placebo and after treatment with 120 mg verapamil given three times daily over 4 weeks. During placebo, plasma ANP levels proved to be higher in elderly patients than in young subjects. Chronic treatment with verapamil induced a rise in ANP levels in both young and elderly patients with hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Humans; Hypertension; Middle Aged; Time Factors; Verapamil

We studied, under outpatient conditions, nine patients with autosomal dominant polycystic kidney disease who were hypertensive on their usual diet, and nine normotensive healthy probands. The subjects were examined in random order on the 7th day after equilibration on a low-sodium diet (20 mmol/day) and again on the 7th day after equilibration on the same diet but with added sodium to yield a final intake of 200 mmol/day (or vice versa). Blood pressure was monitored non-invasively for 2 h at 4-min intervals using an automatic system. In healthy probands, mean arterial pressure (MAP) was similar on the low- and the high-sodium diets (92.7 versus 91.9 mmHg). In hypertensive patients, a significant (P less than 0.02) increase in mean MAP (107.2 versus 111.2 mmHg) and in systolic blood pressure (140.6 versus 148.7 mmHg) was observed irrespective of whether the glomerular filtration rate (GFR) was normal or reduced. The natriuresis pressure curve showed an upward shift (resetting) and a positive slope (sodium sensitivity). Patients with a reduced GFR as shown by inulin clearance differed from probands and patients with a normal GFR, by showing greater proportional changes in GFR and body weight. In hypertensive patients, atrial natriuretic factor (ANF) levels were higher at baseline and showed an exaggerated response to sodium loading. Changes in angiotensin II (Ang II) or in Ang II binding sites on platelets were similar in patients and controls and changed appropriately with the sodium intake. These data show a resetting of the natriuresis-blood pressure relationship and an increased blood pressure sensitivity to sodium in hypertensive patients with adult, dominant, polycystic kidney disease.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Natriuresis; Polycystic Kidney Diseases; Receptors, Angiotensin; Sodium, Dietary

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF [human ANF-(99-126)] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8 +/- 2.0 mmol (mean +/- SEM) sodium more than during the time-matched placebo phase natriuresis (p less than 0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p less than 0.001) placebo values. Plasma renin activity (0.4 +/- 0.05 vs. 0.9 +/- 0.12 nmol/l/hr, p less than 0.0001) and aldosterone concentrations (102 +/- 4 vs. 184 +/- 47 pmol/l, p less than 0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268 +/- 17 vs. 439 +/- 35 pg/ml, p less than 0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Hormones; Humans; Hypertension; Kidney; Male; Natriuresis; Reference Values

Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations d

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Hematocrit; Hormones; Humans; Hypertension; Infusions, Intravenous; Magnesium; Middle Aged; Natriuresis; Pulmonary Artery; Vascular Resistance

1. To study the anti-hypertensive effects of atrial natriuretic peptide (ANP), eight patients with mild to moderate essential hypertension, on no treatment, were infused with alpha-human ANP (102-126) (37 pmol min-1 kg-1) or placebo for 60 min and observed for a further 4 h on the fifth day of low and high sodium diets in a randomized, cross-over study. 2. Plasma ANP levels increased over 30-fold into the high pathophysiological range during ANP infusion, but had returned to control values by 60 min after the end of infusion. With ANP infusion, there was a large decrease in supine blood pressure which was similar on both the low and high sodium intakes and was maximal 20-40 min after completion of the infusion. These reductions in blood pressure were sustained for a further 4 h after the end of ANP infusion and for 3 h after plasma ANP levels had returned to control values. 3. Maximal urinary sodium excretion increased 10-fold on the low sodium diet (negative sodium balance 20 mmol) and threefold on the high sodium diet (negative sodium balance 30 mmol) during ANP infusion; however, during the 4 h after infusion, urinary sodium excretion was below placebo values. During ANP infusion, packed cell volume increased significantly on both diets but returned to control values by 4 h after the end of infusion. 4. There were no significant changes in plasma renin activity compared with placebo during or after ANP infusion. However, plasma aldosterone was significantly greater than placebo values after the end of ANP infusion on both low and high sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Diet, Sodium-Restricted; Female; Heart Rate; Hematocrit; Humans; Hypertension; Male; Middle Aged; Renin; Sodium; Sodium, Dietary

To see whether the acute natriuretic effect of nifedipine is accompanied by changes in atrial natriuretic peptide levels, a group of eight hypertensive patients were studied. After at least a week of constant sodium intake, placebo or nifedipine (10 mg s.I.) were administered and blood pressure, heart rate, plasma renin activity, plasma aldosterone and atrial natriuretic peptide plasma levels, urinary sodium, urinary volume and creatinine clearance were monitored for 2 hours. While placebo did not induce changes in any of the above parameters, nifedipine administration was followed by a significant decrease in blood pressure and an increase in urinary sodium, urinary volume and creatinine clearance; these changes were accompanied by a significant rise in atrial natriuretic peptide levels from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 pg/ml and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 minutes, respectively. In conclusion, our data do not rule out the possibility that atrial natriuretic peptide participates in the nifedipine-induced increase in sodium and water excretion.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Heart Rate; Humans; Hypertension; Middle Aged; Nifedipine; Potassium; Radioimmunoassay; Renin; Sodium

To test whether dopaminergic mechanisms can modulate the humoral and renal effects of atrial natriuretic factor (ANF), seven untreated, mildly hypertensive patients without complications were given a placebo (saline for 60 min) followed by a low dose of ANF (0.005 microgram/kg per min), or D-sulpiride (0.05 mg/kg per min), a specific dopamine-1 antagonist, or ANF + D-sulpiride at the same doses, for 60 min. The sequence of the three treatments was random, with a 72-h interval between treatments. The ANF infusion, which increased plasma ANF within the physiological range, significantly increased urinary sodium excretion, fractional sodium excretion and haematocrit; it reduced plasma aldosterone and tended to reduce plasma renin activity without changing blood pressure, the heart rate, renal plasma flow or the glomerular filtration rate. D-Sulpiride, when given alone, significantly increased mean blood pressure and reduced absolute and fractional sodium excretion without changing the heart rate, glomerular filtration rate, renal plasma flow, haematocrit, plasma renin activity or plasma aldosterone. When infused with D-sulpiride, ANF did not change absolute or fractional sodium excretion or haematocrit. This study provides evidence that dopaminergic mechanisms play a role in the natriuretic and plasma volume effects of a synthetic human ANF analogue infused at a low dose in patients with essential hypertension.

Topics: Adult; Atrial Natriuretic Factor; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuresis; Receptors, Dopamine; Sulpiride

Dilevalol, an agent that combines nonselective beta-blocking and beta 2-mediated vasodilating properties, was compared with placebo in 16 subjects with moderate hypertension in a double-blind crossover study. Dilevalol or a placebo was administered intravenously in bolus injections of 25, 50, and 50 mg at 15-minute intervals. Fifteen minutes after a cumulative dose of 125 mg, the blood pressure was lowered by 11/9 mm Hg, compared with 2/1 mm Hg after placebo (p less than 0.01 between groups for systolic and diastolic blood pressure), an effect that persisted for at least 105 minutes. Standing systolic blood pressure was also lowered in dilevalol-treated patients without orthostatic symptoms. No significant effects on heart rate were noted. Fifteen minutes after the last dose of dilevalol, plasma norepinephrine levels increased from a baseline of 200 +/- 24 to 495 +/- 44 pg/ml (p less than 0.01), compared with a nonsignificant rise from 262 +/- 21 to 306 +/- 28 pg/ml with placebo vehicle. Dilevalol also increased alpha-human atrial natriuretic factor by 5.4 pg/ml, compared with 0.5 pg/ml after placebo (p less than 0.01 between groups). Plasma renin activity and plasma epinephrine, aldosterone, and cyclic guanosine monophosphate levels were unchanged by dilevalol. There were no significant adverse effects with dilevalol administration. Compared with placebo, dilevalol given intravenously appears to be safe and effective antihypertensive treatment.

Topics: Aldosterone; Atrial Natriuretic Factor; Catecholamines; Cyclic GMP; Double-Blind Method; Humans; Hypertension; Injections, Intravenous; Labetalol; Male; Middle Aged; Placebos; Random Allocation; Renin

To verify the hypothesis that the angiotensin converting enzyme (ACE) level may affect the metabolism of circulating atrial natriuretic factor (ANF), the acute and chronic effects of benazepril on plasma ANF levels were studied in hypertensive patients under basal conditions and in response to acute volume expansion. Ten essential hypertensives entered a double-blind crossover study, and were randomly allocated either to placebo or to 10 mg benazepril orally once a day for 2 days; after a placebo washout period of 2 days the groups were crossed over. On the second day of each crossover period, volume expansion was induced by infusing 1 litre saline in 30 min, and blood samples for ANF measurements were drawn at times -5, 0, 5, 15, 30, 35, 40, 50 and 60 min. Oral benazepril at 10 mg/day was then given to all patients for 4 weeks, and the volume expansion with saline was repeated. After the 2-day acute benazepril treatment, blood pressure fell from 166.1 +/- 3.6/105.1 +/- 0.9 to 140.1 +/- 4.6/85.6 +/- 2.1 mmHg (P less than 0.01 for both systolic and diastolic blood pressure), whereas ANF fell from 29.4 +/- 3.6 to 24.1 +/- 3.7 pg/ml (NS) after the acute benazepril treatment and to 17.7 +/- 3.6 pg/ml (P less than 0.01) after the chronic benazepril treatment. The volume expansion itself did not induce significant changes in mean arterial pressure, either during the placebo treatment or during the acute chronic benazepril treatment. The rise in ANF values in response to saline infusion during placebo was prompt, beginning at min 15 and reaching a maximum at min 40.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Blood Pressure; Blood Volume; Double-Blind Method; Humans; Hypertension; Middle Aged; Peptidyl-Dipeptidase A; Randomized Controlled Trials as Topic; Time Factors

Phenylephrine infusions enhance diuresis and natriuresis both in normal subjects and patients with essential hypertension, whereas they have an opposite effect on urinary aldosterone excretion, decreasing it in normal subjects and enhancing it in hypertensive patients. With the new knowledge concerning the atrial natriuretic factor (ANF), it seemed a strong possibility that in normal subjects phenylephrine infusions should exert its effect through the increased release of ANF, as suggested by in vitro studies. Phenylephrine infusions at high pressor dose (to increase diastolic pressure by 25 mmHg) in six healthy volunteers increased plasma ANF and cGMP and decreased plasma renin activity and aldosterone concentrations. Urinary volume, sodium, and cGMP excretion were also increased. Phenylephrine infusions at low pressor dose (to increase diastolic pressure by 12-15 mmHg), in healthy subjects and in five patients with mild essential hypertension, significantly increased plasma ANF concentrations and decreased plasma renin activity to the same degree in both groups. But, whereas in normal subjects plasma aldosterone decreased significantly, it increased in patients with mild essential hypertension despite the simultaneous rise in plasma ANF concentration.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Diuresis; Humans; Hypertension; Natriuresis; Phenylephrine; Renin

We studied two groups of hypertensive patients in order to ascertain whether the acute natriuretic effect of nifedipine is mediated by humoral factors such as renal kallikrein or atrial natriuretic factor (ANF). First, 17 patients with mild to moderate essential hypertension maintained on a 130-mmol/day diet, received either nifedipine (10 mg orally) or placebo during a 6-h infusion of the kallikrein inhibitor aprotinin (2 x 10(6) KIU) or saline as control. Aprotinin, while significantly reducing urinary kallikrein activity, did not interfere with the acute effects of nifedipine on blood pressure, heart rate, urinary volume, urinary Na+ and creatinine clearance. In another group of eight patients on a constant daily Na+ intake of 130 mmol and in the supine position, placebo or nifedipine (10 mg sublingually) were administered, and blood pressure, heart rate, plasma renin activity, plasma aldosterone and plasma ANF, urinary Na+, urine volume and creatinine clearance, were monitored for 2 h. While placebo did not induce changes in any of the above parameters, nifedipine administration induced a significant decrease in blood pressure and increase in urinary Na+, urine volume and creatinine clearance, and a significant rise in ANF levels, from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 min, respectively. In conclusion, our data do not support a role for renal kallikrein as a humoral mediator of the natriuretic effect of calcium antagonists, but do not exclude the possibility that ANF might participate in the nifedipine-induced increase in sodium and water excretion.

Topics: Adult; Aprotinin; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Drug Evaluation; Humans; Hypertension; Kallikreins; Kidney; Kinins; Middle Aged; Natriuresis; Nifedipine; Sodium

The effect of atrial natriuretic peptide (ANP), before and after converting enzyme (CE) inhibition, was investigated in six primary hypertensive patients taking a constant diet. In this placebo-controlled, single-blind, randomized study, the patients received, on three different days, i.v. infusions of (a) placebo, or (b) alpha-human ANP, 150 micrograms over 30 min, or (c) alpha-human ANP after acute CE inhibition by enalapril (EN) 20 mg P.O., 4 h before ANP infusion. ANP infusion increased urinary sodium (p less than 0.001) and volume excretion. Blood pressure (BP), heart rate, stroke volume and shortening fraction (echocardiography), plasma renin activity (PRA), and plasma aldosterone did not change significantly. Urinary norepinephrine and dopamine were significantly increased (p less than 0.05) after ANP infusion. BP was significantly reduced after EN in every patient (p less than 0.05). ANP infusion during CE inhibition induced a more sustained increase of sodium excretion and diuresis with respect to ANP infusion alone (p less than 0.05). PRA was significantly reduced while no further reduction of BP was observed. These data suggest that CE inhibition may increase the natriuretic and diuretic effect of ANP in hypertensive patients.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Humans; Hypertension; Infusions, Intravenous; Male; Single-Blind Method

To determine the nature of the resultant effect on blood pressure when angiotensin converting enzyme (ACE) inhibitors are combined with other hypotensive agents in the treatment of uncomplicated essential hypertension, two randomized, double-blind, crossover trials were conducted. In each trial there were four treatment phases, each 4 weeks in duration, comprising a 2 X 2 factorial experiment. Twenty-one patients completed the first study in which the effects of enalapril (10 mg twice daily) were compared with hydrochlorothiazide (25 mg twice daily), with the two drugs in combination and with placebo. All blood pressure parameters were reduced in the three active treatment phases compared with placebo (P less than 0.001). Enalapril and hydrochlorothiazide were equally effective and in combination their hypotensive effects were fully additive. Sixteen patients completed the second study which compared the effects of enalapril (20 mg daily), atenolol (50 mg daily), the two drugs in combination and placebo. All blood pressure parameters were again reduced in all phases compared with placebo (P less than 0.001). Enalapril and atenolol were also equally effective, but in combination their hypotensive effects were less than fully additive, with attenuation of the potential additive response by 30-50%. These results indicate that a diuretic-ACE inhibitor combination can be expected to have a greater hypotensive effect than a beta-blocker-ACE inhibitor combination. Both hydrochlorothiazide and atenolol increased plasma atrial natriuretic peptide (ANP) concentrations (P less than 0.01), suggesting that ANP could contribute to the hypotensive effects of these two drug classes.

Topics: Angiotensin II; Atenolol; Atrial Natriuretic Factor; Double-Blind Method; Drug Therapy, Combination; Enalapril; Factor Analysis, Statistical; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Random Allocation; Renin

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Diet, Sodium-Restricted; Female; Humans; Hypertension; Male; Middle Aged; Sodium; Sodium Chloride; Sodium, Dietary

Synthetic atrial natriuretic factor (ANF) was administered in ascending doses (0.03, 0.20, 0.45 microgram/kg/min) to eight mildly essential hypertensive men on high (200 mEq/day) or low (10 mEq/day) sodium diets. Responses of blood pressure, heart rate, urinary volume and electrolyte excretion, renin, and aldosterone were measured. For the entire group, ANF lowered blood pressure and increased heart rate during the 0.20 and 0.45 microgram/kg/min infusions, and the antihypertensive effect of the peptide persisted for at least 2 hours after the infusions ended. Four patients (2 at 0.20 microgram/kg/min and 2 at 0.45 microgram/kg/min) experienced sudden bradycardia and hypotension at the end of or shortly after completion of ANF infusion. Renal excretion of water, sodium, chloride, calcium, and phosphorus increased in a dose-dependent fashion in response to infused ANF. Patients on the 200 mEq/day sodium diet had greater increases in urinary volume (11.1 +/- 2.8 vs 3.0 +/- 2.0 ml/min; p less than 0.05), sodium (870 +/- 134 vs 303 +/- 27 microEq/min; p less than 0.05), and chloride (801 +/- 135 vs 176 +/- 75 microEq/min; p less than 0.02) compared with patients on the low sodium diet. The apparent direct suppressive effect of a 0.03 microgram/kg/min infusion of ANF on renin and aldosterone levels was overcome at higher doses by counterregulation provoked by the depressor action. Renin was slightly (-12%) suppressed during the 0.03 microgram/kg/min infusion of ANF but increased at the 0.20 (+50%) and 0.45 microgram/kg/min (+90%; p less than 0.03) rates. Aldosterone declined significantly during the 0.03 microgram/kg/min infusion (-45%; p less than 0.01) of ANF but not during the two higher dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Diuretics; Dose-Response Relationship, Drug; Heart Rate; Hormones; Humans; Hypertension; Hypotension; Male; Middle Aged; Peptide Fragments; Renin-Angiotensin System; Sodium Chloride; Water-Electrolyte Balance

The hypotensive and hormonal effects of the angiotensin converting enzyme (ACE) inhibitor enalapril (10 mg twice daily) were compared with those of hydrochlorothiazide (25 mg twice daily), with the two drugs in combination and with placebo in 21 patients with essential hypertension. For each patient there were four randomised double-blind treatment phases, each of four weeks' duration, which comprised a 2 X 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine mean blood pressures were 119 mmHg (placebo), 113 mmHg (hydrochlorothiazide), 108 mmHg (enalapril), and 98 mmHg (hydrochlorothiazide plus enalapril) (SEM 3 mmHg, ANOVA). Enalapril and hydrochlorothiazide were equally effective and well tolerated and their hypotensive effects were additive. Enalapril increased plasma renin activity (PRA), reduced plasma angiotensin II (AII) and aldosterone concentrations, and reduced ACE activity, whereas hydrochlorothiazide increased PRA, plasma AII, and aldosterone concentrations without altering ACE activity. With combination treatment the effects of enalapril on PRA and plasma AII concentrations were potentiated whereas those on plasma aldosterone concentration and ACE activity were additive. Atrial natriuretic factor plasma concentration in the placebo phase was 92 pg/ml and increased to 145 pg/ml in the hydrochlorothiazide phase (p less than 0.001, SEM 13 pg/ml), but there was no significant change in either the enalapril or combination phases.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Random Allocation; Renin-Angiotensin System

We analyzed the polymorphisms of 7 antihypertensive drugs-related genes and the factors associated with hypertension in hypertensive patients of Han ethnicity in Qingyang, China. A total of 354 hypertensive patients of Han ethnicity were enrolled from Qingyang, China. The ACE (I/D), ADRB1 (1165G > C), AGTR1 (1166A > C), CYP2C9*3, CYP2D6*10, CYP3A5*3 and NPPA (T2238C) polymorphisms were assessed. Clinical data of patients was also obtained. The influencing factors of hypertension were evaluated. The genotype frequencies of ACE, ADRB1, AGTR1, CYP2C9, CYP3A5 and NPPA loci were in Hardy-Weinberg equilibrium, with mutation frequencies of 39.27%, 74.29%, 6.21%, 4.80%, 72.46% and 0.71%, respectively. CYP2D6 locus was not in Hardy-Weinberg equilibrium. There was no statistical difference in allele frequencies between different genders (P > .05). There was significant difference in the frequencies of ACE (I/D) and NPPA (T2238C) loci among different regions of China (P < .05). Gender, ACE (I/D) and ADRB1 (1165G > C) gene polymorphism, smoking, homocysteine and HDL levels were associated hypertension. The mutation frequencies of ADRB1 (1165G > C) and CYP3A5*3 were high in hypertensive patients of Han ethnicity in Qingyang, suggesting these patients may be more sensitive to beta-blockers and calcium ion antagonists. Meanwhile, hypertension was associated with gender, ACE (I/D) and ADRB1 (1165G > C) gene polymorphisms, smoking, homocysteine and HDL levels.

Topics: Atrial Natriuretic Factor; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; East Asian People; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Receptor, Angiotensin, Type 1

Topics: Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Humans; Hypertension; Natriuresis; Sodium

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Natriuretic Factor; Cardiomyopathies; Fibrosis; Heart Atria; Humans; Hypertension; Natriuretic Peptide, Brain; Serine Endopeptidases; Siblings

cGMP MANP (M-atrial natriuretic peptide) is a best-in-class activator of the pGC-A (particulate guanylyl cyclase A) receptor. Furosemide increases the effectiveness of antihypertensive agents, but activates renin-angiotensin-aldosterone system. We aimed to investigate for the first time cardiorenal and neurohumoral actions of MANP in a genetic model of hypertension in spontaneously hypertensive rats. We also assessed how MANP would potentiate the blood pressure (BP)-lowering actions of furosemide while reducing the production of aldosterone.. Spontaneously hypertensive rats (N=60) were randomized in vehicle, MANP, furosemide, or MANP+furosemide groups. Furosemide (1, 5, 10 mg/kg) was given as a single bolus which in MANP+furosemide groups was followed by a 60-minute infusion of MANP.. BP was reduced in MANP300 (300 pmol/[kg·min]) and MANP600 (600 pmol/[kg·min]) groups (. We provide novel evidence that MANP potentiates the BP-lowering actions of furosemide, suppresses the activation of renin-angiotensin-aldosterone system, and preserves renal function. These data are highly relevant to clinical needs in the treatment of hypertension and heart failure.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Furosemide; Guanosine Monophosphate; Hypertension; Natriuresis; Rats

Atrial natriuretic peptide (ANP), encoded by Nppa, is a vasodilatory hormone that promotes salt excretion. Genome-wide association studies identified Nppa as a causative factor of blood pressure development, and in humans, ANP levels were suggested as an indicator of salt sensitivity. This study aimed to provide insights into the effects of ANP on cardiorenal function in salt-sensitive hypertension. To address this question, hypertension was induced in SSNPPA-/- (KO of Nppa in the Dahl salt-sensitive [SS] rat background) or SSWT (WT Dahl SS) rats by a high-salt (HS) diet challenge (4% NaCl for 21 days). Chronic infusion of ANP in SSWT rats attenuated the increase in blood pressure and cardiorenal damage. Overall, the SSNPPA-/- strain demonstrated higher blood pressure and intensified cardiac fibrosis (with no changes in ejection fraction) compared with SSWT rats. Furthermore, SSNPPA-/- rats exhibited kidney hypertrophy and higher glomerular injury scores, reduced diuresis, and lower sodium and chloride excretion than SSWT when fed a HS diet. Additionally, the activity of epithelial Na+ channel (ENaC) was found to be increased in the collecting ducts of the SSNPPA-/- rats. Taken together, these data show promise for the therapeutic benefits of ANP and ANP-increasing drugs for treating salt-sensitive hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Genome-Wide Association Study; Hypertension; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary

Hypertension occurred in 50% obstructive sleep apnea-hypopnea syndrome (OSAHS) patients meanwhile OSAHS occurred in 30% hypertension patients. The present study aimed to explore the molecular mechanism of GATA2-EDN1-AGT induced hypertension in the development of obstructive sleep apnea-hypopnea syndrome. OSAHS patients (56 cases: 36 cases of male, 20 cases of female, 42~60 years old) were divided into two groups (case group: patients with hypertension monitored by 24 h ambulatory blood pressure and polysomnography; control group: patients without hypertension). Wistar rats were used to establish the OSAHS model (narrow pharyngeal cavity). PaO2 and PaCO2 of patients and rats were measured by an automatic blood gas analyzer. The profile of total protein in the OSAHS group and normal group was evaluated. Protein-protein-interaction (PPI) was carried out to show all matter proteins related. The levels of EDN-1, AGTII and atrial natriuretic peptide (ANP) in blood samples of patients and rats were analyzed by enzyme-linked immunosorbent assay (ELISA). The expression of GATA2, EDN1, endothelin-converting enzyme 1 (ECE-1) and AGTⅡ was measured. The results showed that SaO2 and AHI were positively associated with systolic pressure (P<0.05) in OSAHS patients. There was no correlation among other indexes (P>0.05). It was also observed that GATA2 had a strong relationship with AGTⅡ and EDN1. The results of ELISA presented that the levels of EDN1, AGTⅡ and ANP in the OSAHS group of human and animal models were significantly increased (P<0.05). The results of immunochemistry showed that the expression of GATA2 and AGTⅡ in the vascular of OSAHS group was upregulated manifestly (P<0.05). It was concluded that OSAHS can induce AHI, which increases hypertension via the GATA2-EDN1-AGT Ⅱ axis.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Endothelin-1; Female; GATA2 Transcription Factor; Hypertension; Male; Rats; Rats, Wistar; Sleep Apnea, Obstructive; Syndrome

Atrial natriuretic peptide (ANP)-mediated natriuresis is known as a cardiac endocrine function in sodium and body fluid homeostasis. Corin is a protease essential for ANP activation. Here, we studied the role of renal corin in regulating salt excretion and blood pressure. We created corin conditional knockout (cKO), in which the

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Homeostasis; Hypertension; Kidney; Mice; Serine Endopeptidases; Sodium; Sodium Chloride; Sodium Chloride, Dietary

Plasma kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therapy; however, its role in spontaneous intracerebral hemorrhage is currently not available. This report investigates the role of PKa on hemorrhage and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were fed with a high salt-containing stroke-prone diet to increase blood pressure and induce intracerebral hemorrhage. The roles of PKa on blood pressure, hemorrhage, and survival in SHRSP were examined in rats receiving a PKa inhibitor or plasma prekallikrein antisense oligonucleotide (PK ASO) compared with rats receiving control ASO. Effects on PKa on the proteolytic cleavage of atrial natriuretic peptide (ANP) were analyzed by tandem mass spectrometry. We show that SHRSP on high-salt diet displayed increased levels of PKa activity compared with control rats. Cleaved kininogen was increased in plasma during stroke compared to SHRSP without stroke. Systemic administration of a PKa inhibitor or PK ASO to SHRSP reduced hemorrhage and blood pressure, and improved neurological function and survival compared with SHRSP receiving control ASO. Since PKa inhibition was associated with reduced blood pressure in hypertensive rats, we investigated the effects of PKa on the cleavage of ANP. Incubation of PKa with ANP resulted in the generation fragment ANP

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cerebral Hemorrhage; Hypertension; Plasma Kallikrein; Rats; Rats, Inbred SHR; Stroke

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

Topics: Angiotensin I; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Flow Velocity; Blood Pressure; Cardiovascular System; Disease Models, Animal; Genotype; Glial Fibrillary Acidic Protein; Hemodynamics; Hypertension; Male; Peptide Fragments; Phenotype; Rats, Sprague-Dawley; Rats, Transgenic; Recombinant Fusion Proteins; Regional Blood Flow; Sympathetic Nervous System; Time Factors; Vascular Resistance

[Figure: see text].

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Natriuresis; Sodium

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Receptors, Atrial Natriuretic Factor

The causal relationship between obesity and high blood pressure is established; however, the detailed pathways for such association are still under research. This work aims to assess the changes in neprilysin, vasoconstrictor and vasodilatory molecules in obese hypertensive patients undergoing laparoscopic sleeve gastrectomy (LSG).. The present prospective study was done on 59 hypertensive obese patients in whom LGS was performed. Blood pressure, as well as blood samples for neprilysin, angiotensinogen, angiotensin II, renin, endothelin-1 "ET-1", aldosterone, atrial natriuretic peptide "ANP" and B-type natriuretic peptide "BNP", were assessed before and 15 months after surgery. Patients were divided into two groups according to the remission of hypertension (HTN).. After 15 months, remission of hypertension was seen in 42 patients (71%). The declines in the following measurements were significantly higher in patients with remission than those with persistent HTN: aldosterone (p = .029567), angiotensin II (p < .000001), angiotensinogen (p = .000021), neprilysin (p = .000601), renin (p = .000454) and endothelin-1(p = .000030). There was a significantly higher increment in ANP (p = .000002) and a non-significant increment in BNP (p = .081740). Angiotensin II 15 months after LSG and Δ ANP % were significant independent predictors of persistent HTN.. In the setting of LSG, aldosterone, angiotensinogen, angiotensin II, renin and neprilysin were significantly lower in patients with remission of HTN after 15 months than those with persistent HTN, and natriuretic peptides were significantly higher. A lower postoperative level of angiotensin II and a larger percentage increment of ANP are independently associated with hypertension remission after LSG.

Topics: Atrial Natriuretic Factor; Gastrectomy; Humans; Hypertension; Laparoscopy; Obesity; Prospective Studies

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle

Topics: Aminobutyrates; Animals; Atrial Natriuretic Factor; Biphenyl Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hypertension; Kidney Glomerulus; Male; Neprilysin; Rats; Rats, Inbred Dahl; Renal Insufficiency

Increased marinobufagenin (MBG) synthesis has been suggested in response to high dietary salt intake. The aim of this study was to determine the effects of short-term changes in sodium intake on plasma MBG levels in patients with primary salt-sensitive and salt-insensitive hypertension. In total, 51 patients with primary hypertension were evaluated during acute sodium restriction and sodium loading. Plasma or serum concentrations of MBG, natriuretic pro-peptides, aldosterone, sodium, potassium, as well as hematocrit (Hct) value, plasma renin activity (PRA) and urinary sodium and potassium excretion were measured. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed at baseline. In salt-sensitive patients with primary hypertension plasma MBG correlated positively with diastolic blood pressure (ABPM) and serum NT-proANP concentration at baseline and with serum NT-proANP concentration after dietary sodium restriction. In this subgroup plasma MBG concentration decreased during sodium restriction, and a parallel increase of PRA was observed. Acute salt loading further decreased plasma MBG concentration in salt-sensitive subjects in contrast to salt insensitive patients. No correlation was found between plasma MBG concentration and left ventricular mass index. In conclusion, in salt-sensitive hypertensive patients plasma MBG concentration correlates with 24-h diastolic blood pressure and dietary sodium restriction reduces plasma MBG levels. Decreased MBG secretion in response to acute salt loading may play an important role in the pathogenesis of salt sensitivity.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Bufanolides; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Renin; Sodium; Sodium, Dietary

Topics: Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Obesity

Pentraxin 3 (PTX3) is synthesized locally and released into the circulation, reflecting local inflammation in the cardiovascular system. Therefore, we conducted a study to explore the effect of PTX3 in spontaneously hypertensive heart failure (SHHF) rats. Sprague Dawley (SD) and SHHF rats were treated with recombinant PTX3 protein, and the blood pressure (BP) and echocardiographic parameters were collected. Radioimmunoassay, enzyme immunoassay and enzyme-linked immunosorbent assay (ELISA) were applied to detect plasma levels of atrial/B-type natriuretic peptide (ANP/BNP) and PTX3. The pathological changes in the myocardial tissues were observed by hematoxylin and eosin (HE) and Masson stainings. The mRNA and protein expressions were detected by quantitative real-time reverse-transcription polymerase chain reaction (qPCR) and western blotting. Cardiomyocyte apoptosis was evaluated by TUNEL staining and DNA fragmentation test. Increased plasma concentrations of PTX3 were found in SHHF rats compared with SD rats, which was further enhanced by recombinant PTX3 protein. After injection with recombinant PTX3 protein, the heart function was improved in SHHF rats with the decreased systolic and diastolic BP, and the reduced plasma levels of ANP and BNP. Moreover, PTX3 improved the myocardial damage and interstitial fibrosis in SHHF rats with reduced cardiomyocyte apoptosis and decreased mRNA expressions of pro-inflammatory factors in myocardial tissues. PTX3 could decrease the BP and plasma levels of ANP and BNP in SHHF rats, as well as improve the inflammation, cardiomyocyte apoptosis, and pathological changes of myocardial tissues, suggesting it may be a useful intervention in the treatment of SHHF.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Pressure; C-Reactive Protein; Cytokines; Disease Models, Animal; Heart Failure; Hypertension; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Rats, Inbred SHR; Rats, Sprague-Dawley; Recombinant Proteins; Serum Amyloid P-Component; Ventricular Function, Left

Topics: Albuminuria; Animals; Atrial Natriuretic Factor; Atrial Remodeling; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Dinoprostone; Drug Evaluation, Preclinical; Fibrosis; Glomerular Filtration Rate; Heart; Hypertension; Kidney; Kidney Diseases; Male; Myocytes, Cardiac; Natriuresis; Peptide Fragments; Potassium; Rats; Rats, Inbred Dahl; Smad2 Protein; Sodium Chloride, Dietary; Ventricular Remodeling

Topics: Atrial Natriuretic Factor; Biopsy; Blood Pressure; Cyclic GMP; Humans; Hypertension

The intensity of accumulation and excretion of atrial natriuretic peptide in myocytes of the right atrium in rat models of renovascular hypertension and salt loading was studied by immunocytochemical analysis and transmission electron microscopy. The data suggest that high BP is not the decisive factor affecting secretion of atrial natriuretic peptide in atrial cardiomyocytes. The regulatory mechanisms of the accumulation and release of the peptide from myocyte granules can vary and depend on the pathogenesis of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Hypertension; Hypertrophy, Left Ventricular; Immunohistochemistry; Male; Microscopy, Electron, Transmission; Mitochondria; Myocytes, Cardiac; Rats; Rats, Wistar

Atrial natriuretic peptide (ANP), one of the main members of the natriuretic peptides system, has been associated with hypertension and related complications, but the underlying molecular mechanisms are not very clear. Here, we aimed to examine whether DNA methylation, a molecular modification to the genome, of the natriuretic peptide A gene (NPPA), the coding gene of ANP, was associated with hypertension.. Peripheral blood DNA methylation of NPPA promoter was quantified by target bisulfite sequencing in 2498 community members (mean aged 53 years, 38% men) as a discovery sample and 1771 independent participants (mean aged 62 years, 54% men) as a replication sample. In both samples, we conducted a single CpG association analysis, followed by a gene-based association analysis, to examine the association between NPPA promoter methylation and hypertension, adjusting for age, sex, education level, cigarette smoking, alcohol consumption, obesity, fasting glucose, and lipids. Multiple testing was controlled by the false discovery rate approach.. Of the 9 CpG loci assayed, hypermethylation at 5 CpGs (CpG1, CpG3, CpG6, CpG8, and CpG9) was significantly associated with a lower odds of prevalent hypertension in the discovery sample, and one CpG methylation (CpG1 located at Chr1:11908353) was successfully replicated in the replication sample (OR = 0.82, 95%CI 0.74-0.91, q = 0.002) after adjusting for covariates and multiple testing. The gene-based analysis found that DNA methylation of the 9 CpGs at NPPA promoter as a whole was significantly associated with blood pressure and prevalent hypertension in both samples (all P < 0.05).. DNA methylation levels at NPPA promoter were decreased in Chinese adults with hypertension. Aberrant DNA methylation of the NPPA gene may participate in the mechanisms of hypertension.

Topics: Atrial Natriuretic Factor; China; Cohort Studies; DNA Methylation; Female; Humans; Hypertension; Male; Middle Aged; Promoter Regions, Genetic

Salt-sensitivity is more common in blacks than whites but the underlying cause is not fully known. Atrial natriuretic peptide (ANP) concentrations might play a role.  This study investigated plasma ANP concentrations and effect of salt-loading in salt-sensitive (SS) and salt-resistant (SR) normotensive (NT) and hypertensive (HT) Nigerians of both genders  Forty-three (43) apparently healthy (NT) adult volunteers and thirty-seven (37) age-matched newly diagnosed (HT) Nigerians were grouped into SS and SR volunteers based on the mean changes in their mean arterial blood pressure ≥ 5 mmHg, following a 5-day administration of 200 mmol of sodium in each of the volunteers. ANP concentrations were determined before and after salt loading. Prevalence of SS and SR in the NT and HT Nigerians was 51.2% and 48.8%, respectively. Basal ANP levels in SS and SR NT and HT participants were similar but salt significantly raised ANP concentrations in SS (p < 0.01), SR (p < 0.001) NT volunteers only. Besides, basal ANP concentrations observed in SS and SR NT and HT males and females were similar but salt loading significantly increased ANP levels in SS NT males (p <0.05), SR NT (p < 0.001) and HT (p < 0.05) females only. These findings showed that salt-sensitive hypertensive individuals demonstrated a blunted ANP response to salt loading. However, salt-resistant normotensive volunteers showed a significant increase in ANP concentrations. with higher levels in NT females than males. The impaired ANP response to salt challenge might be the basis for the higher prevalence of salt-sensitivity among blacks.

Topics: Adult; Atrial Natriuretic Factor; Black People; Blood Pressure; Female; Humans; Hypertension; Male; Nigeria

Sex hormones contribute to sex differences in blood pressure. Inappropriate activation of the renin-angiotensin system is involved in vascular dysfunction and hypertension. This study evaluated the role of androgens (testosterone) in angiotensin II (Ang II)-induced increase in blood pressure, vascular reactivity, and cardiac hypertrophy. Eight-week-old male Wistar rats underwent sham operation, castration, or castration with testosterone replacement. After 12 weeks of chronic changes in androgen status, Ang II (120 ng/kg per minute) or saline was infused for 28 days via subcutaneous miniosmotic pump, and changes in blood pressure was measured. Vascular reactivity and Ang II receptor levels were examined in mesenteric arteries. Heart weight, cardiac ANP mRNA levels, and fibrosis were also assessed. Ang II infusion increased arterial pressure in intact males. The Ang II-induced increase in hypertensive response was prevented in castrated males. Testosterone replacement in castrated males restored Ang II-induced hypertensive responses. Castration reduced vascular AT1R/AT2R ratio, an effect that was reversed by testosterone replacement. Ang II-induced hypertension was associated with increased contractile response of mesenteric arteries to Ang II and phenylephrine in intact and testosterone-replaced castrated males; these increases were prevented in castrated males. Ang II infusion induced increased left ventricle-to-body weight ratio and ANP mRNA expression, indicators of left ventricular hypertrophy, and fibrosis in intact and testosterone-replaced castrated males, and castration prevented the increase in these parameters caused by Ang II. This study demonstrates that testosterone plays a permissive role in development and maintenance of Ang II-induced vascular dysfunction, hypertension, and cardiac hypertrophy.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Cardiomegaly; Hypertension; Male; Mesenteric Arteries; Orchiectomy; Rats; Rats, Wistar; Receptors, Androgen; Receptors, Angiotensin; Renin-Angiotensin System; Testosterone

Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure.. The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin.. Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.

Topics: Animals; Atrial Function, Left; Atrial Natriuretic Factor; Benzhydryl Compounds; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Fibrosis; Gene Expression Regulation; Glucosides; Heart Failure; Hemodynamics; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Rats, Inbred SHR; Rats, Inbred WKY; Recovery of Function; Sodium-Glucose Transporter 2 Inhibitors; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Ventricular Remodeling

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cholesterol; Cystatin C; Diabetes Mellitus; Female; Glycopeptides; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peripheral Arterial Disease; Prospective Studies; Protein Precursors; Risk Factors; Sex Factors; Smoking; Sweden

Topics: Angiotensin II; Animals; Antihypertensive Agents; Apoptosis; Atrial Natriuretic Factor; bcl-2-Associated X Protein; Blood Pressure; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiotonic Agents; Caspase 3; Cell Line; Gallic Acid; Gene Expression Regulation; Hypertension; Hypertrophy, Left Ventricular; Isoenzymes; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Nitric Oxide Synthase; p300-CBP Transcription Factors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Tumor Suppressor Protein p53

Obese persons have lower circulating natriuretic peptide (NP) concentrations. It has been proposed that this natriuretic handicap plays a role in obesity-related hypertension. In contrast, hypertensive patients with left atrial enlargement have higher circulating NP concentrations. On this background, we investigated whether obese hypertensive men could have lower circulating NP concentrations despite evidence of pressure-induced greater left atrial size.. We examined 98 obese men (body mass index [BMI] ≥ 30.0 kg/m2) and 27 lean normotensive men (BMI 20.0-24.9 kg/m2). All men were healthy, medication free, with normal left ventricular ejection fraction. We measured blood pressure using 24-hour ambulatory blood pressure (ABP) recordings. Hypertension was defined as 24-hour ABP ≥ 130/80 mm Hg, and normotension was defined as 24-hour ABP < 130/80 mm Hg. We determined left atrial size using echocardiography, and we measured fasting serum concentrations of midregional proatrial NP (MR-proANP).. Of the 98 obese men, 62 had hypertension and 36 were normotensive. The obese hypertensive men had greater left atrial size (mean ± SD: 28.7 ± 6.0 ml/m2) compared with the lean normotensive men (23.5 ± 4.5 ml/m2) and the obese normotensive men (22.7 ± 5.1 ml/m2), P < 0.01. Nevertheless, despite evidence of pressure-induced greater left atrial size, the obese hypertensive men had lower serum MR-proANP concentrations (median [interquartile range]: 48.5 [37.0-64.7] pmol/l) compared with the lean normotensive men (69.3 [54.3-82.9] pmol/l), P < 0.01, whereas the obese normotensive men had serum MR-proANP concentrations in between the 2 other groups (54.1 [43.6-62.9] pmol/l).. Despite greater left atrial size, obese hypertensive men have lower circulating MR-proANP concentrations compared with lean normotensive men.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cross-Sectional Studies; Echocardiography; Heart Atria; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Obesity

Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy.. The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis.. At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn't statistically significant difference between the SHR and intervention groups. Staining with Masson's trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks.. This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

Topics: Animals; Apoptosis; Atorvastatin; Atrial Natriuretic Factor; Blood Pressure; CCAAT-Enhancer-Binding Protein-beta; Echocardiography; Hypertension; Hypertrophy; Male; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Uncoupling Protein 3; Up-Regulation; Ventricular Remodeling

The combination of AT1 blocker/neutroendopeptidase neprilysin inhibition (ARNi) represents an interesting approach to reduce cardiovascular risk in hypertension. We assessed the efficacy of ARNi, compared with angiotensin II type 1 receptor blockade alone, on blood pressure (BP) and on protection from target organ damage development in the stroke-prone spontaneously hypertensive rat (SHRSP).. In high-salt fed SHRSP, we assessed plasma and tissue natriuretic peptides, urinary volume, BP and body weight over a short-term treatment (6 weeks) with either ARNi (sacubitril/valsartan 68 mg/kg per day) or valsartan (30 mg/kg per day), protection from stroke and renal damage (as documented by proteinuria) over 4 months of treatment with either sacubitril/valsartan or valsartan; the ability of either treatment to reduce progression of cerebrovascular and renal damage after 2 weeks of high-salt diet.. Higher levels of plasma and tissue atrial natriuretic peptide, of urinary cyclic guanosine 3'5'monophosphate and urine volumes, along with lower BP levels, were found upon sacubitril/valsartan as compared with valsartan over the short-term treatment. Sacubitril/valsartan caused a significant reduction of both BP and proteinuria levels and complete prevention of stroke over the long-term treatment. Once organ damage was established, a significant delay of its progression was observed with sacubitril/valsartan.. The dual angiotensin II type 1 receptor/neutroendopeptidase inhibition significantly increased atrial natriuretic peptide level and reduced BP. Complete prevention of stroke was achieved in this model. The ability of sacubitril/valsartan to reduce organ damage progression was superior to that of valsartan alone. ARNi may represent a highly effective therapeutic agent to protect from target organ damage development in hypertension.

Topics: Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Cyclic GMP; Drug Combinations; Hypertension; Male; Neprilysin; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Tetrazoles; Valsartan

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Topics: Animals; Arterial Pressure; Atrial Natriuretic Factor; Autonomic Nervous System; Baroreflex; Computer Simulation; Dogs; Electric Stimulation Therapy; Heart; Heart Rate; Humans; Hypertension; Kidney; Models, Animal; Models, Cardiovascular; Norepinephrine; Pressoreceptors; Sympathectomy; Time Factors

Topics: Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Essential Hypertension; Humans; Hypertension

To investigate the relationships among aldosterone level, use of antihypertensive (anti-HTN) medications, clinical profile, and atrial natriuretic peptide (ANP) level in individuals with HTN.. In a community-based cohort, we analyzed aldosterone plasma levels based on the presence (n=477) or absence (n=1073) of HTN. In individuals with HTN, we evaluated circulating aldosterone levels according to the number of anti-HTN drugs used, analyzed the associated clinical characteristics, and determined the relationship to the counterregulatory cardiac hormone ANP. Data were collected from August 25, 1997, through September 5, 2000.. Participants with HTN had higher serum aldosterone levels than those without HTN (6.4 vs 4.1 ng/dL [to convert to pmol/L, multiply by 27.74]; P<.001). When individuals with HTN were stratified according to the number of anti-HTN medications used, the increase in number of medications (0, 1, 2, and ≥3) was associated with higher aldosterone levels (4.8, 6.4, 7.10, and 7.9 ng/dL, respectively; P=.002), worse metabolic profile, and higher prevalence of cardiovascular, renal, and metabolic disease. In participants with HTN, ANP plasma levels were inversely related to aldosterone levels when the latter was divided into tertiles.. In this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

Topics: Aged; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Glucose; Cholesterol, LDL; Cohort Studies; Coronary Artery Disease; Diuretics; Female; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Hypolipidemic Agents; Insulin; Male; Metabolic Syndrome; Middle Aged; Minnesota; Myocardial Infarction; Obesity; Sampling Studies; Stroke; Triglycerides

In the absence of ocular target organ damage (ocular-TOD), diagnosis of hypertension is challenging in cats. Biomarkers would provide additional support for the diagnosis of hypertension.. Vascular endothelial growth factor (VEGF), N-terminal probrain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), and urine protein-to-creatinine ratio (UPC) are predictors of systemic hypertension, will be increased in cats with hypertension with or without ocular-TOD, and will decrease with antihypertensive treatment.. Plasma VEGF, NT-proBNP, and cTnI concentrations and UPC were determined in healthy geriatric cats, normotensive cats with chronic kidney disease (CKD), hypertensive cats with evidence of hypertensive retinopathy (HT-ocular-TOD), and hypertensive cats without hypertensive ocular-TOD (HT-noTOD). Comparisons among groups were performed. Multivariable binary logistic regression models were built to identify independent biomarkers of hypertension and ocular-TOD. Receiver operator characteristic (ROC) curves were drawn to assess clinical use.. Cats with HT-ocular-TOD had significantly higher VEGF than all other groups (P < .05) and significantly higher NT-proBNP than healthy cats (P < .001). Healthy cats had significantly lower cTnI than all other groups (P < .05). No differences were found among groups for UPC (P = .08). Cardiac troponin I and VEGF were independent predictors of hypertension (P < .05), but none of the biomarkers were independent predictors of ocular-TOD. N-terminal probrain natriuretic peptide concentrations decreased with antihypertensive treatment (P < .001). The ROC curves indicated that none of the biomarkers met the criteria to function as diagnostic tests for the diagnosis of hypertension or associated ocular-TOD.. Despite statistical significance and changes with ocular-TOD, antihypertensive treatment, or both, VEGF, NT-proBNP, and cTnI did not function as useful diagnostic tests for hypertension. Persistently increased systolic blood pressure (SBP) measurements in combination with fundoscopy remains the preferred method for diagnosis of feline hypertension.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cat Diseases; Cats; Hypertension; Hypertensive Retinopathy; Predictive Value of Tests; Protein Precursors; Retrospective Studies; Troponin I; Vascular Endothelial Growth Factor A

Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine nonsynonymous variants, of which eight were not characterized previously. Among them, variants c.131A > G (p.Tyr13Cys), c.376G > T (p.Asp95Tyr), c.1094T > G (p.Leu334Trp), and c.1667G > A (p.Arg525His) occurred similarly in both normal and hypertensive individuals. Variants c1139G > A (p.Arg349His), c.2689C > T (p.Pro866Ser), and c.2864C > T (p.Thr924Met) were found once each in hypertensive individuals. Variant c.1683G > T (p.Arg530Ser) occurred preferentially in hypertensive individuals [10/401 (2.5%) vs. 1/300 (0.3%) in normal individuals; P = 0.023], which was confirmed in another independent cohort [9/368 (2.44%) in hypertensive and 2/377 (0.53%) in normal individuals; P = 0.033]. In biochemical and cell-based functional studies, variants p.Arg530Ser and p.Thr924Met, but not p.Tyr13Cys, p.Asp95Tyr, p.Leu334Trp, p.Arg349His, p.Arg525His, and p.Pro866Ser, exhibited reduced pro-ANP processing activity, which was caused by endoplasmic reticulum retention and poor zymogen activation, respectively. These results indicate that genetic variants impairing corin function are not uncommon in general populations and that such variants may be an important contributing factor in hypertension.

Topics: Atrial Natriuretic Factor; China; Cohort Studies; Enzyme Precursors; Exons; Genetic Variation; Humans; Hypertension; Models, Molecular; Protein Transport; Sequence Analysis, DNA; Serine Endopeptidases

Heart failure often presents with prognosis-relevant impaired renal function. To investigate whether the chronic activation of guanylate cyclase-A (GC-A) protects both heart and kidney, we examined the effects of TDT, a neprilysin (NEP)-resistant natriuretic peptide (NP) derivative, on cardiac and renal dysfunction in Dahl salt-sensitive hypertensive (DS) rats. Pretreatment with NEP or NEP inhibitor did not influence GC-A activation by TDT both in vitro and in vivo, resulting in a long-acting profile of TDT compared with native human atrial NP (hANP). The repeated administration of TDT to DS rats suppressed the progress of cardiac hypertrophy, systolic/diastolic dysfunction, and proteinuria in a dose-dependent manner. Compared with vehicle and hANP, salt diet-induced podocyte injury was reduced by TDT, as analyzed by urinary podocalyxin concentration, renal expression of nephrin mRNA, and glomerular expression of desmin protein. Since glomerular TRPC6 plays detrimental roles in podocyte homeostasis, we examined the renal expression of TRPC6 in DS rats and found that salt diet upregulated the expression of TRPC6. Importantly, TRPC6 induction was significantly decreased in TDT-treated rats, compared with vehicle and hANP. Consistently, in primary-culture podocytes from DS rats, TDT inhibited ATP-induced calcium influx, similar to TRPC inhibitor SKF96365. Finally, TDT-mediated protection of podocytes was abolished by protein kinase G inhibitor KT5823. In conclusion, TDT treatment attenuated heart and kidney dysfunction, accompanied by podocyte protection through inhibition of TRPC6. Thus, long-acting NPs could be a new avenue for treatment of heart failure.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Cell Culture Techniques; CHO Cells; Cricetulus; Cyclic GMP; Dose-Response Relationship, Drug; Heart; Humans; Hypertension; Kidney; Podocytes; Rats, Inbred Dahl; Receptors, Atrial Natriuretic Factor; Recombinant Proteins

Topics: Atrial Natriuretic Factor; Blood Pressure; Genome-Wide Association Study; Humans; Hypertension; Natriuretic Peptide, Brain

Blood pressure is influenced by hereditary factors and dietary habits. The objective of this study was to examine the effect of dietary salt consumption and single-nucleotide polymorphisms (SNPs) on blood pressure (BP).. This was a cross-sectional analysis of 2728 male participants who participated in a health examination in 2009. Average dietary salt consumption was estimated using electronically collected meal purchase data from cafeteria. A multivariate analysis, adjusting for clinically relevant factors, was conducted to examine whether the effect on BP of salt consumption, SNPs, and interaction between salt consumption and each SNP. This study examined the SNPs AGT rs699 (Met235Thr), ADD1 rs4961 (Gly460Trp), NPPA rs5063 (Val32Met), GPX1 rs1050450 (Pro198Leu), and AGTR1 rs5186 (A1166C) in relation to hypertension and salt sensitivity.. BP was not significantly associated with SNPs or salt consumption. The interaction between salt consumption and SNPs with systolic BP showed a significant association in NPPA rs5063 (Val32Met) (P = 0.023) and a marginal trend toward significance in rs4961 and rs1050450 (P = 0.060 and 0.067, respectively).. The effect of salt consumption on BP differed by genotype. Dietary salt consumption and genetic variation can predict a high risk of hypertension.

Topics: Adult; Asian People; Atrial Natriuretic Factor; Blood Pressure; Chi-Square Distribution; Cross-Sectional Studies; Employment; Feeding Behavior; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Hypertension; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Occupational Health; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Sex Factors; Sodium, Dietary

Obese persons have low circulating natriuretic peptide (NP) concentrations. It has been proposed that this 'natriuretic handicap' could play a role in obesity-related hypertension. The normal physiological response of the NP system to an increase in blood pressure (BP) is an increase in NP secretion with concomitant higher circulating NP concentrations. In this study, we investigated whether higher BP would also be related to higher circulating NP concentrations in obese men; furthermore, we verified that BP had affected the hearts of our study participants, by determining left ventricular mass (LVM).. We examined 103 obese healthy medication-free men. We measured 24-hour ambulatory BP (ABP). LVM was calculated using the Cornell voltage-duration product method. Fasting serum concentrations of midregional proatrial NP (MR-proANP), a surrogate for active ANP, were measured. Linear regression analysis was used to calculate age-adjusted standardised regression coefficients (β).. LVM and BP increased across systolic ABP quartiles (mean LVM±SD: 1599.1±387.2 mm ms in first vs 2188.5±551.3 mm ms in fourth quartile, p<0.001; mean systolic ABP±SD: 114.5±4.2 mm Hg in first vs 149.0±7.7 mm Hg in fourth quartile, p<0.001). Systolic ABP was robustly associated with LVM (ß=0.48, p<0.001). Despite evidence of BP-related increases in LVM, serum MR-proANP was negatively associated with systolic ABP (ß=-0.32, p=0.004) and with diastolic ABP (ß=-0.45, p<0.001).. Contrary to known physiological BP responses, MR-proANP was negatively associated with ABP in our study. This suggests that a low amount of circulating NPs could play a role in the early stage of obesity-related hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Female; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Obesity

Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important.. Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype).. There were 14 nonsynonymous variants (NSVs) of CYP11B2: 3 previously described and associated with alterations in aldosterone synthase production (R87G, V386A, and G435S). Out of 14, 9 variants were found in all 9 patients sequenced. There were 4 NSV of GRK4 (R65L, A116T, A142V, V486A): at least one was found in all 9 patients; 3 were previously described and associated with hypertension. There were 3 NSV of SCNN1B (R206Q, G442V, and R563Q); 2 previously described and 1 associated with hypertension. NPPA was found to have 1 NSV (V32M), not previously described and NEDD4L did not have any variants. UMOD had 3 NSV: D25G, L180V, and T585I.. A phenotypic approach to investigating the genetic architecture of RHT uncovered a surprisingly high yield of variants in candidate genes. These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Black People; Blood Pressure; Cytochrome P-450 CYP11B2; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channels; Female; G-Protein-Coupled Receptor Kinase 4; Gene Frequency; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertension; Kenya; Male; Middle Aged; Nedd4 Ubiquitin Protein Ligases; Phenotype; Prognosis; Renin; Renin-Angiotensin System; Risk Assessment; Risk Factors; South Africa; Stroke; Ubiquitin-Protein Ligases; Uromodulin

Atrial fibrillation (AF) may present variously in time, and AF may progress from self-terminating to non-self-terminating AF, and is associated with impaired prognosis. However, predictors of AF types are largely unexplored. We investigate the clinical, biomarker, and genetic predictors of development of specific types of AF in a community-based cohort.. We included 8042 individuals (319 with incident AF) of the PREVEND study. Types of AF were compared, and multivariate multinomial regression analysis determined associations with specific types of AF.. Mean age was 48.5 ± 12.4 years and 50% were men. The types of incident AF were ascertained based on electrocardiograms; 103(32%) were classified as AF without 2-year recurrence, 158(50%) as self-terminating AF, and 58(18%) as non-self-terminating AF. With multivariate multinomial logistic regression analysis, advancing age (P< 0.001 for all three types) was associated with all AF types, male sex was associated with AF without 2-year recurrence and self-terminating AF (P= 0.031 and P= 0.008, respectively). Increasing body mass index and MR-proANP were associated with both self-terminating (P= 0.009 and P< 0.001) and non-self-terminating AF (P= 0.003 and P< 0.001). The only predictor associated with solely self-terminating AF is prescribed anti-hypertensive treatment (P= 0.019). The following predictors were associated with non-self-terminating AF; lower heart rate (P= 0.018), lipid-lowering treatment prescribed (P= 0.009), and eGFR <60 mL/min/1.73 m2 (P= 0.006). Three known AF-genetic variants (rs6666258, rs6817105, and rs10821415) were associated with self-terminating AF.. We found clinical, biomarker and genetic predictors of specific types of incident AF in a community-based cohort. The genetic background seems to play a more important role than modifiable risk factors in self-terminating AF.

Topics: Adult; Age Factors; Albuminuria; Aminopeptidases; Antihypertensive Agents; Atrial Fibrillation; Atrial Natriuretic Factor; Blood Glucose; Body Mass Index; C-Reactive Protein; Cohort Studies; Creatinine; Cystatin C; Female; Genetic Predisposition to Disease; Glomerular Filtration Rate; Heart Rate; Homeobox Protein PITX2; Homeodomain Proteins; Humans; Hypertension; Hypolipidemic Agents; Logistic Models; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Phosphotransferases (Phosphate Group Acceptor); Polymorphism, Single Nucleotide; Risk Factors; Sex Factors; Small-Conductance Calcium-Activated Potassium Channels; Transcription Factors

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Remodeling; Biomarkers; Blood Pressure; Cardiomyopathy, Hypertrophic; Case-Control Studies; Catheter Ablation; Female; Heart Atria; Heart Diseases; Humans; Hypertension; Imaging, Three-Dimensional; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Veins; Tomography, X-Ray Computed; Troponin T; Vascular Remodeling

Augmented blood pressure (BP) variability over various time periods has been recognized as a risk factor for cardiovascular diseases. Both atrial and B-type natriuretic peptides (ANP and BNP) are secreted in response to volume or pressure overload to the heart, exerting natriuretic and vasodilator actions. In this study, we examined the relationships between year-by-year BP variability and plasma levels of ANP and BNP in the general population. Study subjects were local residents receiving an annual heath checkup, who had an estimated glomerular filtration rate of >30 ml min

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Female; Humans; Hypertension; Japan; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Prognosis; Retrospective Studies; Risk Factors; Time Factors; Up-Regulation

The pioneer overall ultrastructural and immune-enzymatic evaluation of the secretory activity of atrial myoendocrine cells in WAG strain (control) and in ISIAH rats with inherited stress induced arterial hypertension has been carried out. It was revealed that under basal conditions the cardiac hormone synthesis, storage and secretion in myoendocrine cells of hypertensive rats were certainly intensified, and the atrial natriuretic peptide (ANP) blood concentration was reliably higher than in normotensive WAG rats. All rats demonstrated the unidirectional reaction during the subchronic restraint stress: the ANP release was depressed, the peptides accumulated in the cardiomyocyte numerous large secretory granules, and ANP blood concentration 6 times decreased, while interline differences preserved. It is concluded that the cardiac natriuretic peptides as a hypotensive chain of the hemodynamic regulation, compensatory response to the development of inherited arterial hypertension and participate in the realization of stress reactions.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Heart Atria; Hypertension; Immobilization; Male; Myocytes, Cardiac; Organ Size; Rats; Stress, Psychological

Proximal resistance vessels, such as the mesenteric arteries, contribute substantially to the peripheral resistance. The reactivity of resistance vessels to vasoactive substance like natriuretic peptides plays an important role in the regulation of blood pressure. In current study, we investigated the reactivity of mesenteric arteries to atrial natriuretic peptide (ANP), a well known vasodilating factor, in spontaneously hypertensive rats (SHR), as well as the effects of exercise training on it. As a result, ANP-induced vasorelaxation was attenuated in SHR with significantly increased phosphodiesterase type 5 (PDE5), and decreased cGMP/ANP ratio, compared with WKY rats as control. Intriguingly, the decreased reactivity to ANP in SHR was markedly reversed by exercise training. In addition, ANP resistance of in vitro mesenteric arteries was diminished by sildenafil a potent selective inhibitor of PDE5. In conclusion, ANP resistance occurs in resistance vessels of SHR, suggesting predisposition to hypertension, which can be reversed by exercise.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Drug Resistance; Hypertension; Mesenteric Arteries; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cell Line; Enzyme Activation; Humans; Hypertension; Mice; Mice, Knockout; Myocardium; Proprotein Convertases; Protein Precursors; Serine Endopeptidases; Signal Transduction; Transfection

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Cyclin-Dependent Kinase Inhibitor p15; Disease Models, Animal; Echocardiography; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Natriuretic Peptide, Brain; Oligonucleotides; Pulmonary Fibrosis; Ventricular Remodeling

Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the α subunit of Na(+)/K(+)-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides.

Topics: Adrenal Cortex; Adrenal Glands; Animals; Atrial Natriuretic Factor; Cardenolides; Catalysis; Cell Membrane; Digoxin; Humans; Hypertension; Hypothalamus; Models, Theoretical; Signal Transduction; Sodium-Potassium-Exchanging ATPase

Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population.

Topics: Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Essential Hypertension; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Malaysia; Male; Middle Aged; Polymorphism, Single Nucleotide

Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Connexins; DNA Methylation; Endothelium, Vascular; Epigenesis, Genetic; Female; Hypertension; Male; Maternal Exposure; Nerve Tissue Proteins; Parathyroid Hormone; Paternal Exposure; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Receptors, Calcitriol; Renin; RNA, Messenger; Vasodilation; Vitamin D; Vitamin D Deficiency

To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow-release nifedipine, the three peptides were measured again in the PA and low-renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low-renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions.

Topics: Adrenalectomy; Adrenomedullin; Adult; Atrial Natriuretic Factor; Essential Hypertension; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nifedipine; Vasodilator Agents

Male ISIAH rats with inherited stress-induced arterial hypertension (BP 174.0 ± 1.3 mm Hg) received antagonist of angiotensin II receptors losartan in a dose of 10 mg/kg/day for 16 days. Ultrastructural study of the right atrium showed signs of dramatic and pronounced inhibition of synthesis of the natriuretic peptides (changes in the composition of secretory granules and decrease in their population density and size) the atrial myocytes against the background of persistent BP decrease in hypertensive rats to 142.0 ± 4.2 mm Hg. We concluded that myoendocrine cells in rats with stable hypertension retain ability to respond adequately to distention of the atria with blood.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Heart; Hypertension; Losartan; Male; Myocytes, Cardiac; Natriuretic Peptides; Rats

The aim of this study was to investigate the effects of chronic treatment with atrial natriuretic peptide (ANP) on renal function, nitric oxide (NO) system, oxidative stress, collagen content and apoptosis in kidneys of spontaneously hypertensive rats (SHR), as well as sex-related differences in the response to the treatment.. 10 week-old male and female SHR were infused with ANP (100 ng/h/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). Systolic blood pressure (SBP) was recorded and diuresis and natriuresis were determined. After treatment, renal NO synthase (NOS) activity and eNOS expression were evaluated. Thiobarbituric acid-reactive substances (TBARS), glutathione concentration and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in the kidney. Collagen was identified in renal slices by Sirius red staining and apoptosis by Tunel assay.. Female SHR showed lower SBP, oxidative stress, collagen content and apoptosis in kidney, and higher renal NOS activity and eNOS protein content, than males. ANP lowered SBP, increased diuresis, natriuresis, renal NOS activity and eNOS expression in both sexes. Renal response to ANP was more marked in females than in males. In kidney, ANP reduced TBARS, renal collagen content and apoptosis, and increased glutathione concentration and activity of GPx and SOD enzymes in both sexes.. Female SHR exhibited less organ damage than males. Chronic ANP treatment would ameliorate hypertension and end-organ damage in the kidney by reducing oxidative stress, increasing NO-system activity, and diminishing collagen content and apoptosis, in both sexes.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Pressure; Diuresis; Female; Hypertension; Kidney; Male; Natriuresis; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Inbred SHR; Sex Factors

Proteinuria is a hallmark of chronic kidney disease (CKD) and cardiovascular disease (CVD), and a good predictor of clinical outcome. Selective endothelin A (ETA) receptor antagonist used with renin-angiotensin system (RAS) inhibitors prevents development of proteinuria in CKD. However, whether the improvement in proteinuria would have beneficial effects on CVD, independent of RAS inhibition, is not well understood. In this study, we investigated whether atrasentan, an ETA receptor antagonist, has renal and cardiovascular effects independent of RAS inhibition. Male Dahl salt sensitive (DSS) rats, at six weeks of age, received water with or without different doses of atrasentan and/or enalapril under high salt (HS) diet or normal diet (ND) for 6 weeks. At the end of 12th week, atrasentan at a moderate dose significantly attenuated proteinuria and serum creatinine without reducing mean arterial pressure (MAP), thereby preventing cardiac hypertrophy and improving cardiac function. ACE inhibitor enalapril at a dose that did not significantly lowered BP, attenuated cardiac hypertrophy while moderately improving cardiac function without reducing proteinuria and serum creatinine level. Nonetheless, combined therapy of atrasentan and enalapril that does not altering BP exerted additional cardioprotective effect. Based on these findings, we conclude that BP independent monotherapy of ETA receptor antagonist attenuates the progression of CKD and significantly mitigates CVD independent of RAS inhibition.

Topics: Animals; Atrasentan; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Disease Models, Animal; Echocardiography; Endothelin A Receptor Antagonists; Gene Expression; Heart Diseases; Hemodynamics; Hypertension; Hypertrophy; Kidney Function Tests; Male; Myocytes, Cardiac; Phenylephrine; Pyrrolidines; Rats; Receptor, Endothelin A; Renal Insufficiency, Chronic

The renin-angiotensin-aldosterone system (RAAS) and their candidate genes are principally involved in regulation of blood pressure through salt-water homeostasis. Atrial natriuretic peptide (ANP) and Aldosterone synthase (CYP11B2) are the important RAAS mediators, play a major role in hypertension through regulation of cardiorenal homeostasis and water-electrolytes balance, respectively. Present study reports the expression of ANP and CYP11B2 gene at mRNA and proteins levels in patients with essential hypertension in North Indian subjects. Gene expression at mRNA and protein levels was carried out by Real time PCR and Western blot, respectively. We found a significant down regulation in the ANP gene expression at mRNA (85%) and protein (72.6%) levels and significant increase in the CYP11B2 protein expression in patients as compared to controls. A significant increase in Serum creatinine (14.6%), Sodium (1.15%) and decrease in the Blood urea (8.18%) and Potassium (2.32%) levels were also observed among the patients group having higher expression (based on median delta-CT value) in comparison to the lower expression of CYP11B2 gene. Our results suggest that the down-regulation of ANP gene expression at mRNA and protein levels and up-regulated CYP11B2 protein expression levels may be correlated with the essential hypertension and could serve as circulating prognostic biomarkers for essential hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Base Sequence; Biomarkers; Blotting, Western; Case-Control Studies; Cytochrome P-450 CYP11B2; DNA Primers; Female; Humans; Hypertension; Male; Middle Aged

Topics: Atrial Natriuretic Factor; Female; Gastric Bypass; Humans; Hypertension; Male; Obesity, Morbid

Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Calcineurin; Cardiomegaly; Hypertension; Injections, Subcutaneous; Kidney; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Renin

Atrial natriuretic peptide (ANP) plays an important role in vascular functions such as blood pressure regulation and relaxant activity. Individual vascular beds exhibit differences in vascular reactivity to various ligands, however, the difference in responsiveness to ANP between carotid and renal arteries and the molecular mechanisms of its vasorelaxant activity in a pathophysiological state, including hypertension, remain unclear. We therefore investigated this issue by exposing carotid and renal artery rings obtained from spontaneously hypertensive rats (SHR) to ANP. In the SHR artery (vs. control WKY artery), the ANP-induced relaxations were reduced in carotid artery but not renal artery. Acetylcholine-induced relaxations were reduced in both arteries in SHR (vs. WKY). Sodium nitroprusside-induced relaxation was similar in both arteries between the groups. In carotid arteries, the ANP-induced relaxation was not affected by endothelial denudation or by treatment with inhibitors of nitric oxide synthase, cyclooxygenase, the voltage-dependent potassium channel, or ATP-sensitive potassium channel in arteries from both SHR and WKY. In the carotid artery from WKY but not SHR, the ANP-induced relaxation was significantly reduced by inhibition of the large-conductance calcium-activated potassium channel (BKCa). The BKCa activator-induced relaxation was reduced in the SHR artery (vs. WKY). These results suggest that ANP-induced relaxation is impaired in the carotid artery from SHR and this impairment may be at least in part due to the reduction of BKCa activity rather than endothelial components.

Topics: Acetylcholine; Animals; Atrial Natriuretic Factor; Blood Pressure; Carotid Arteries; Hypertension; Male; Nitroprusside; Potassium Channels, Calcium-Activated; Rats, Inbred SHR; Renal Artery; Vasodilation

Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly recognized phenotype is commonly associated with renal dysfunction and there is an unmet need for renal enhancing therapies. In a canine model of HF and acute vasoconstrictive hypertension we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP), a novel particulate guanylyl cyclase (pGC) activator, and nitroglycerin, a soluble guanylyl cyclase (sGC) activator.. HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II infusion. We characterized the cardiorenal and humoral actions prior to, during, and following intravenous M-ANP (n=7), nitroglycerin (n=7), and vehicle (n=7) infusion. Mean arterial pressure (MAP) was reduced by M-ANP (139 ± 4 to 118 ± 3 mm Hg, P<0.05) and nitroglycerin (137 ± 3 to 116 ± 4 mm Hg, P<0.05); similar findings were recorded for pulmonary wedge pressure (PCWP) with M-ANP (12 ± 2 to 6 ± 2 mm Hg, P<0.05) and nitroglycerin (12 ± 1 to 6 ± 1 mm Hg, P<0.05). M-ANP enhanced renal function with significant increases (P<0.05) in glomerular filtration rate (38 ± 4 to 53 ± 5 mL/min), renal blood flow (132 ± 18 to 236 ± 23 mL/min), and natriuresis (11 ± 4 to 689 ± 37 mEq/min) and also inhibited aldosterone activation (32 ± 3 to 23 ± 2 ng/dL, P<0.05), whereas nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.. Our results advance the differential cardiorenal actions of pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation. These distinct renal and aldosterone modulating actions make M-ANP an attractive therapeutic for HF with concomitant hypertension, where renal protection is a key therapeutic goal.

Topics: Aldosterone; Angiotensin II; Animals; Arterial Pressure; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Enzyme Activation; Enzyme Activators; Guanylate Cyclase; Heart Failure; Hypertension; Male; Natriuresis; Nitroglycerin; Pulmonary Wedge Pressure; Receptors, Cytoplasmic and Nuclear; Renal Circulation; Soluble Guanylyl Cyclase; Time Factors

To evaluate the impact of a functional genetic variant in the natriuretic peptide clearance receptor, NPR3, on circulating natriuretic peptides (NPs) and myocardial structure and function in the general community.. NPR3 plays an important role in the clearance of NPs and through direct signaling mechanisms modulates smooth muscle cell function and cardiac fibroblast proliferation. A NPR3 nonsynonymous single nucleotide polymorphism (SNP) rs2270915, resulting in a N521D substitution in the intracellular catalytic domain that interacts with Gi could affect receptor function. Whether this SNP is associated with alterations in NPs levels and altered cardiac structure and function is unknown.. DNA samples of 1931 randomly selected residents of Olmsted County, Minnesota were genotyped. Plasma NT-proANP1-98, ANP1-28, proBNP1-108, NT-proBNP1-76, BNP1-32 and BNP3-32 levels were measured. All subjects underwent comprehensive echocardiography.. Genotype frequencies for rs2270915 were as follows: (A/A 60%, A/G 36%, G/G 4%). All analyses performed were for homozygotes G/G versus wild type A/A plus the heterozygotes A/G. Diastolic dysfunction was significantly more common (p = 0.007) in the homozygotes G/G (43%) than the A/A+A/G (28%) group. Multivariate regression adjusted for age, sex, body mass index and hypertension demonstrated rs2270915 to be independently associated with diastolic dysfunction (odds ratio 1.94, p = 0.03). There was no significant difference in NPs levels between the 2 groups suggesting that the clearance function of the receptor was not affected.. A nonsynonymous NPR3 SNP is independently associated with diastolic dysfunction and this association does not appear to be related to alterations in circulating levels of natriuretic peptides.

Topics: Aged; Amino Acid Substitution; Atrial Natriuretic Factor; Diastole; Echocardiography, Doppler; Female; Gene Frequency; Genotype; Heart; Humans; Hypertension; Linear Models; Logistic Models; Male; Middle Aged; Minnesota; Multivariate Analysis; Natriuretic Peptide, Brain; Polymorphism, Single Nucleotide; Prevalence; Receptors, Atrial Natriuretic Factor; Ventricular Dysfunction, Left

Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.

Topics: Adiponectin; Aldosterone; Animals; Antioxidants; Arginine; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiomyopathies; Cardiotonic Agents; Chemokine CCL2; Chemokine CCL3; Cyclic GMP; Dinoprost; Endothelin-1; Enzyme Induction; Extracellular Matrix Proteins; Heart Failure; Heme; Heme Oxygenase (Decyclizing); Hypertension; Interleukin-1beta; Interleukin-6; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Tyrosine

The abnormal blood volume regulation is one of the most important pathogenesis in postural tachycardia syndrome in children. This study was designed to investigate the plasma atrial natriuretic peptide and antidiuretic hormone levels in postural tachycardia syndrome children, and their associations with the changes in heart rate and blood pressure in head-up test.. Twenty-one postural tachycardia syndrome patients ((12 ± 2) years) and 26 healthy children ((12 ± 1) years) were included. According to blood pressure changes in head-up test, the postural tachycardia syndrome patients were divided into two subgroups: postural tachycardia syndrome with orthostatic hypertension and postural tachycardia syndrome without orthostatic hypertension. The plasma atrial natriuretic peptide and antidiuretic hormone levels were measured using enzyme-linked immunosorbent assay.. The plasma atrial natriuretic peptide level in postural tachycardia syndrome patients was higher than the control (P = 0.004), whereas the difference in plasma antidiuretic hormone level between postural tachycardia syndrome and controls was not significant (P = 0.222). The plasma antidiuretic hormone level of patients suffering from postural tachycardia syndrome with orthostatic hypertension was much higher than that of children having postural tachycardia syndrome without orthostatic hypertension (P < 0.05). In postural tachycardia syndrome patients, the upright max heart rate was positively correlated with the plasma atrial natriuretic peptide level (r = 0.490, P < 0.05) and the upright systolic blood pressure was positively correlated with the plasma antidiuretic hormone levels (r = 0.472, P < 0.05).. There was a disturbance of plasma atrial natriuretic peptide and antidiuretic hormone in postural tachycardia syndrome children.

Topics: Adolescent; Atrial Natriuretic Factor; Case-Control Studies; Child; Humans; Hypertension; Postural Orthostatic Tachycardia Syndrome; Vasopressins

Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ-specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated.. Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation-specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium-specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension.. PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.

Topics: Aged; Amyloid beta-Protein Precursor; Atrial Function; Atrial Natriuretic Factor; Female; Fibrosis; Heart Atria; Humans; Hypertension; Immunohistochemistry; Male; Middle Aged; Prealbumin; Protein Aggregates; Randomized Controlled Trials as Topic

The aim of the study was to investigate the role of osteoprotegerin (OPG) in left ventricular hypertrophy (LVH) development in patients with essential hypertension (EH). A total of 1092 patients diagnosed with EH were recruited. The LVHs were determined and OPG gene polymorphisms were genotyped. Patients with LVH had a significantly higher mean serum OPG level than those without LVH. The 1181CC genotype carriers had significantly lower risk for LVH compared with GC and GG genotype carriers. The serum OPG level and OPG 1181 G>C polymorphism were found to be independent risk factors for the occurrence of LVH in hypertensive patients. In vitro study shows that OPG overexpression upregulates cell surface size, protein synthesis per cell, and hypertrophy- and fibrosis-related proteins in both cardiomyocytes and cardiac fibroblasts, whereas OPG inhibition can abolish the above-mentioned changes. Consistent with the in vitro data, our in vivo study revealed that the OPG administration induced the LVH in hypertensive rats. This study is the first to report the close association between OPG and LVH development in EH patients and the regulatory effect of OPG on cardiomyocytes and cardiac fibroblasts.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Case-Control Studies; Cells, Cultured; Female; Fibroblasts; Gene Frequency; Genotype; Heart Ventricles; Heterozygote; Humans; Hypertension; Hypertrophy, Left Ventricular; Logistic Models; Male; Middle Aged; Myocytes, Cardiac; Osteoprotegerin; Polymorphism, Genetic; Rats, Sprague-Dawley; Risk Factors; RNA, Small Interfering; Troponin I; Ventricular Myosins

It is well known now that atrial cardiomyocytes carry out both contractile and endocrine activities--they synthesize, accumulate in specific secretory granules and release the natriuretic peptides. The main physiological effects of natriuretic peptides are antagonistic to the renin-angiotensin-aldostrol system, but their role in the development of hypertension is still disputable. The aim of this investigation is to estimate using electron microscopy the secretory activities of atrial myoendocrine cells in rats with inherited stress-induced arterial hypertension (ISIAH stain). It has been shown that myoendocrine cells in the ISIAH rats with arterial pressure about 180 mm Hg reveal morphological features of increased synthesis, extra accumulation and release of natriuretic peptides compared with normotensive control rats. In the ISIAH rats treated with losartan (angiotensin II receptor blocker) and therefore having a sustained decrease in arterial pressure to 140 mm Hg, changes in granular pool composition, reduction of the number and diameter of the secretory granules, reduction of Golgi complexes, and increased intracellular degradation of secretory stores were found in the myoendocrine cells. At the same time the marked capillary hyperemia and interstitial edema in the myocardium were observed. Thus, in rats with severe inherited hypertension, the secretory activity of heart myoendocrine cells is sharply increased and directly depends on the arterial blood pressure level. This proves that natriuretic peptides actively participate in the regulation of hemodynamics during with cardiovascular pathology.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Golgi Apparatus; Heart Atria; Hemodynamics; Hypertension; Losartan; Male; Myocardium; Myocytes, Cardiac; Rats; Secretory Vesicles

The α2-isoform of the Na,K-ATPase (α2) is the minor isoform of the Na,K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing α2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of α2 to further define the tissue-specific role of α2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of α2 in the heart using β-myosin heavy chain Cre. We have achieved a 90% knockout of α2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of α2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of α2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of α2 determines its unique roles in the regulation of cardiovascular function.

Topics: Adrenocorticotropic Hormone; Animals; Atrial Natriuretic Factor; Blood Pressure; Gene Knockout Techniques; Hypertension; Hypertrophy, Left Ventricular; Integrases; Mice; Mice, Knockout; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Natriuretic Peptide, Brain; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; RNA, Messenger; Sodium-Potassium-Exchanging ATPase; Ultrasonography; Vasoconstriction; Ventricular Dysfunction, Left

Long-acting natriuretic peptide (LANP) is one of the peptide hormones in atrial natriuretic peptide (ANP) prohormone. Its biological properties are blood pressure regulation, maintenance of plasma volume and anticancer effects. The aim of this study was to evaluate the relationship between metabolic syndrome (MetS) and fasting serum LANP concentration in hypertensive patients.. Fasting blood samples were obtained from 224 patients with or without hypertension. MetS and its components were defined using diagnostic criteria from the International Diabetes Federation.. Eighty-eight hypertensive patients (59.5 %) had MetS. Hypertensive patients with MetS had higher body weight (p = 0.003), waist circumference (p = 0.003), body mass index (p = 0.002), triglyceride concentrations (p = 0.029), insulin levels (p = 0.001), HOMA-IR (p <0.003) and HOMA-β (p = 0.049) and lower HDL-C concentrations (p = 0.001), LANP levels (p = 0.012) than those without MetS. The univariable linear regression analysis showed that age (p = 0.038) and the BUN concentration (p = 0.022) were positively correlated with the serum LANP levels, whereas the insulin level (p = 0.001), HOMA-IR (p = 0.004), and HOMA-β (p = 0.001) were negatively correlated with the fasting serum LANP levels among the hypertensive patients. Multivariable forward stepwise linear regression analysis of the significant variables showed that the HOMA-β (β = -0.387, R(2) = 0.141, p <0.001) was an independent predictor of fasting serum LANP levels in hypertensive patients.. LANP level is significantly reduced in hypertensive patients affected by MetS and is negatively related to pancreatic beta cell function in hypertensive patients.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Body Mass Index; Cholesterol, HDL; Cross-Sectional Studies; Fasting; Female; Humans; Hypertension; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Peptide Fragments; Triglycerides; Waist Circumference

miRNAs play an important role in the pathogenesis of cardiac hypertrophy and dysfunction. However, little is known about how miR-30a regulates cardiomyocyte hypertrophy. In the study, Male C57BL/6 mice were subjected to thoracic aortic constriction, and hearts were harvested at 3 weeks. We assayed miR-30a expression level by real-time PCR and defined the molecular mechanisms of miR-30a-mediated cardiomyocyte hypertrophy. We found that myocardial expression of miR-30a was decreased in mouse models of hypertrophy and in H9c2 cells treated with phenylephrine. MiR-30a inhibition markedly increased mRNA expression of cardiac hypertrophy markers such as atrial natriuretic factor and brain natriuretic peptide in H9c2, and cell size was increased after miR-30a inhibitor treatment. Downregulated miR-30a activated autophagy by inhibiting beclin-1 expression in H9c2 cell. More important, autophagy inhibition suppressed miR-30a inhibitor-induced cardiomyocyte hypertrophy. Together, our data demonstrated that downregulated miR-30a aggravates pressure overload-induced cardiomyocyte hypertrophy by activating autophagy, thus offering a new target for the therapy of cardiomyocyte hypertrophy.

Topics: 3' Untranslated Regions; Animals; Atrial Natriuretic Factor; Autophagy; Cardiomegaly; Cell Line; Cell Size; Down-Regulation; Gene Expression Regulation; HEK293 Cells; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Rats

Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese hypertensive men (obeseHT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure, <130/80 mm Hg), and in 27 lean normotensive men (leanNT: body mass index, 20.0-24.9 kg/m(2); 24-hour ambulatory blood pressure, <130/80 mm Hg). All study subjects were medication free. As a surrogate estimate for dietary sodium intake, we measured sodium excretion in a 24-hour urine collection and we measured serum levels of midregional proatrial NP and plasma levels of renin and angiotensin II. The obese men had higher mean (±SD) urinary sodium excretion (obeseHT, 213.6±85.2 mmol; obeseNT, 233.0±70.0 mmol) than the lean normotensive men (leanNT, 155.5±51.7 mmol; P=0.003). ObeseHT had lower (median [interquartile range]) serum midregional proatrial NP levels (49.2 [37.3-64.7] pmol/L) than leanNT (69.3 [54.3-82.9] pmol/L; P=0.003), whereas obeseNT had midregional proatrial NP levels in between (54.1 [43.2-64.7] pmol/L); obeseNT had lower (median [interquartile range]) plasma levels of renin (5.0 [3.0-8.0] mIU/L versus 9.0 [4.0-18.0]) and angiotensin II (2.4 [1.5-3.5] pmol/L versus 4.2 [2.2-7.9]) than obeseHT (P≤0.049), whereas obeseHT had similar plasma levels of renin and angiotensin II as leanNT (P≥0.19). Thus, despite a high sodium intake and a high blood pressure, obese hypertensive men have a relative NP deficiency and an inadequate renin-angiotensin system suppression.

Topics: Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Composition; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Obesity; Prognosis; Renin; Renin-Angiotensin System

Epidemiological studies have shown considerable heritability of blood pressure, thus suggesting a role for genetic factors. Previous studies have shown an association of a single nucleotide polymorphism rs5068 in the NPPA locus gene with higher levels of circulating atrial natriuretic peptide as well as with lower intra individual blood pressure, but up to date, no association between rs5068 and cardiac organ damage, i.e. left ventricular hypertrophy, has been accounted for in humans. We sought to explore if rs5068 is associated with left ventricular hypertrophy as measured by echocardiographic examination in a non-diabetic population.. 968 non-diabetic individuals from the Malmö Preventive Project (mean age 67 years; 31% women) were genotyped and examined with echocardiography. Logistic regression was used to adjust for covariates.. The minor allele of rs5068 was associated with decreased prevalence of left ventricular hypertrophy (p = 0.021) after adjustment for sex and age. In the multivariate logistic analysis including; age, sex, systolic blood pressure, antihypertensive and/or cardioprotective treatment, body mass index and fasting plasma glucose, the association of rs5068 with left ventricular hypertrophy was, as expected, attenuated (p = 0.061).. In a non-diabetic population, the minor allele of rs5068 was associated with lower left ventricular mass. These findings suggest that rs5068, or genetic variants in linkage disequilibrium, might affect susceptibility to left ventricular hypertrophy and support the possible protective role of natriuretic peptides.

Topics: Aged; Alleles; Atrial Natriuretic Factor; Blood Pressure; Cohort Studies; Echocardiography; Female; Genetic Variation; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Linkage Disequilibrium; Logistic Models; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Sweden

The peculiarities of cardiac natriuretic peptide secretion have been investigated during ontogenesis using the hypertonic disease model in ISIAH rat line (with inherited stress induced arterial hypertension). The qualitative and quantitative ultrastructural investigations of right atrium myocardium revealed that the cardiac hormonal synthetic and secretory activities in ISIAH rats are higher as compared with normotensive even-aged rats from control group. Secretory hyperactivity of atrial myocytes in ISIAH rats during early ontogeny precedes the manifestations of hereditary hypertension. Natriuretic peptides present the hypotensive circuit of hemodynamic regulation during the whole ontogeny and the complementary chain in hypertension development.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Female; Golgi Apparatus; Heart; Heart Atria; Hypertension; Male; Rats; Rats, Inbred Strains

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.

Topics: 3' Untranslated Regions; Adult; Animals; Atrial Natriuretic Factor; Chlorocebus aethiops; COS Cells; Cyclic GMP; Female; Gene Expression; Gene Frequency; Genetic Association Studies; Humans; Hypertension; Male; MicroRNAs; Polymorphism, Single Nucleotide; RNA Interference; Sequence Analysis, DNA; Sodium Chloride, Dietary; Young Adult

The aim of this study was to investigate both the effects of chronic treatment with atrial natriuretic peptide (ANP) on systolic blood pressure (SBP), cardiac nitric oxide (NO) system, oxidative stress, hypertrophy, fibrosis and apoptosis in spontaneously hypertensive rats (SHR), and sex-related differences in the response to the treatment.. 10 week-old male and female SHR were infused with ANP (100 ng/hr/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). SBP was recorded and nitrites and nitrates excretion (NOx) were determined. After treatment, NO synthase (NOS) activity, eNOS expression, thiobarbituric acid-reactive substances (TBARS) and glutathione concentration were determined in left ventricle, as well as the activity of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD). Morphological studies in left ventricle were performed in slices stained with hematoxylin-eosin or Sirius red to identify collagen as a fibrosis indicator; immunohistochemistry was employed for identification of transforming growth factor beta; and apoptosis was evaluated by Tunel assay.. Female SHR showed lower SBP, higher NO-system activity and less oxidative stress, fibrosis and hypertrophy in left ventricle, as well as higher cardiac NOS activity, eNOS protein content and NOx excretion than male SHR. Although ANP treatment lowered blood pressure and increased NOS activity and eNOS expression in both sexes, cardiac NOS response to ANP was more marked in females. In left ventricle, ANP reduced TBARS and increased glutathione concentration and activity of CAT and SOD enzymes in both sexes, as well as GPx activity in males. ANP decreased fibrosis and apoptosis in hearts from male and female SHR but females showed less end-organ damage in heart. Chronic ANP treatment would ameliorate hypertension and end-organ damage in heart by reducing oxidative stress, increasing NO-system activity, and diminishing fibrosis and hypertrophy.

Topics: Animals; Antihypertensive Agents; Apoptosis; Atrial Natriuretic Factor; Blood Pressure; Catalase; Disease Models, Animal; Female; Glutathione; Heart; Hypertension; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rats, Inbred SHR; Sex Factors; Superoxide Dismutase; Transforming Growth Factor beta

The combination of systemic arterial hypertension and diabetes mellitus (DM) induces greater cardiac remodeling than either condition alone. However, this association has been poorly addressed in senescent rats. Therefore, this study aimed to analyze the influence of streptozotocin-induced DM on ventricular remodeling and oxidative stress in aged spontaneously hypertensive rats (SHR).. Fifty 18 month old male SHR were divided into two groups: control (SHR, n = 25) and diabetic (SHR-DM, n = 25). DM was induced by streptozotocin (40 mg/kg, i.p.). After nine weeks, the rats underwent echocardiography and myocardial functional study in left ventricular (LV) isolated papillary muscle preparations. LV samples were obtained to measure myocyte diameters, interstitial collagen fraction, and hydroxyproline concentration. Gene expression of atrial natriuretic peptide (ANP) and α- and β-myosin heavy chain (MyHC) isoforms was evaluated by RT-PCR. Serum oxidative stress was assessed by measuring lipid hydroperoxide concentration and superoxide dismutase and glutathione peroxidase activities.. Student's t test or Mann-Whitney test, p < 0.05.. SHR-DM presented higher blood glucose (487 ± 29 vs. 89.1 ± 21.1 mg/dL) and lower body weight (277 ± 26 vs. 339 ± 38 g). Systolic blood pressure did not differ between groups. Echocardiography showed LV and left atrial dilation, LV diastolic and relative wall thickness decrease, and LV systolic and diastolic function impairment in SHR-DM. Papillary muscle study showed decreased myocardial contractility and contractile reserve in SHR-DM. Myocyte diameters and myocardial interstitial collagen fraction and hydroxyproline concentration did not differ between groups. Increased serum pro-oxidant activity and gene expression of ANP and β/α-MyHC ratio were observed in DM.. Diabetes mellitus induces cardiac dilation and functional impairment, increases oxidative stress and activates fetal gene program in aged spontaneously hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Myosins; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Echocardiography; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Myosin Heavy Chains; Oxidative Stress; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Transcriptome; Ventricular Remodeling

The role of aldosterone blockers during transition from long-term compensated hypertrophy to dilated failure is not completely understood. In this study we evaluated the effects of early administration of spironolactone on cardiac remodeling, myocardial function, and mortality in spontaneously hypertensive rats (SHR).. Sixteen-month-old SHR received no treatment (SHR-C, n=72) or spironolactone (SHR-SPR, 20 mg/kg/day, n=34) for six months. Echocardiogram was performed before and after treatment. Myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Myocardial collagen and hydroxyproline concentration were evaluated by morphometry and spectrophotometry, respectively. LV gene expression was assessed by real time RT-PCR.. Student's t test; Log rank test (Kaplan Meyer).. SHR-C and SHR-SPR presented mortality rates of 71 and 38%, respectively (p=0.004). Systolic arterial pressure did not differ between groups (SHR-C 199±43; SHR-SPR 200±35 mmHg). Initial and final echocardiograms did not show significant differences in cardiac structures or LV function between groups. Myocardial function was similar between groups at basal and after inotropic stimulation. Collagen fractional area, hydroxyproline concentration, gene expression for α- and β-myosin heavy chain, atrial natriuretic peptide, and Serca2a were not different between groups.. Early spironolactone administration reduces mortality without changing cardiac remodeling in spontaneous hypertensive rats.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Electrocardiography; Gene Expression Regulation; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Papillary Muscles; Rats; Rats, Inbred SHR; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Spironolactone; Ventricular Function, Left; Ventricular Remodeling

The wide experience in the ultrastructural study of myoendocrine cells of different animal species in normal and experimental conditions allows us to choose the optimal methodology that gives the most complete information about the state of intracellular secretory apparatus. It is revealed that the combined set of atrial myoendocrine cell qualitative and quantitative parameters allows defining the natriuretic regulatory system status, as well as it's acute and chronic responses to hemodynamic changes. The information value of such approach is illustrated by examples of the ontogenetic investigation in two rat lines: with normal arterial blood pressure and with inherited stress-induced arterial hypertension. The proposed methodology is quite sensitive and descriptive; so it is of high importance due to insufficiency of other universal, specific, and accurate methods for cardiac natriuretic peptides investigation.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Blood Pressure; Cell Size; Embryo, Mammalian; Female; Heart Atria; Hemodynamics; Hypertension; Male; Microscopy, Electron; Myocytes, Cardiac; Organelle Size; Rats; Rats, Inbred Strains; Secretory Vesicles

To study the relationship between C-type natriuretic peptide (NT-proCNP) and other natriuretic peptides, such as pro-atrial natriuretic peptide [proANP(1-98)] and N-terminal pro-brain natriuretic peptide (NT-proBNP), in the elderly, investigating also their correlation with other traditional clinical markers of the hypertensive condition.. NT-proCNP, NT-proBNP and proANP(1-98) were measured in 57 elderly patients. They were hypertensive patients (n = 36) and normotensive controls (n = 21). Their anthropometric parameters, including Winsor's index and total and high-density lipoprotein cholesterol, were determined.. A diagnostic role of NT-proBNP in hypertensive patients was detected by a model of logistic regression, which gave a significant result [odds ratio (OR) 1.0115, P = 0.0184]. By this model the area (AUC) under the receiver-operating characteristic (ROC) curve was 0.69 ± 0.071 (P = 0.0075). On the basis of the ROC curve, the calculated serum NT-proBNP cut-off for the prediction of hypertension was greater than 164 pmol/l - the value being provided with a sensitivity of 89% coupled with a specificity of 55%. NT-proCNP and proANP(1-98) did not predict the hypertensive condition, although significant correlations were detected with serum lipid profile and creatinine levels.. By using the logistic regression analysis, NT-proBNP was identified as a significant predictor of hypertension, whereas NT-proCNP and proANP circulating levels were not shown to reliably predict the hypertensive condition. Further validation by means of larger cohort studies is undoubtedly needed to assess the use of all three peptides to increase the performance of a possible test for the prediction of the hypertensive condition in humans.

Topics: Aged; Aged, 80 and over; Anthropometry; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Cholesterol; Creatinine; Female; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments; Sensitivity and Specificity

Psychosocial factors have been associated with cardiovascular outcomes, but few studies have examined the association between psychosocial function and natriuretic peptides.. The purpose of this study is to determine the predictive value of hostility, anger, and social support in relation to atrial natriuretic peptide (ANP), a marker of vascular health, among middle-aged men.. One hundred twenty-one men (mean age = 39.8 years, SD = 4.1) underwent assessments of ANP and completed the Cook-Medley Hostility Scale, the Spielberger State-Trait Anger Scale, and the Interview Schedule for Social Interaction.. Higher levels of hostility (β = 0.22 [95 % CI 0.04, 0.40], P = 0.032) and trait anger (β = 0.18 [95 % CI 0.01, 0.37], P = 0.044) were associated with greater ANP levels. In contrast, higher perceived social support was also associated with lower ANP levels, (β = -0.19 [95 % CI -0.05, -0.41], P = 0.010).. Psychosocial factors, including hostility, anger, and social support, are associated with varying ANP levels among middle-aged men, independent of cardiovascular and behavioral risk factors.

Topics: Adult; Anger; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cholesterol; Hostility; Humans; Hypertension; Male; Middle Aged; Personality Inventory; Risk Factors; Social Support

Topics: Atrial Natriuretic Factor; Female; Humans; Hypertension; Male; Natriuretic Peptide, Brain

Ghrelin is the endogenous ligand for the growth hormone-secretagogue receptor expressed in various tissues including the heart, blood vessels and kidney. This study sought to determine the effects of long-term treatment with ghrelin (10 nmol/kg, twice a day, intraperitoneally) on the hypertension induced by high salt (8.0% NaCl) diet in Dahl salt-sensitive hypertensive (DS) rats. Systolic blood pressure (SBP) was measured by a tail cuff method. During the treatment period for 3 weeks, high salt diet increased blood pressure compared to normal salt (0.3% NaCl) diet, and this hypertension was partly but significantly (P<0.01) attenuated by simultaneous treatment with ghrelin. Ghrelin significantly increased urine volume and tended to increase urine Na⁺ excretion. Furthermore, ghrelin increased urine nitric oxide (NO) excretion and tended to increase renal neuronal nitric oxide synthase (nNOS) mRNA expression. Ghrelin did not alter the plasma angiotensin II level and renin activity, nor urine catecholamine levels. Furthermore, ghrelin prevented the high salt-induced increases in heart thickness and plasma ANP mRNA expression. These results demonstrate that long-term ghrelin treatment counteracts salt-induced hypertension in DS rats primarily through diuretic action associated with increased renal NO production, thereby exerting cardio-protective effects.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiomegaly; Cardiotonic Agents; Diuresis; Diuretics; Enzyme Induction; Ghrelin; Heart Ventricles; Hypertension; Injections, Intraperitoneal; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium; Sodium Chloride, Dietary; Ultrasonography; Up-Regulation

The aim of the present study was to verify the effects of low-intensity endurance training and detraining on the mechanical and molecular properties of cardiomyocytes from spontaneously hypertensive rats (SHRs). Male SHRs and normotensive control Wistar rats at 16-weeks of age were randomly divided into eight groups of eight animals: NC8 and HC8 (normotensive and hypertensive control for 8weeks); NT8 and HT8 (normotensive and hypertensive trained at 50-60% of maximal exercise capacity for 8weeks); NC12 and HC12 (normotensive and hypertensive control for 12weeks); NDT and HDT (normotensive and hypertensive trained for 8weeks and detrained for 4weeks). The total exercise time until fatigue (TTF) was determined by a maximal exercise capacity test. Resting heart rate (RHR) and systolic arterial pressure (SAP) were measured. After the treatments, animals were killed by cervical dislocation and left ventricular myocytes were isolated by enzymatic dispersion. Isolated cells were used to determine intracellular global Ca(2+) ([Ca(2+)]i) transient and cardiomyocyte contractility (1Hz; ~25°C). [Ca(2+)]i regulatory proteins were measured by Western blot, and the markers of pathologic cardiac hypertrophy by quantitative real-time polymerase chain reaction (q-RT-PCR). Exercise training augmented the TTF (NC8, 11.4±1.5min vs. NT8, 22.5±1.4min; HC8, 11.7±1.4min vs. HT8, 24.5±1.3min; P<0.05), reduced RHR (NT8initial, 340±8bpm vs. NT8final, 322±10bpm; HT8initial, 369±8bpm vs. HT8final, 344±10bpm; P<0.05), and SBP in SHR animals (HC8, 178±3mmHg vs. HT8, 161±4mmHg; P<0.05). HC8 rats showed a slower [Ca(2+)]i transient (Tpeak, 83.7±1.8ms vs. 71.7±2.4ms; T50%decay, 284.0±4.3ms vs. 264.0±4.1ms; P<0.05) and cell contractility (Vshortening, 86.1±6.7μm/s vs. 118.6±6.7μm/s; Vrelengthening, 57.5±7.4μm/s vs. 101.3±7.4μm/s; P<0.05), and higher expression of ANF (300%; P<0.05), skeletal α-actin (250%; P<0.05) and a decreased α/β-MHC ratio (70%; P<0.05) compared to NC8. Exercise training increased [Ca(2+)]i transient (NC8, 2.39±0.06F/F0 vs. NT8, 2.72±0.06F/F0; HC8, 2.28±0.05F/F0 vs. HT8, 2.82±0.05F/F0; P<0.05), and cell contractility (NC8, 7.4±0.3% vs. NT8, 8.4±0.3%; HC8, 6.8±0.3% vs. HT8, 7.8±0.3%; P<0.05). Furthermore, exercise normalized the expression of ANF, skeletal α-actin, and the α/β-MHC ratio in HT8 rats, augmented the expression of SERCA2a (NC8, 0.93±0.15 vs. NT8, 1.49±0.14; HC8, 0.83±0.13 vs. HT8, 1.32±0.14; P<0.05) and PLBser16 (NC8, 0.89±0.18 vs. NT8, 1.23±0.17; HC8, 0.77

Topics: Animals; Atrial Natriuretic Factor; Calcium Signaling; Calcium-Binding Proteins; Cells, Cultured; Exercise Therapy; Gene Expression; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardial Contraction; Myocytes, Cardiac; Myosin Heavy Chains; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Inbred SHR; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases

To study the effects of a diet rich in salt and/or saturated fat on atrial natriuretic peptide (ANP)-granules, hypertension, renin expression, and cardiac structure in C57Bl/6 mice.. Young adult male mice were separated into four groups (n = 12) and fed one of the following for 9 weeks: standard chow/normal salt (SC-NS), high-fat chow/normal salt (HF-NS), standard chow/high salt (SC-HS) and high-fat chow/high salt (HF-HS). Alterations in the serum ANP, ultrastructural analysis of cardiomyocytes that produce ANP, structural analysis of the left ventricle, blood pressure, renin expression, glomerular filtration rate (GFR), feed efficiency, and lipid and glucose parameters were examined.. The HF-NS diet showed a small increase in ANP production and left ventricular hypertrophy, increased food efficiency, and abnormal lipid and glucose parameters. The SC-HS diet showed a large increase in ANP granules in myocytes and corresponding elevation in ANP serum levels, left ventricular hypertrophy, hypertension, decrease in renin levels, and increase in GFR. The combination of the two diets (HF-HS) had an additive effect.. The incorporation of a high-fat high-salt diet induced ultrastructural changes in cardiomyocytes, increased the production of ANP and increased its serum level, and reduced the amount of renin in the kidney.

Topics: Animals; Atrial Natriuretic Factor; Diet, High-Fat; Dietary Fats; Down-Regulation; Glomerular Filtration Rate; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Random Allocation; Renin; Secretory Vesicles; Sodium Chloride, Dietary; Soybean Oil; Up-Regulation

Pulse pressure (an indirect measure of arterial stiffness) is a robust predictor of cardiovascular events, but its pathophysiology remains poorly understood. To gain insight into the pathophysiology of arterial stiffness we conducted an exploratory investigation of the associations of 47 circulating biomarkers in etiologic pathways of arteriosclerosis with brachial artery pulse pressure.. Participants included 1,193 African-Americans and 1,145 non-Hispanic whites belonging to hypertensive sibships. Blood pressure (BP) was measured with a random-zero sphygmomanometer. Multivariable linear regression was employed to assess the associations of biomarkers with pulse pressure after adjustment for age, sex, conventional risk factors, mean arterial pressure, heart rate, and use of aspirin, statins, estrogens, and antihypertensives. Statistical significance was set at P ≤ 0.001 (Bonferroni correction for multiple testing).. Log N-terminal probrain natriuretic peptide (NT-proBNP) (African-Americans: β = 2.11 ± 0.52, non-Hispanic whites: β = 2.65 ± 0.55), log midregional proatrial natriuretic peptide (African-Americans: β = 4.83 ± 0.70, non-Hispanic whites: β = 3.70 ± 0.67), and log osteoprotegerin (African-Americans: β = 4.64 ± 1.02, non-Hispanic whites: β = 4.19 ± 0.99) were independently associated with pulse pressure (P < 0.001 for all) in both ethnicities. Log C-reactive protein (CRP) (β = 1.56 ± 0.35), log midregional proadrenomedullin (MR-proADM) (β = 5.53 ± 1.19) and log matrix metalloproteinase-2 (β = 3.89 ± 1.06) were associated with greater pulse pressure in African-Americans only (P ≤ 0.001 for all), whereas higher fibrinogen was associated with pulse pressure in non-Hispanic whites only (β = 0.02 ± 0.004. P < 0.001).. Our results suggest that hemodynamic stress, vascular inflammation and calcification, and matrix remodeling may have a role in the pathogenesis and/or adverse consequences of increased pulse pressure.

Topics: Adrenomedullin; Aged; Arteriosclerosis; Atrial Natriuretic Factor; Biomarkers; Black People; Blood Pressure; C-Reactive Protein; Female; Fibrinogen; Humans; Hypertension; Male; Matrix Metalloproteinase 2; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Vascular Stiffness; White People

The human SLC4A5 gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) levels and hypertension status. The biochemical basis of this association is unknown particularly since no single gene variant was linked to hypertension in humans. SLC4A5 (NBCe2, NBC4) is expressed in the collecting duct of the kidney and acts as an electrogenic ion-transporter that transports sodium and bicarbonate with a 1:2 or 1:3 stoichiometry allowing bicarbonate reabsorption with relatively minor concurrent sodium uptake. We have mutated the Slc4a5 gene in mice, which caused a persistent increase in systolic and diastolic BP. Slc4a5 mutant mice also displayed a compensated metabolic acidosis and hyporeninemic hypoaldosteronism. Analysis of kidney physiology revealed elevated fluid intake and urine excretion and increased glomerular filtration rate. Transcriptome analysis uncovers possible compensatory mechanisms induced by SLC4A5 mutation, including upregulation of SLC4A7 and pendrin as well as molecular mechanisms associated with hypertension. Induction of metabolic alkalosis eliminated the BP difference between wild-type and Slc4a5 mutant mice. We conclude that the impairment of the function of SLC4A5 favors development of a hypertensive state. We reason that the loss of sodium-sparing bicarbonate reabsorption by SLC4A5 initiates a regulatory cascade consisting of compensatory bicarbonate reabsorption via other sodium-bicarbonate transporters (e.g. SLC4A7) at the expense of an increased sodium uptake. This will ultimately raise BP and cause hypoaldosteronism, thus providing a mechanistic explanation for the linkage of the SLC4A5 locus to hypertension in humans.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Aldosterone; Animals; Atrial Natriuretic Factor; Blood; Blood Chemical Analysis; Blood Pressure; Gene Expression Regulation; Glomerular Filtration Rate; Hydrogen-Ion Concentration; Hypertension; In Situ Hybridization; Kidney; Kidney Tubules; Male; Mice; Mutation; Sequence Deletion; Sodium; Sodium Bicarbonate; Sodium-Bicarbonate Symporters; Urination; Urine

Left ventricular hypertrophy (LVH) is predictive of cardiovascular disease. The vasodilator, natriuretic and diuretic actions of atrial natriuretic peptide (ANP) support a role in the pathophysiology of hypertension. Measuring the redundant precursor fragment mid-regional portion of pro-atrial natriuretic peptide (MRproANP) overcomes the technical difficulties of quantifying the bioactive ANP. This study sought to investigate the diagnostic and prognostic utility of MRproANP in a hypertensive Caucasian patient population. A total of 194 hypertensive patients (39 patients with LVH, 69±7.82 years of age, 74% female vs 155 patients without LVH, 68±6.51 years of age, 71% female) were derived from a screening study. Plasma MRproANP concentrations were quantified using immunoluminometric assays. Hypertensive patients with LVH had higher MRproANP concentrations than those without LVH (103.04 (50.58) vs 84.11 pmol l(-1) (44.82); P=0.014). Independent predictors of left ventricular mass index were LogMRproANP (P=0.022), male gender (P<0.001), body mass index (P=0.001) and history of angina or myocardial infarction (P=0.009). The receiver operating curve for MRproANP for the detection of LVH was limited, yielding an area under the curve of only 0.628 (confidence interval 0.523-0.733; P=0.014). Therefore, the role of MRproANP may not lie in the diagnosis of LVH but in monitoring the response to therapy. A nonsignificant trend towards greater mortality in patients with above-median MRproANP levels compared with below-median levels (P=0.167) was observed. Larger studies are required to assess its prognostic utility further.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Comorbidity; Confidence Intervals; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; ROC Curve; Survival Rate; White People

Evidence has shown that endoplasmic reticulum stress (ERS) is associated with the pathogenesis of cardiac hypertrophy. The aim of this study was to investigate whether direct alleviation of ER stress by 4-phenylbutyric acid (PBA), a known chemical chaperone drug, could attenuate pressure-overload cardiac hypertrophy in mice. The effects of orally administered PBA (100mg/kg body weight daily for a week) were examined using mice undergoing transverse aortic constriction (TAC-mice), an animal model to produce pressure overload. TAC application for 1 week led to a 1.8-fold increase in the ratio of the heart weight over body weight (HW/BW) and up-regulation of the hypertrophy markers ANF and BNF accompanied by up-regulation of ERS markers (GRP78, p-PERK, and p-elF2α). The oral administration of PBA to the TAC-mice reduced hypertrophy (19%) and severely downregulated the fibrosis-related genes (transforming growth factor-β1, phospho-smad2, and pro-collagen isoforms). We conclude that ERS is induced as a consequence of remodeling during pathological hypertrophy and that PBA may help to relieve ERS and play a protective role against cardiac hypertrophy and possibly heart failure. We suggest PBA as a novel therapeutic agent for cardiac hypertrophy and fibrosis.

Topics: Administration, Oral; Animals; Aorta; Apoptosis; Atrial Natriuretic Factor; Biomarkers; Cardiomegaly; Disease Models, Animal; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hypertension; Mice; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phenylbutyrates; Pressure; Transcription Factors; Unfolded Protein Response

Concentration of natriuretic peptides (NPs) in arterial hypertension (AH) patients is higher than that in healthy people. One of the first symptoms of left ventricular hypertrophy (LVH) is left ventricular diastolic dysfunction (LVDD). The aim of this study was to examine whether determination of NPs in blood can be a useful indicator of LVDD detection in idiopathic AH patients. The study was conducted on three groups of patients: group Ia, 19 patients (average age 57 ± 3) with eccentric hypertrophy; group Ib, 13 patients (59 ± 4) with concentric hypertrophy; group II, 33 patients (58 ± 4) without AH or LVH. In all groups, mitral inflow profile was evaluated with Doppler test to detect LVDD, blood flow in upper right pulmonary vein, and concentration of atrial natriuretic peptide (ANP), N-terminal ANP (N-ANP), brain natriuretic peptide (BNP), and N-terminal BNP (N-BNP). In group Ia, significant correlations were observed between the following pairs: ratio of maximum early to late mitral inflow and ANP; deceleration time of early mitral inflow speed and ANP; atrial contraction (AR) and ANP; atrial contraction (AR) and N-ANP; similarly, in group Ib, significant correlations were observed between the following: relative wall thickness and BNP; isovolumic relaxation time and BNP; AR and BNP; relative wall thickness and N-BNP; isovolumic relaxation time and N-BNP; AR and N-BNP.

Topics: Atrial Natriuretic Factor; Echocardiography, Doppler; Female; Heart Atria; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptides; Ventricular Dysfunction, Left

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Topics: Amides; Analysis of Variance; Animals; Atrial Natriuretic Factor; Chemokine CCL2; Disease Models, Animal; Fumarates; Humans; Hypertension; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Nephrectomy; Oxidative Stress; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Ventricular Remodeling

Blacks represent a high-risk population for salt-sensitive hypertension and heart disease, but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in blacks with hypertension and cardiac hypertrophy. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type (WT) or T555I/Q568P variant corin in the heart under the control of α-myosin heavy chain promoter. The mice were crossed into a corin knockout (KO) background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of proatrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12 to 14 months of age when fed a normal salt diet or at a younger age when fed a high-salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in blacks who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in blacks.

Topics: Animals; Atrial Natriuretic Factor; Black People; Blood Pressure; Blotting, Western; Cardiomegaly; Female; Humans; Hypertension; Male; Mice; Mice, Knockout; Mice, Transgenic; Myocardium; Polymorphism, Single Nucleotide; Serine Endopeptidases; Sodium Chloride, Dietary

This study sought to investigate plasma levels of circulating cardiac natriuretic peptides, atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP), in the general community, focusing on their relative differences in worsening human hypertension.. Although ANP and BNP are well-characterized regulators of blood pressure in humans, little is known at the population level about their relationship with hypertension. The authors hypothesized that hypertension is associated with a lack of activation of these hormones or their molecular precursors.. The study cohort (N = 2,082, age >45 years) was derived from a random sample from Rochester, Minnesota, and each subject had a medical history, clinical examination, and assessment of different plasma forms of ANP and BNP. Patients were stratified by blood pressure. Multivariable linear regression was used to assess differences in natriuretic peptide levels in worsening hypertension.. Compared to normotensive, BNP(1-32) and N-terminal proBNP(1-76) (NT-proBNP(1-76)) were significantly decreased in pre-hypertension (p < 0.05), with BNP(1-32) significantly decreased in stage 1 as well (p < 0.05). Although proBNP(1-108) remained unchanged, the processed form was significantly increased only in stage 2 hypertension (p < 0.05). ANP(1-28) remained unchanged, while NT-ANP(1-98) was reduced in pre-hypertension (p < 0.05).. The authors demonstrated the existence of an impaired production and/or release of proBNP(1-108) along with a concomitant reduction of BNP(1-32) and NT-proBNP(1-76) in the early stages of hypertension, with a significant elevation only in stage 2 hypertension. Importantly, they simultaneously demonstrated a lack of compensatory ANP elevation in advanced hypertension.

Topics: Aged; Atrial Natriuretic Factor; Female; Humans; Hypertension; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain

Cardiovascular hypertrophy is a common feature of hypertension and an important risk factor for heart damage. The regression of cardiovascular hypertrophy is currently considered an important therapeutic target in reducing the omplications of hypertension. The aim of this study was to investigate the inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt (PSPY) with high γ-aminobutyric acid (GABA) content in spontaneously hypertensive rat (SHR) hearts. Six-week-old male SHRs were separated randomly and equally into 4 experimental groups: sterile water, captopril and 2 PSPY groups with different doses (10 and 100%) for 8 weeks. The changes in myocardial architecture and key molecules of the hypertrophy-related pathway in the excised left ventricle from these rats were determined by histopathological analysis, hematoxylin and eosin staining and western blot analysis. Abnormal myocardial architecture and enlarged interstitial spaces observed in the SHRs were significantly decreased in the captopril and PSPY groups compared with the sterile water group. Moreover, the increases in atrial natriuretic peptide, B-type natriuretic peptide, phosphorilated protein kinase Cα and calmodulin-dependent protein kinase II levels in the left ventricle were accompanied by hypertension and increases in phosphorylated extracellular signal-regulated kinase 5 activities with enhanced cardiac hypertrophy. However, the protein levels of the hypertrophic-related pathways were completely reversed by the administration of PSPY. PSPY may repress the activation of ANP and BNP which subsequently inhibit the dephosphorylation of the nuclear factor of activated T-cells, cytoplasmic 3 and ultimately prevent the progression of cardiac hypertrophy.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Calcineurin; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Captopril; gamma-Aminobutyric Acid; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Insulin-Like Growth Factor II; Interleukin-6; Ipomoea batatas; Male; Mitogen-Activated Protein Kinase 7; Natriuretic Peptide, Brain; NFATC Transcription Factors; Organ Size; Protein Kinase C-alpha; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Yogurt

A method for the estimation of severity of chronic cardiac failure (CCF) based on the quantitative evaluation of the regulatory and adaptive status (RAS) of the organism. Patients with FC I-III HCF concomitant with grade I-III hypertensive disease and/or coronary heart disease underwent cardiorespiratory synchronism test for the quantitative estimation of RAS (6 min walk), echocardiography, treadmill measuring maximum oxygen consumption (VO2max), measurement of plasma N-terminal precursor of brain natriuretic peptide. The lowering of RAS was especially pronounced when HCF FC changed from I to III, in agreement with results of traditional instrumental and laboratory tests. Specifically, left ventricle systolic and diastolic function was impaired, tolerance of physical exercise decreased while neurohumoral regulation was activated. There was positive correlation between RAS indices at HCF CF I and II for left ventricular ejection fraction, maximum physical load, VO2max and negative correlation for N-terminal precursor of brain natriuretic hormone. At HCF FC II and III, positive correlation was documented for left ventricular ejection fraction, maximum physical load, VO2max and negative correlation for the N-terminal precursor of brain natriuretic hormone. It means that the qualitative estimate of RAS obtained in the cardiorespiratory synchronism test can be used to assess severity of HCF in patients with hypertensive disease and/or coronary heart disease.

Topics: Atrial Natriuretic Factor; Chronic Disease; Coronary Disease; Dimensional Measurement Accuracy; Female; Heart Failure; Heart Function Tests; Humans; Hypertension; Male; Middle Aged; Oxygen Consumption; Predictive Value of Tests; Severity of Illness Index; Ventricular Dysfunction, Left

Ultrastructure of the right atrial cardiomyocytes of suckling ISIAH rats was studied to clarify the role of cardiac natriuretic peptides in hypertension development during the period when blood pressure is not yet elevated. Cardiomyocytes diameter was significantly greater, Golgi complex was more developed, and granules in the sarcoplasm were more abundant in ISIAH rats as soon as on postnatal day 12 in comparison with age-matched normotensive animals. The smaller diameter of granules and their qualitative composition (ratio of forming, mature, and dissolving forms) attest to active synthesis and release of secretory product. In 21-day-old ISIAH rats, granule size and qualitative composition reflected increased accumulation of hormones in the cells. Thus, morphological features of increased production of natriuretic peptides in the right atrial myocytes were revealed in rats during the first postnatal month before manifestation of hereditary hypertension.

Topics: Age Factors; Animals; Animals, Newborn; Atrial Natriuretic Factor; Blood Pressure; Golgi Apparatus; Heart Atria; Hypertension; Microscopy, Electron; Myocytes, Cardiac; Rats; Secretory Vesicles

Low nephron number is a recently identified cause of arterial hypertension. We set out to test the effect of nephron number dosing on blood pressure and cardiorenal damage including left ventricular (LV) remodeling and function. Because exact determination of nephron number in vivo is currently not possible, we combined the Munich Wistar Frömter (MWF) genetic rat model of inborn nephron deficit with the 5/6 renal ablation model (Nx).. To obtain distinct levels of nephron number dose (NND), rats underwent either sham-operation (Wistar-Sham NND 1.0, and MWF-Sham NND 0.6, n = 15, respectively) or 5/6 renal ablation (Nx, Wistar-Nx NND 0.17, and MWF-Nx NND 0.1, n = 20, respectively). Two additional groups were treated orally for 4 weeks with 1 mg/kg/day ramipril (Wistar-Nx-ACEI and MWF-Nx-ACEI, n = 15, respectively).. Systolic blood pressure (SBP), LV hypertrophy, mRNA expression of atrial natriuretic factor, LV contractility, and relaxation were exponentially correlated with NND (P < 0.0001, respectively). Creatinine clearance (Cl(Cr)) decreased, albuminuria, renal interstitial fibrosis, tubulointerstitial damage, and glomerulosclerosis index increased with lowering NND in both Wistar-Nx (NND 0.17) and MWF-Nx (NND 0.1) animals. LV perivascular and interstitial fibrosis and sarcoplasmic reticular (SR) Ca(2+) cycling were not directly related to NND. Angiotensin-converting enzyme (ACE) inhibition with ramipril demonstrated strong cardio- and renoprotective effects even in the setting of very low NND of 0.1 in MWF-Nx animals.. These data demonstrate that reduced nephron number is a significant, independent determinant of blood pressure, cardiorenal damage, and LV dysfunction in a direct dose-dependent way.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium; Fibrosis; Heart Ventricles; Hypertension; Myocardium; Nephrons; Ramipril; Rats; Rats, Wistar; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Remodeling

The present study was designed to develop an animal model of hypertension and cardiac hypertrophy associated with obesity in female rats. Furthermore, we studied the involvement of the natriuretic peptide system in the mechanisms of these conditions. Obesity was induced in Wistar rats by a high fat diet and ovariectomy. The rats were divided into four groups: ovariectomized or sham-operated with high-fat diet and ovariectomized or sham-operated with control diet. After 24 weeks of diet, rats were killed, and their tissues were removed. Cardiac atrial natriuretic peptide (ANP), clearance receptor (NPr-C) gene expression was determined by PCR. ANP concentrations were measured in plasma. Ovariectomized fat-fed rats (OF) showed increased body weight, visceral fat depot and blood pressure and decreased sodium excretion compared to other groups. Also, these rats showed higher heart-to-body weight and cell diameters of ventricular cardiomyocytes and lower cardiac ANP mRNA and plasma ANP than the control group. The adipocyte and renal NPr-C mRNA of OF rats were higher than the control group. These data showed that combined ovariectomy and high fat diet elicited obesity, hypertension and cardiac hypertrophy. These results suggest that the impairment of the natriuretic peptide system may be one of the mechanisms involved not only in development of hypertension but also in cardiac hypertrophy associated with obesity in ovariectomized rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Diet; Dietary Fats; Disease Models, Animal; Female; Gene Expression; Heart; Hypertension; Intra-Abdominal Fat; Obesity; Organ Size; Ovariectomy; Ovary; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Sodium

Early detection of left ventricular hypertrophy (LVH) is beneficial, since treatment-induced regression of LVH has been unequivocally associated with a better prognosis. Our aim was to study the relation of cardiac remodelling and natriuretic peptides (NPs) in stage 1 hypertension. We studied 175 (46±7 years, 87 women and 88 men) apparently healthy middle-aged that had never been treated for hypertension. Left ventricular and atrial parameters were determined by magnetic resonance imaging. Systolic blood pressure (BP) correlated with left ventricular mass index (LVMI) (r=0.23, P<0.01) and ventricular septum thickness index (IVSI) (r=0.29, P<0.001). N-terminal pro-B-type NP (NT-proBNP) or N-terminal pro-atrial NP (NT-proANP) did not correlate with BP, LVMI or IVSI. NT-proANP correlated with left atrial area index (LAAI) (r=0.38, P<0.001), and subjects with LVH had higher LAAI than subjects with normal left ventricular geometry and no LVH (11.2±0.3 vs 10.0±0.2 cm(2) m(-2), P<0.001). In conclusion, measurement of NT-proBNP or NT-proANP does not appear to discriminate LVH in middle-aged, never treated and apparently healthy hypertensives. NT-proANP, but not NT-proBNP, reflects early cardiac remodelling in hypertensive heart disease.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Incidence; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Severity of Illness Index; Ventricular Remodeling

Salt sensitivity, a trait characterized by a pressor blood pressure response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity.. Prospective cohort study.. We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55 ± 9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially 'salt sensitive' if their serum aldosterone was >sex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic blood pressure on follow-up (median four years).. Participants who were 'salt sensitive' (N = 437) experienced significantly greater increases in blood pressure (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and -0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and -0.2 mmHg; on higher versus lower sodium diet, respectively; P = 0.033 and P = 0.0127 for differences between groups in Δ systolic and Δ diastolic blood pressure, respectively).. Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Down-Regulation; Female; Humans; Hypertension; Linear Models; Male; Massachusetts; Middle Aged; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Sex Factors; Sodium Chloride, Dietary; Time Factors; Up-Regulation

Hypertension is a major risk factor of Alzheimer's disease (AD); however, controlled studies on the effect of antihypertensive treatment on the risk of dementia are inconclusive. Therefore, a biological marker that predicts individual response to antihypertensive treatment would be of high clinical relevance. Midregional proatrial natriuretic peptide (MR-proANP), an inactive surrogate molecule of the mature atrial natriuretic peptide, is related to circulatory function and hypertension.. A sample population of 134 subjects with mild cognitive impairment (MCI) was followed for up to 6 years. Multivariable Cox regression analysis was conducted to predict conversion to AD based on all relevant variables.. Baseline MR-proANP was significantly increased in the AD converter group (p < .0001). The conversion rate of patients treated with antihypertensive drugs was significantly reduced only in patients with elevated MR-proANP at baseline (p = .046). Using an optimized MR-proANP cutoff of 74 pmol/L, representing a value in the upper normal range, treatment with antihypertensive drugs reduced the conversion rate to AD by 36% (p = .035) for patients with levels >74 pmol/L. Further subgrouping by age (>/≤ 72 years at baseline) increased the positive correlation of antihypertensive treatment and MCI outcome for patients below the age of 72 years (conversion rate reduced by 74%, p = .016).. These data seem to support the notion of a potential impact of circulatory function for the prognosis of AD at a prodromal stage. The MR-proANP levels may be useful to predict the effect of antihypertensive treatment on conversion rates to AD in subjects with MCI.

Topics: Aged; Alzheimer Disease; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cognition Disorders; Disease Progression; Female; Humans; Hypertension; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Regression Analysis; Retrospective Studies

The present study was aimed to determine whether there is an altered role of local nitric oxide (NO) and atrial natriuretic peptide (ANP) systems in the kidney in association with the angiotensin (Ang) II-induced hypertension. Male Sprague-Dawley rats were used. Ang II (100 ng·min⁻¹·kg⁻¹) was infused through entire time course. Thirteenth day after beginning the regimen, kidneys were taken. The protein expression of NO synthase (NOS) and nitrotyrosine was determined by semiquantitative immunoblotting. The mRNA expression of components of ANP system was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and ANP, respectively. There developed hypertension and decreased creatinine clearance in the experimental group. The protein expression of eNOS, nNOS and nitrotyrosine was increased in the cortex, while that of iNOS remained unaltered. The urinary excretion of NO increased in Ang II-induced hypertensive rats. The catalytic activity of soluble guanylyl cyclase was blunted in the glomerulus in Ang II-induced hypertensive rats. The mRNA expression of ANP was increased in Ang II-induced hypertensive rats. Neither the expression of NPR-A nor that of NPR-C was changed. The protein expression of neutral endopeptidase was decreased and the activity of particulate guanylyl cyclase was blunted in the glomerulus and papilla in Ang II-induced hypertensive rats. In conclusion, the synthesis of NO and ANP was increased in the kidney of Ang II-induced hypertension, while stimulated cGMP response was blunted. These results suggest desensitization of guanylyl cyclase in the kidney of Ang II-induced hypertensive rats, which may contribute to the associated renal vasoconstriction and hypertension.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Hypertension; Kidney; Kidney Function Tests; Male; Neprilysin; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Transcription, Genetic; Tyrosine

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Female; Glycopeptides; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Stroke Volume

Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries.

Topics: Analysis of Variance; Animals; Aorta; Atrial Natriuretic Factor; Coronary Vessels; Disease Models, Animal; Disease Progression; Fibrosis; Gene Expression Regulation; Heart Failure; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Ligation; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stroke Volume; Time Factors; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Atrial Natriuretic Factor; Endocrine System; Heart; Humans; Hypertension; Natriuretic Peptide, Brain

To study the effect of Qianyang Recipe (QYR) on the Gan-yang hyperactivity syndrome (GYHS), the blood pressure, and correlated vascular regulatory factors of hypertension rat.. Thirty SD rats were randomly divided into the normal control group, the model group, and the QYR group, ten in each. Hypertension rat model of GYHS was prepared using Aconiti Praeparata Decoction plus ephedrine plus salt water. Rats in the QYR group orally took QYR physic liquor, while distilled water was given to rats in the normal control group and the model group. They were medicated for 28 successive days. The facial temperature, the grip strength, and the systolic pressure were determined once every 7 days. Rats' irritable degree and feather color were observed and recorded once every 14 days. After the last administration the plasma renin (PR), angiotensin II (Ang II), aldosterone (ALD), atrial natriuretic peptide (ANP), calcitonin gene-related peptide (cGRP) were determined.. Compared with the model group of the same phase, the facial temperature of rats in the QYR group significantly decreased on the 14th, 21th and 28th day after administration. The systolic pressure obviously decreased on the 21st day after administration. On the 28th day after administration symptoms such as irritability, dry hair were improved, and the Ang II level decreased. There was significant difference in all these changes (P<0.05, P<0.01).. QYR could relieve GYHS rats' symptoms such as facial hotness, irritability, dry hair, and so on, and decrease the systolic pressure. Decreased Ang II level might be one of its mechanisms.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Drugs, Chinese Herbal; Hypertension; Male; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley; Renin

Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure-dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiovascular Diseases; Diet, Sodium-Restricted; Echocardiography; Heart; Heart Failure; Heart Rate; Hydrazones; Hypertension; Kidney; Male; Myocytes, Cardiac; Pyridazines; Rats; Rats, Inbred Dahl; RNA, Messenger; Simendan; Sodium Chloride, Dietary; Sodium, Dietary; Tetrazoles; Valine; Valsartan; Vasodilator Agents; Ventricular Remodeling

Topics: Adolescent; Adult; Animals; Atrial Natriuretic Factor; Diuretics; DNA; Genotype; Humans; Hydrochlorothiazide; Hypertension; Mice; Middle Aged; Polymorphism, Genetic; Potassium; Young Adult

The objective was to study atrial natriuretic peptide (ANP) effects on mean arterial pressure (MAP) and cardiovascular nitric oxide (NO) system in spontaneously hypertensive rats (SHRs), investigating the receptors and signaling pathways involved. In vivo, SHRs and Wistar-Kyoto (WKY) rats were infused with saline (0.05 ml/min) or ANP (0.2 microg.kg(-1).min(-1)) for 1 h. MAP and nitrites and nitrates excretion (NOx) were determined. NO synthase (NOS) activity and endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) NOS expression were measured in the heart and aorta. In vitro, heart and aortic NOS activity induced by ANP was determined in the presence of iNOS and nNOS inhibitors, natriuretic peptide receptor (NPR)-A/B blocker, G(i) protein, and calmodulin inhibitors. As a result, ANP diminished MAP and increased NOx in both groups. Cardiovascular NOS activity was higher in SHRs than in WKY rats. ANP increased NOS activity, but the activation was lower in SHRs than in WKY rats. ANP had no effect on NOS isoform expression. NOS activity induced by ANP was not modified by iNOS and nNOS inhibitors. NPR-A/B blockade blunted NOS stimulation via ANP in ventricle and aorta but not in atria. Cardiovascular NOS response to ANP was reduced by G(i) protein and calmodulin inhibitors in both groups. In conclusion, in atria, ventricle, and aorta, ANP interacts with NPR-C receptors, activating Ca(2+)-calmodulin eNOS through G(i) protein. In ventricle and aorta, NOS activation also involves NPR-A/B. The NOS response to ANP was impaired in heart and aorta of SHRs. The impaired NO-system response to ANP in hypertensive animals, involving alterations in the signaling pathway, could participate in the maintenance of high blood pressure in this model of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular System; Disease Models, Animal; Hypertension; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Humans; Hypertension; Hypertrophy; Leukocytes; Mice; Mitogen-Activated Protein Kinases; Models, Biological; Myocardium; Phosphorylation; Pressure

Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal-regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal-regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Blotting, Western; Constriction, Pathologic; Enzyme Activation; Female; Gene Expression; Humans; Hypertension; Hypertrophy; Leukocytes; Male; MAP Kinase Signaling System; Mice; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Myocardium; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pressure

Leptin is a circulating adipocyte-derived hormone that influences blood pressure (BP) and metabolism. This study was designed to define the possible role of leptin in regulation of the atrial natriuretic peptide (ANP) system using acute and chronic experiments. Intravenous infusion of rat leptin (250 microg/kg injection plus 2 microg.kg(-1).min(-1) for 20 min) into Sprague-Dawley rats increased BP by 25 mmHg and decreased plasma level of ANP from 80.3 +/- 3.45 to 51.8 +/- 3.3 pg/ml. Reserpinization attenuated the rise in BP, but not the reduction of plasma ANP during leptin infusion. N(omega)-nitro-l-arginine methyl ester prevented the effects of leptin on the reduction of ANP level. In hyperleptinemic rats that received adenovirus containing rat leptin cDNA (AdCMV-leptin), BP increased during first 2 days and then recovered to control value. Plasma concentration of ANP and expression of ANP mRNA, but not of atrial ANP, in hyperleptinemic rats were lower than in the control groups on the first and second week after administration of AdCMV-leptin. These effects were not observed by the pretreatment with N(omega)-nitro-l-arginine methyl ester. No differences in renal function and ANP receptor density in the kidney were found between hyperleptinemic and control rats. Basal ANP secretion and isoproterenol-induced suppression of ANP secretion from isolated, perfused atria of hyperleptinemic rats were not different from those of other control groups. These data suggest that leptin inhibits ANP secretion indirectly through nitric oxide without changing basal or isoproterenol-induced ANP secretion.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Carotid Arteries; Hypertension; Isoproterenol; Jugular Veins; Kidney; Leptin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reserpine; RNA, Messenger

The use of bioengineered human skin as a bioreactor to deliver therapeutic factors has a number of advantages including accessibility that allows manipulation and monitoring of genetically modified cells. We demonstrate a skin gene therapy approach that can regulate blood pressure and treat systemic hypertension by expressing atrial natriuretic peptide (ANP), a hormone able to decrease blood pressure, in bioengineered human skin equivalents (HSE). Additionally, the expression of a selectable marker gene, multidrug resistance (MDR) type 1, is linked to ANP expression on a bicistronic vector and was coexpressed in the human keratinocytes and fibroblasts of the HSE that were grafted onto immunocompromised mice. Topical treatments of grafted HSE with the antimitotic agent colchicine select for keratinocyte progenitors that express both MDR and ANP. Significant plasma levels of human ANP were detected in mice grafted with HSE expressing ANP from either keratinocytes or fibroblasts, and topical selection of grafted HSE resulted in persistent high levels of ANP expression in vivo. Mice with elevated plasma levels of human ANP showed lower renin levels and, correspondingly, had lower systemic blood pressure than controls. Furthermore, mice with HSE grafts expressing human ANP did not develop elevated blood pressure when fed a high-salt diet. These findings illustrate the potential of this human skin gene therapy approach to deliver therapeutic molecules systemically for long-term treatment of diverse diseases.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cells, Cultured; Flow Cytometry; Genetic Therapy; Humans; Hypertension; Male; Mice; Skin Transplantation

Hemodynamic parameters and natriuretic peptide levels were evaluated in cardiac hypertrophy produced by sequentially applied renovascular (RV) and deoxycorticosterone acetate-salt (DS) models of hypertension. We studied hypertensive rats by RV or DS treatment at 2 and 4 wk, as well as by the combination of 2 wk of each treatment in an inverse sequence: RV 2 wk/DS 2 wk (RV2/DS2) and DS 2 wk/RV 2 wk (DS2/RV2). The in vivo cardiac function, interstitial fibrosis, and synthesis and secretion of types A (ANP) and B (BNP) natriuretic peptides were monitored in hypertensive models compared with their corresponding sham (Sh2, Sh4). There were no differences in relaxation parameters among RV or DS groups and combined treatments. Left ventricular +dP/dt(max) increased only in RV4 (P < 0.01 vs. Sh4), and this increase was abolished in RV2/DS2. Interstitial collagen concentration increased after 4 wk in both RV4 and RV2/DS2 groups. Although there were no changes in collagen concentration in either DS2 or DS4 groups, clipping after 2 wk of DS (DS2/RV2) remarkably stimulated interstitial fibrosis (P < 0.01 vs. DS2). Plasma BNP increased in RV treatment at 4 wk (P < 0.001 vs. Sh4), but not in DS. Interestingly, RV applied after the 2 wk of DS treatment induced a marked increase in BNP levels (P < 0.001 vs. Sh4). In this regard, plasma BNP appears to be a reliable indicator of pressure overload. Our results suggest that the second stimulus of mechanical overload in combined models of hypertension determines the evolution of hypertrophy and synthesis and secretion of ANP and BNP.

Topics: Animals; Atrial Natriuretic Factor; Biomechanical Phenomena; Blood Pressure; Collagen; Desoxycorticosterone; Disease Models, Animal; Hypertension; Hypertension, Renovascular; Male; Natriuretic Peptide, Brain; Natriuretic Peptides; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

We investigated the role of heme oxygenase (HO), adiponectin, and atrial natriuretic peptide (ANP) in uninephrectomized (UnX) deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, a volume-overload model characterized by elevated endothelin-1 (ET-1), mineralocorticoid-induced oxidative/inflammatory insults, fibrosis, hypertrophy, and severe renal histopathological lesions that closely mimic end-stage renal disease (ESRD). HO was enhanced with heme arginate (HA) or blocked with chromium mesoporphyrin (CrMP). Histological, morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric analysis were used. Our experimental design included the following groups of rats: A, controls [surgery-free Sprague-Dawley, UnX-sham, UnX-salt (0.9% NaCl + 0.2% KCl), and UnX-DOCA]; B, UnX-DOCA-salt hypertensive; C, UnX-DOCA-salt + HA; D, UnX-DOCA-salt + HA + CrMP; E, UnX-DOCA-salt + CrMP; F, UnX-DOCA-salt + captopril; G, UnX-DOCA-salt + L-arginine; H, UnX-DOCA-salt + spironolactone; and I, UnX-DOCA-salt + vehicle. HA lowered blood pressure and abated kidney hypertrophy and renal lesions, including glomerulosclerosis, tubular dilation, tubular cast formation, interstitial mononuclear cell infiltration, glomerular hypertrophy, and renal-arteriolar thickening in UnX-DOCA hypertension. Correspondingly, HO activity, adiponectin, adenosine monophosphate-activated protein kinase (AMPK), ANP, cGMP, antioxidants such as bilirubin, ferritin, superoxide dismutase, and catalase, and total antioxidant capacity were increased, whereas ET-1, transforming growth factor beta (TGF-beta), fibronectin, and 8-isoprostane were abated. These were accompanied by reduced proteinuria/albuminuria, but increased creatinine clearance. Interestingly, HA was more renoprotective than sipronolactone, L-arginine, and captopril, whereas the HO blocker CrMP exacerbated oxidative injury, aggravating renal lesions and function. Because 8-isoprostane stimulates ET-1 to potentiate oxidative stress and fibrosis, up-regulating HO-1 enhanced tissue antioxidant status alongside cellular targets such as adiponectin, AMPK, ANP, and cGMP to suppress ET-1, TGF-beta, and fibronectin with a corresponding decline of renal lesions, proteinuria/albuminuria, and thus improved renal function. The potent renoprotection of HA could be explored to combat renal hypertrophy and histopathological lesions characteristic of ESRD.

Topics: Adiponectin; Animals; Arginine; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Desoxycorticosterone; Disease Models, Animal; Endothelin-1; Heme; Heme Oxygenase (Decyclizing); Hypertension; Kidney; Kidney Diseases; Male; Mineralocorticoids; Rats; Rats, Sprague-Dawley

The role of biomarkers is rapidly emerging as an important tool in the management of the cardiorenal syndromes (CRS). Natriuretic peptides (NPs), due to their low cost and rapid and accurate ability to provide additional information not surmised from clinical evaluation, are the standard bearer for the newer biomarkers. Although the NP-guided therapy has been shown to improve patient outcomes, this has yet to be demonstrated for the novel renal biomarkers. Most of the renal biomarkers studies in CRS have been performed in the setting of cardiac surgery. It will be critical to validate these new biomarkers in multicenter and prospective studies encompassing a broad spectrum of patients. Work with NPs has also shown that novel biomakers are not to be used as 'stand-alone' tests; rather they are best used as adjuncts to everything else the health care provider brings to the table. It is likely that panels of multiple biomarkers will be needed for optimal evaluation, risk stratification, timely treatment initiation and follow-up of patients with CRS.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Gelatinases; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Lipocalins; Natriuretic Peptides; Neutrophils; Prognosis; Renal Insufficiency; Syndrome

Cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) exert well recognized vasodilatory, diuretic, and tubular fluid-electrolyte transport actions that are predictive of a hypotensive effect. The study sought to determine the improvement of hypertension and cardiac function by overexpressing P450 epoxygenases in vivo. Long-term expression of CYP102 F87V or CYP2J2 in spontaneously hypertensive rats (SHR) was mediated by using a type 8 recombinant adeno-associated virus (rAAV8) vector. Hemodynamics was measured by a Millar Instruments, Inc. (Houston, TX) microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time polymerase chain reaction. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months after injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p < 0.05). During the course of the 6-month study, systolic blood pressure significantly decreased in P450 epoxygenase-treated rats, but the CYP2J2-specific inhibitor C26 blocked rAAV-CYP2J2-induced hypotension and the increase in EET production. Cardiac output was improved by P450 epoxygenase expression at 6 months (p < 0.05). Furthermore, cardiac collagen content was reduced in P450 epoxygenase-treated rats. ANP mRNA levels were up-regulated 6- to 14-fold in the myocardium, and ANP expression was significantly increased in both myocardium and plasma in P450 epoxygenase-treated rats. However, epidermal growth factor (EGF) receptor antagonist 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG-1478) significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of P450 epoxygenases attenuates the development of hypertension and improves cardiac function in SHR, and that these effects may be mediated, at least in part, by ANP via activating EGF receptor.

Topics: 8,11,14-Eicosatrienoic Acid; Adenoviridae; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Genetic Vectors; Heart Function Tests; Hemodynamics; Hypertension; Immunohistochemistry; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction

We prospectively evaluated long-term (12 months) effects of telmisartan on blood pressure (BP), circulating renin-angiotensin-aldosterone levels, and lipids in hypertensive patients. There were 13 men and 11 women, 59 +/- 8.7 years of age (mean +/- SEM), with untreated essential hypertension. The 20-60 mg doses of telmisartan were administered once daily in the morning until BP130/85 was obtained. Blood pressure and plasma renin activity, plasma angiotensin (Ang) I and Ang II, serum angiotensin-converting enzyme (ACE) activity, plasma aldosterone concentration, plasma human atrial natriuretic peptide (hANP) concentration, and serum lipids were obtained 6 and 12 months after starting telmisartan administration. Systolic and diastolic BP were significantly (P < 0.001, P < 0.001) decreased from 162 +/- 3.3 and 97.7 +/- 2.1 mmHg to 128 +/- 3.8 and 79.6 +/- 2.0 mmHg after 12 months of treatment, respectively. Plasma Ang I and Ang II were unchanged at 12 months. Plasma renin activity and serum ACE activity were significantly (P < 0.001, P < 0.05) increased and plasma aldosterone concentration was unchanged during the study period. Total cholesterol levels were unchanged, but serum triglycerides levels were significantly decreased at 12 months (P < 0.01). Plasma hANP showed no significant alteration throughout the 12-month period. In hypertensive patients, telmisartan is a beneficial antihypertensive drug that also lowers serum triglycerides.

Topics: Aged; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrial Natriuretic Factor; Benzimidazoles; Benzoates; Biomarkers; Blood Pressure; Cholesterol; Drug Administration Schedule; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renin; Renin-Angiotensin System; Telmisartan; Time Factors; Treatment Outcome; Triglycerides

Myocardial hypertrophy has been recognized to be an adaptive response to a variety of external stimuli (e.g., myocardial infarction, pressure overload, catecholamine treatment, endocrine disorders) that are involved in several subcellular factors that mediate signaling pathways, from external stimuli to nuclear protein synthesis. Glycogen synthase kinase-3beta (GSK-3beta) is one of the subcellular factors that regulate nuclear transcription factors, such as activated T-cell (NFAT) proteins, that are related to gene programming during cardiac hypertrophy. On the other hand, GSK-3beta, known as a regulator of cardiomyocyte growth in Wnt signaling of cardiogenesis, is involved in beta-catenin degradation. Inhibition of GSK-3beta has been reported to induce cardiac hypertrophy. Tateishi et al. demonstrated in an aortic constriction-induced acute hypertrophy model using 6-week-old Wister rats that if GSK-3b is inhibited by LiCl up-regulated beta-catenin expression and additional hypertrophy were observed. They suggested that Li(2+) had an additive effect on pressure overload-induced hypertrophy through the GSK-3beta-beta-catenin pathway. Their article provides promising information on the mechanism of hypertrophic myocyte growth during acute pressure overload.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; beta Catenin; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypertension; Hypertrophy, Left Ventricular; Ligation; Lithium Chloride; Phosphorylation; Protein Kinase Inhibitors; Rats; RNA, Messenger; Serine; Time Factors

A large number of diverse signaling molecules in cell and animal models participate in the stimulus-response pathway through which the hypertrophic growth of the myocardium is controlled. However, the mechanisms of signaling pathway including the influence of lithium, which is known as an inhibitor of glycogen synthase kinase-3beta, in pressure overload hypertrophy remain unclear. The aim of our study was to determine whether glycogen synthase kinase-3beta inhibition by lithium has acute effects on the myocyte growth mechanism in a pressure overload rat model.. First, we created a rat model of acute pressure overload cardiac hypertrophy by abdominal aortic banding. Protein expression time courses for beta-catenin, glycogen synthase kinase-3beta, and phosphoserine9-glycogen synthase kinase-3beta were then examined. The rats were divided into four groups: normal rats with or without lithium administration and pressure-overloaded rats with or without lithium administration. Two days after surgery, Western blot analysis of beta-catenin, echo-cardiographic evaluation, left ventricular (LV) weight, and LV atrial natriuretic peptide mRNA levels were evaluated.. We observed an increase in the level of glycogen synthase kinase-3beta phosphorylation on Ser 9. A significant enhancement of LV heart weight (P < 0.05) and interventricular septum and posterior wall thickness (P < 0.05) with pressure-overloaded hypertrophy in animals treated with lithium were also observed. Atrial natriuretic peptide mRNA levels were significantly increased with pressure overload hypertrophy in animals treated with lithium.. We have shown in an animal model that inhibition of glycogen synthase kinase-3beta by lithium has an additive effect on pressure overload cardiac hypertrophy.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; beta Catenin; Blood Pressure; Blotting, Western; Cardiovascular Agents; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypertension; Hypertrophy, Left Ventricular; Ligation; Lithium Chloride; Male; Phosphorylation; Polymerase Chain Reaction; Protein Kinase Inhibitors; Rats; Rats, Wistar; RNA, Messenger; Serine; Time Factors; Ultrasonography

An increasing amount of evidence demonstrates the beneficial role of oxytocin (OT) in the cardiovascular system. Similar actions are attributed to genistein, an isoflavonic phytoestrogen. The treatment with genistein activates the OT system in the aorta of ovariectomized (OVX) Sprague-Dawley (SD) rats. The objective of this study was to determine the effects of low doses of genistein on the OT-induced effects in rat hypertension. The hypothesis tested was that treatment of OVX spontaneously hypertensive rats (SHRs) with genistein improves heart structure and heart work through a mechanism involving the specific OT receptor (OTR). OVX SHRs or SD rats were treated with genistein (in microg/g body wt sc, 10 days) in the presence or absence of an OT antagonist (OTA) [d(CH(2))(5), Tyr(Me)(2), Orn(8)]-vasotocin or a nonspecific estrogen receptor antagonist (ICI-182780). Vehicle-treated OVX rats served as controls. RT-PCR and Western blot analysis demonstrated that left ventricular (LV) OTR, downregulated by ovariectomy, increased in response to genistein. In SHRs or SD rats, this effect was blocked by OTA or ICI-182780 administration. The OTR was mainly localized in microvessels expressing the CD31 marker and colocalized with endothelial nitric oxide synthase. In SHRs, the genistein-stimulated OTR increases were associated with improved fractional shortening, decreased blood pressure (12 mmHg), decreased heart weight-to-body weight ratio, decreased fibrosis, and lowered brain natriuretic peptide in the LV. The prominent finding of the study is the detrimental effect of OTA treatment on the LV of SHRs. OTA treatment of OVX SHRs resulted in a dramatic worsening of ejection fractions and an augmented fibrosis. In conclusion, these results demonstrate that cardiac OTRs are involved in the regulation of cardiac function of OVX SHRs. The decreases of OTRs may contribute to cardiac pathology following menopause.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Female; Fibrosis; Fulvestrant; Genistein; Hypertension; Myocardial Contraction; Myocardium; Natriuretic Peptide, Brain; Ovariectomy; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Estrogen; Receptors, Oxytocin; RNA, Messenger; Vasotocin; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

To investigate the potential of gene therapy for the treatment of chronic diseases such as hypertension, chronic heart failure, and chronic renal failure, we established the neonatal rat fibroblast line engineered to secrete the mutant human atrial natriuretic peptide (mhANP), and then transplanted the cell line into young spontaneously hypertensive rats (SHR) subcutaneously. We found that a single transplantation of the cell line caused an obvious rise in the concentration of mhANP in serum 7 d after transplantation ((135 +/- 8) vs (106 +/- 7) pg/mL, P < 0.01). The animals' blood pressure in test group was always remarkably lower than that of empty vector group within 42 d after transplantation, even though the blood pressure in all groups was constantly increasing in the process of ontogeny ((175 +/- 10) mm Hg vs (189 +/- 12) mm Hg, P < 0.05). A maximal blood pressure reduction of 33 mm Hg ((157 +/- 9) mm Hg vs (124 +/- 112) mm Hg, P < 0.01) was observed 14 d post cell transplantation. There was a marked increase in urine volume in test group from second week after treatment beginning ((5.9 +/- 0.7) mL/6 h vs (4.3 +/- 0.8) mL/6 h, P < 0.01) and the effect lasted 14 d ((6.1 +/- 1.1) mL/6 h vs (4.0 +/- 0.8) mL/6 h, P < 0.01), however the statistical difference in concentration of K+ and Na+ in serum and urine was not observed. The results suggested that subcutaneous implantation of fibroblasts-expressing mhANP significantly reduced blood pressure in young SHR during the period of ontogeny and efficiently improved their renal function and the somatic gene transfer of mhANP may have potential value in the treatment of human chronic diseases such as hypertension, chronic heart failure, and chronic renal failure.

Topics: Animals; Atrial Natriuretic Factor; Cell Line; Fibroblasts; Gene Expression; Genetic Therapy; Humans; Hypertension; Male; Mutation; Rats; Rats, Inbred SHR; Transfection; Urination

Angiotensin-(1-7) displays antihypertensive and antiproliferative properties although its effect on cardiac remodeling and hypertrophy in hypertension has not been fully elucidated. The present study was designed to examine the effect of chronic angiotensin-(1-7) treatment on myocardial remodeling, cardiac hypertrophy and underlying mechanisms in spontaneous hypertension. Adult male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with or without angiotensin-(1-7) or the angiotensin-(1-7) antagonist A-779 for 24 weeks. Mean arterial pressure, left ventricular geometry, expression of the hypertrophic markers ANP and β-MHC, collagen contents (type I and III), collagenase (MMP-1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of MMPs-1 (TIMP-1) were evaluated in WKY and SHR rats with or without treatment. Our data revealed that chronic angiotensin-(1-7) treatment significantly suppressed hypertension, left ventricular hypertrophy, expression of ANP and β-MHC as well as myocardial fibrosis in SHR rats, the effects of which were nullified by the angiotensin-(1-7) receptor antagonist A-779. In addition, angiotensin-(1-7) treatment significantly counteracted hypertension-induced changes in the mRNA expression of MMP-2 and TIMP-1 and collagenase activity, the effects of which were blunted by A-779. In vitro study revealed that angiotensin-(1-7) directly increased the activity of MMP-2 and MMP-9 while decreasing the content of TIMP-1 and TIMP-2. Taken together, our results revealed a protective effect of angiotensin-(1-7) against cardiac hypertrophy and collagen deposition, which may be related to concerted changes in MMPs and TIMPs levels. These data indicated the therapeutic potential of angiotensin-(1-7) in spontaneous hypertension-induced cardiac remodeling.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Collagen; Collagenases; Fibrosis; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardium; Myosin Heavy Chains; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tissue Inhibitor of Metalloproteinases

The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels.. We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1(-/-)) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling.. Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1(-/-) mice.. Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress.

Topics: Age Factors; Aging; Angiotensin II; Animals; Atrial Natriuretic Factor; Cardiomyopathies; Collagen; Coronary Circulation; Disease Models, Animal; Echocardiography; Elasticity; Enzyme Inhibitors; Extracellular Matrix; Female; Gene Expression Profiling; Gene Expression Regulation; Genotype; Heart Ventricles; Hemodynamics; Hypertension; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Microscopy, Electron; Microscopy, Video; Myocardium; Natriuretic Peptide, Brain; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phenotype; Polymerase Chain Reaction; RNA, Messenger; Telemetry; Ventricular Remodeling

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Heart Failure; Humans; Hypertension; Models, Animal; Myocytes, Cardiac; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Rats; Recombinant Fusion Proteins; Signal Transduction; Sodium-Hydrogen Exchangers; Ventricular Remodeling

Topics: Atrial Natriuretic Factor; Biomarkers; Heart Failure; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Renal Insufficiency

M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.

Topics: Acute Disease; Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Diuresis; Dogs; Glomerular Filtration Rate; Humans; Hypertension; Male; Natriuresis; Pulmonary Wedge Pressure; Renal Circulation; Vascular Resistance

The present study aimed to examine whether there is an altered regulation of local hormonal systems in the kidney following the treatment of glycyrrhizic acid (GA), the active ingredient in licorice. Male Sprague-Dawley rats were treated with GA for 3 weeks. The expression of mineralocorticoid receptor (MR) was determined in the kidney by immunoblotting and real-time polymerase chain reaction (PCR). The protein expression of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) was determined. The expression of atrial natriuretic peptide (ANP), natriuretic peptide receptor (NPR)-A and NPR-C was determined by real-time PCR. The activity of guanylyl cyclase was determined by the amount of cGMP generated in responses to sodium nitroprusside (SNP) or ANP. Following the GA treatment, systolic blood pressure was increased. The mRNA and protein expressions of MR were increased in the kidney. The protein expression of eNOS and iNOS was also increased. The expression of ANP mRNA was increased although that of NPR-A and NPR-C mRNA was not changed. The cGMP production provoked by either SNP or ANP was not changed. The increased expression of MR may contribute to GA-induced hypertension. The enhanced expression of NOS and ANP may play a compensatory role in GA-induced hypertension.

Topics: Animals; Atrial Natriuretic Factor; Gene Expression; Glycyrrhizic Acid; Hypertension; Kidney; Male; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Receptors, Mineralocorticoid

Clinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)].. We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha.. Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.

Topics: Adenylate Kinase; Adiponectin; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Linseed Oil; Male; Myocardial Contraction; Myosin Heavy Chains; Phospholipids; Rats; Rats, Wistar; RNA, Messenger; Thromboxane B2; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Ventricular Remodeling

Arterial stiffness increases with age and contributes to the pathogenesis of systolic hypertension and cardiovascular disease in the elderly. Knowledge about the pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches.. We related 7 circulating biomarkers representing distinct biological pathways (C-reactive protein, aldosterone-to-renin ratio, N-terminal proatrial natriuretic peptide and B-type natriuretic peptide, plasminogen activator inhibitor-1, fibrinogen, and homocysteine) to 5 vascular function measures (central pulse pressure, carotid-femoral pulse-wave velocity, mean arterial pressure, forward pressure wave amplitude [all measures of conduit artery stiffness], and augmented pressure, an indicator of wave reflection) in 2000 Framingham Offspring Study participants (mean age, 61 years; 55% women). Tonometry measures were obtained on average 3 years after the biomarkers were measured. In multivariable linear regression models adjusting for covariates, the biomarker panel was significantly associated with all 5 vascular measures (P<0.003 for all). On backward elimination, the aldosterone-to-renin ratio was positively associated with each stiffness measure (P< or =0.002 for all). In addition, C-reactive protein was positively related to augmented pressure (P=0.0003), whereas plasminogen activator inhibitor-1 was positively associated with mean arterial pressure (P=0.003), central pulse pressure (P=0.001), and forward pressure wave (P=0.01).. Our cross-sectional data on a community-based sample suggest a distinctive pattern of positive associations of biomarkers of renin-angiotensin-aldosterone system activation with pan-arterial vascular stiffness, plasminogen activator inhibitor-1 with central vascular stiffness indices, and C-reactive protein with wave reflection. These observations support the notion of differential influences of biological pathways on vascular stiffness measures.

Topics: Aldosterone; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Cross-Sectional Studies; Female; Fibrinogen; Homocysteine; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Plasminogen Activator Inhibitor 1; Protein Precursors; Renin; Renin-Angiotensin System; Risk Factors

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Humans; Hypertension; Mice; Serine Endopeptidases

Midregional pro-atrial natriuretic peptide (MR-proANP) is a newly described stable fragment of the N-terminal part of pro-atrial natriuretic peptide. We tested the hypothesis that in adults with essential hypertension, plasma levels of MR-proANP would be associated with systolic blood pressure (SBP), pulse pressure, and hypertension severity.. Participants included 1,034 African Americans (65 +/- 9 years, 72% women) and 880 non-Hispanic whites (61 +/- 9 years, 55% women) belonging to sibships ascertained on the basis of hypertension. MR-proANP was measured by an immunoluminometric assay. Hypertension severity was based on number of hypertension medication classes used and multiples of SBP and diastolic blood pressure (DBP) deviations from 120/70 mm Hg. Generalized estimating equations were used to assess whether plasma levels of MR-proANP were associated with SBP, pulse pressure, and hypertension severity independent of potential confounding variables.. In African Americans, after adjustment for age, sex, body mass index, estimated glomerular filtration rate (eGFR), smoking history, diabetes, total cholesterol, high-density lipoprotein cholesterol, medication (beta-blocker, statin, and aspirin) use, and previous history of myocardial infarction or stroke, higher MR-proANP levels were significantly associated with greater SBP (P < 0.0001), pulse pressure (P < 0.0001), and hypertension severity (P = 0.0013). The associations were replicated in non-Hispanic whites; after adjustment for the above variables, higher MR-proANP levels were significantly associated with greater SBP (P = 0.013), pulse pressure (P = 0.0006), and hypertension severity (P = 0.028).. Plasma MR-proANP may be a marker of arterial stiffness and severity of hypertension in adults with hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Black or African American; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Minnesota; Mississippi; Vascular Resistance; White People

We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure-lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 x 10(-70)), rs198358 (P = 8 x 10(-30)) and rs632793 (P = 2 x 10(-10)), and of plasma B-type natriuretic peptide with rs5068 (P = 3 x 10(-12)), rs198358 (P = 1 x 10(-25)) and rs632793 (P = 2 x 10(-68)). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 x 10(-6) and 6 x 10(-5), respectively) and diastolic blood pressure (P = 1 x 10(-6) and 5 x 10(-5)), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79-0.92, P = 4 x 10(-5); OR = 0.90, 95% CI = 0.85-0.95, P = 2 x 10(-4), respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptides; Polymorphism, Single Nucleotide

Cold exposure induces hypertension and cardiac hypertrophy via sympathetic activation. The sympathetic nervous system is fundamentally important for the regulation of cardiac atrial natriuretic peptide (ANP) secretion. The present study aimed to define changes in ANP level with renal functions during cold exposure of rats. We also measured the direct effects of adrenergic stimulation on ANP secretion in cold-induced hypertensive rat atria. Sustained elevation of blood pressure and tachycardia were observed by 2-wk cold exposure. Cold exposure increased urine volume, UNaV, UKV and positive water balance. Atrial ANP content, its mRNA level, and plasma ANP concentration increased. Plasma norepinephrine level was increased but both alpha(1A)- and beta(1)-adrenoceptor (AR) mRNA levels in atrium were decreased. In isolated perfused atria from cold-exposed rats, basal ANP secretion increased and pulse pressure decreased. Phenylephrine (alpha(1)-AR agonist)-induced stimulation of ANP secretion, and isoproterenol (beta-AR agonist)-induced suppression of ANP secretion were significantly attenuated. These results suggest that an increased plasma and atrial ANP level by cold exposure may be a compensatory response to changes in hemodynamics and body fluid balance. The phenylephrine- and isoproterenol-induced attenuation of ANP secretion in cold-exposed rat atria may be due to the downregulation of alpha(1A)- and beta(1)-adrenoceptors mRNA levels.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cold Temperature; Cyclic AMP; Dose-Response Relationship, Drug; Guanabenz; Heart Atria; Heart Rate; Hypertension; Isoproterenol; Male; Phenylephrine; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; RNA, Messenger; Sympathetic Nervous System; Time Factors

The renin-angiotensin and sympathetic nervous systems play critical interlinked roles in the development of left ventricular hypertrophy, fibrosis, and dysfunction. These studies investigated the hemodynamic and cardiac effects of monoblockade and coblockade of renin-angiotensin and sympathetic nervous systems. Stroke-prone spontaneously hypertensive rats (16 weeks old; male; n=12 per group) received the sympatholytic imidazoline compound, moxonidine (2.4 mg/kg per day); the angiotensin-receptor blocker eprosartan (30 mg/kg per day), separately or in combination; or saline vehicle for 8 weeks, SC, via osmotic minipumps. Blood pressure and heart rate were continuously measured by radiotelemetry. After 8 weeks, in vivo cardiac function and structure were measured by transthoracic echocardiography and a Millar conductance catheter, and the rats were then euthanized and blood and heart ventricles collected for various determinations. Compared with vehicle, the subhypotensive dose of moxonidine resulted in lower (P<0.01) heart rate, left ventricular hypertrophy, cardiomyocyte cross-sectional area, interleukin 1 beta, tumor necrosis factor-alpha, and mRNA for natriuretic peptides. Eprosartan reduced pressure (P<0.01), as well as extracellular signal-regulated kinase (ERK) 44 phosphorylation, Bax/Bcl-2, and collagen I/III, and improved left ventricular diastolic function (P<0.03). Combined treatment resulted in greater reductions in blood pressure, heart rate, left ventricular hypertrophy, collagen I/III, and inhibited inducible NO synthase and increased endothelial NO synthase phosphorylation, as well as reduced left ventricular anterior wall thickness, without altering the other parameters. Thus, in advanced hypertension complicated with cardiac fibrosis, sympathetic inhibition and angiotensin II blockade resulted in greater reduction in blood pressure and heart rate, inhibition of inflammation, and improved left ventricular pathology but did not add to the benefits of angiotensin II blockade on cardiac function.

Topics: Acrylates; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Heart Rate; Hypertension; Imidazoles; Male; Nitric Oxide Synthase Type III; Phosphorylation; Rats; Rats, Inbred SHR; Stroke; Thiophenes; Ventricular Function, Left

1. It has been demonstrated that epigallocatechin-3-gallate (EGCG) inhibits cardiac hypertrophy through its antihypertensive and anti-oxidant effects. However, the underlying molecular mechanism is not clear. 2. In the present study, we tested the hypothesis that EGCG attenuates transaortic abdominal aortic constriction (TAC)-induced ventricular hypertrophy by regulating mitogen-activated protein kinase (MAPK) signal pathways in hypertensive rats. Four groups of rats were used: (i) a sham-operated control group; (ii) an EGCG-treated (50 mg/kg per day, i.p., for 21 days) sham-operated group; (iii) a TAC group; and (iv) an EGCG-treated TAC group. Histological analysis of whole hearts and biochemical analyses of left ventricular (LV) tissue were used to investigate the effects of EGCG. 3. The results showed that the LV myocyte diameter and the expression of atrial natriuretic peptide, brain natriuretic peptide and β-myocardial heavy chain were significantly decreased in the EGCG-treated (50 mg/kg per day, i.p.) TAC group. Levels of reactive oxygen species and malondialdehyde in the lV were significantly reduced by EGCG in the TAC group. Total superoxide dismutase, catalase and glutathione peroxidase activities were decreased in the TAC group, and this decrease was significantly restored by EGCG treatment. Phosphorylation of extracellular signal-regulated kinase 2, p38 and c-Jun N-terminal kinase 1 was significantly reversed in the LV of EGCG-treated TAC rats (40%, 53% and 52% vs TAC, respectively), accompanied by significant inhibition of nuclear factor-κB and activator protein-1. Transaortic abdominal aortic constriction significantly upregulated LV expression of matrix metalloproteinase-9 from 32 ± 6 to 100 ± 12% and this increase was inhibited by EGCG treatment (from 100 ± 12 to 50 ± 15%). In addition, TAC decreased mitochondrial DNA copy number and the activity of respiratory chain complexes I (from 100 ± 7 to 68 ± 5%), III (from 100 ± 4 to 2 ± 5%) and IV (from 766 ± 2 to 100 ± 5%); this decrease was reversed by EGCG treatment to levels seen in sham-operated rats.

Topics: Animals; Antioxidants; Atrial Natriuretic Factor; Catalase; Catechin; Disease Models, Animal; DNA, Mitochondrial; Electron Transport Chain Complex Proteins; Enzyme Activation; Glutathione Peroxidase; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Malondialdehyde; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitochondria, Heart; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Transcription Factor AP-1

We investigated the effects of iptakalim, a new ATP-sensitive potassium channel (K(ATP)) opener providing endothelial protection, on the progression of cardiac hypertrophy to failure in a rat model of pressure overloading caused by abdominal aortic banding (AAB). Endothelial dysfunction is central to cardiac hypertrophy and failure induced by pressure overload. It would be useful to clarify whether iptakalim could prevent this.. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, evidence of left ventricular hypertrophy (LVH), and transition to heart failure. LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These could be prevented by treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg for 6 weeks. Progression to cardiac failure, demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial and B-type natriuretic peptide mRNA, could also be prevented. The downregulated nitric oxide signalling system was enhanced, whereas the upregulated endothelin signalling system was inhibited, resulting in normalization of the balance between these two systems.. Iptakalim protected the endothelium and prevented progression of cardiac hypertrophy to failure induced by a pressure overload.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Heart Rate; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Male; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Ventricular Remodeling

Genetic risk factors for essential hypertension are largely unknown. The aim of the present study was to assess the association of 77 previously characterized gene variants in 52 candidate genes from various biological pathways with blood pressure (BP) progression and incident hypertension.. We analyzed data from 18 738 white women who participated in a prospective cohort study and were free of hypertension at baseline. BP progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes were assessed by logistic regression and Cox proportional-hazards models, respectively.. At 48 months of follow-up, 7889 of 16 635 women (47.4%) had BP progression. Only three of 70 polymorphisms with a minor allele frequency of at least 2% had a significant association with BP progression. The odds ratio [95% confidence interval (CI)] for 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (minor allele T), natriuretic peptide precursor A (NPPA) rs5063 (minor allele A) and NPPA rs5065 (minor allele C) were 1.05 (1.00-1.10), 0.84 (0.76-0.94) and 0.93 (0.88-1.00), respectively. After adjustment for multiple testing using the false discovery rate, only the NPPA rs5063 association remained significant. During a median follow-up of 9.8 years, 5540 of 18 738 women developed incident hypertension. Only five of 70 polymorphisms were significantly associated with incident hypertension. The hazard ratio (95% CI) for interleukin 6 (IL-6) rs1800795 (minor allele C), MTHFR rs1801133, NPPA rs5063, nitric oxide synthase 3 rs1799983 (minor allele T) and transforming growth factor, beta 1 rs1800469 (minor allele T) were 0.96 (0.92-1.00), 1.06 (1.02-1.10), 0.88 (0.80-0.96), 1.05 (1.01-1.09) and 1.05 (1.01-1.10), respectively. After adjustment for multiple testing, none of these associations remained significant.. NPPA gene polymorphisms may have a role in BP progression and incident hypertension. Our data also provide moderate confirmatory evidence of association between MTHFR rs1801133 and the development of hypertension.

Topics: Alleles; Atrial Natriuretic Factor; Blood Pressure; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertension; Incidence; Longitudinal Studies; Middle Aged; Polymorphism, Genetic; Proportional Hazards Models; Prospective Studies; Time Factors; United States; White People; Women's Health

To determine if natriuretic peptide concentrations are increased in cats with systemic hypertension and/or chronic kidney disease (CKD).. 22 normal cats, 13 normotensive cats with mild-moderate CKD (NT-CKD), 15 hypertensive cats with mild-moderate CKD (HT-CKD) and 8 normotensive cats with severe CKD (NT-CKD-severe).. N-terminal pro-B-type (NT-proBNP) and pro-A-type (NT-proANP) natriuretic peptides were measured in plasma samples from all cats using commercially available assays and concentrations in the normal and diseased groups compared using non-parametric statistical tests. Spearman's rank correlation was used to test for an association between natriuretic peptide and creatinine concentrations.. NT-proANP was significantly higher in the NT-CKD-severe than the normal group of cats (P=0.006) but there were no other differences between groups. NT-proBNP concentrations were significantly higher in the HT-CKD group than both the normal (P<0.001) and the NT-CKD (P<0.001) groups. NT-proBNP concentrations were also higher in the NT-CKD-severe (P<0.001) and the NT-CKD (P=0.005) groups than the normal group. NT-proANP but not NT-proBNP was significantly and positively associated with plasma creatinine concentration.. Measurement of NT-proBNP shows promise as a diagnostic marker for systemic hypertension in the cat. Its concentration is not significantly increased in cats with mild-moderate normotensive CKD.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Cat Diseases; Cats; Creatinine; Female; Hypertension; Kidney Diseases; Male; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; ROC Curve; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

We tested the hypothesis that, in adults with essential hypertension, plasma levels of midregional proatrial natriuretic peptide (MR-proANP) are associated with target organ damage. MR-proANP is a newly described stable fragment of N-terminal proatrial natriuretic peptide. Participants included 1,919 adults with hypertension identified from the community (1,037 African-Americans, 65 +/- 9 years of age, 72% women; 882 non-Hispanic whites, 61 +/- 9 years of age, 55% women). We measured MR-proANP by an immunoluminometric assay. Measurements of target organ damage included the ankle-brachial index (ABI), urinary albumin-creatinine ratio (UACR), and left ventricular (LV) mass (available only in African-Americans). Generalized estimating equations were used to assess whether plasma MR-proANP was associated with measurements of target organ damage, independent of potential confounding variables. In African-Americans, higher MR-proANP was significantly associated with lower ABI (p <0.0001), higher UACR (p <0.0001), and greater LV mass (indexed to height to the power of 2.7, p <0.0001). After adjustment for age, gender, body mass index, systolic blood pressure, estimated glomerular filtration rate, smoking history, diabetes mellitus, total and high-density lipoprotein cholesterols, medication (blood pressure lowering, statin, and aspirin) use, and previous myocardial infarction or stroke, higher MR-proANP levels remained significantly associated with lower ABI (p = 0.01), higher UACR (p = 0.0007), and greater LV mass index (p <0.0001). In non-Hispanic whites, higher MR-proANP levels were significantly associated with lower ABI (p = 0.002) and greater UACR (p = 0.001), but not after adjustment for the covariates listed earlier. In conclusion, plasma MR-proANP may be a marker of target organ damage in the setting of hypertension, especially in African-Americans.

Topics: Age Distribution; Aged; Albuminuria; Ankle Brachial Index; Atrial Natriuretic Factor; Biomarkers; Black or African American; Blood Pressure Determination; Cohort Studies; Comorbidity; Creatinine; Female; Hispanic or Latino; Humans; Hypertension; Hypertrophy, Left Ventricular; Incidence; Male; Middle Aged; Predictive Value of Tests; Probability; Prognosis; Protein Precursors; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Analysis; White People

Hypertension is associated with an increase in vasoactive peptides, but conflicting results are reported concerning their causes of elevation. In this study, cardiac vasodilator hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and vasoconstrictor hormones (renin, aldosterone, cortisol, metanephrins) were determined in 36 hypertensive subjects (HT) without left ventricular hypertrophy (LVH), 19 healthy subjects without family hypertension (NTFN) and 35 healthy subjects with family hypertension (NTFH). Plasma levels of ANP and BNP were significantly higher (p<0.04) in HT subjects (28.1 +/- 6.1 and 22.7 +/- 6.8 pg/ml) compared to NTFN (13.4 +/- 3.3 and 6.1 +/- 1.5 pg/ml) and NTFH (12.5 +/- 1.4 and 7.2 +/- 1.3 pg/ml) subjects, respectively. No significant differences were observed in ANP and BNP concentrations between NTFN and NTFH. Measurement of vasoconstrictor hormones showed no significant differences between the three groups. Plasma ANP and BNP concentrations were significantly correlated in both HT (r=0.73; P<0.001), NTFN (r=0.71; P<0.002) and NTFH (r=0.53; P<0.003) subjects. ANP values were significantly related to systolic blood pressure (r=0.34; P<0.05) in the HT group while BNP values were not. The echocardiographic findings were not correlated with ANP or BNP in the HT patients. This suggests that natriuretic peptides increase is related to the blood pressure elevation rather than LVH to reduce detrimental high BP effects.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Electrocardiography; Humans; Hypertension; Hypertrophy, Left Ventricular; Middle Aged; Natriuretic Peptide, Brain; Vasoconstriction; Vasodilation

Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations. Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (n=18) or aldosterone (n=28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161+/-3 mm Hg) versus saline-infused mice (129+/-2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2+/-0.1 versus 3.6+/-0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137+/-5 mm Hg) and also lowered blood pressure in saline-infused mice (114+/-2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or pulmonary congestion. These functional improvements are likely related to extracardiac effects, such as effects on the vasculature.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Cytokines; Diastole; Drug Therapy, Combination; Echocardiography, Doppler; Exercise Test; Fibrosis; Gene Expression; Heart; Heart Failure; Hydralazine; Hypertension; Isosorbide Dinitrate; Male; Mice; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium Chloride, Dietary; Vascular Cell Adhesion Molecule-1; Vasodilator Agents

Hypertension is one of the most common diseases that induce a series of pathological changes in different organs of the human body, especially in the heart. There is a wealth of evidence about blood vessels in hypertensive myocardium, but little is known about structural changes in the cardiac lymphatic system. To clarify the changes in structure of the cardiac lymphatic system during hypertension, we developed a hypertension animal model with Dahl S rats and we used Dahl R rats as the control group. We examined the expression of collagen fibers, atrial natriuretic peptide, connexin43, and LYVE-1 in the rat heart by immunohistochemistry. The ultrastructure of the cardiac lymphatics was detected by transmission electron microscopy and scanning electron microscopy. We demonstrated extensive lymphatic fibrosis in the hearts of the Dahl S hypertension group, characterized by increased thin collagen fibrils that connected with the lymphatics directly. Ultrastructural changes in the cardiac lymphatic endothelium such as an increase of vesicles and occurrence of vacuoles, active exocytosis, and cytoplasmic processes, restored the draining of tissue fluid. Our study suggests that during hypertension, the changes in structure of the cardiac lymphatics may be one important factor involved in cardiac fibrosis. Therefore, the lymphatics may be a possible target for reducing fibrosis in the treatment of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Connexin 43; Fibrosis; Heart Atria; Hypertension; Lymphatic Vessels; Male; Myocardium; Rats; Rats, Inbred Dahl

Whether a high plasma aldosterone concentration induced by strict salt restriction promotes cardiac remodeling remains controversial. Male Sprague-Dawley rats at 10weeks of age were given normal salt (NS) (1.5% NaCl) or low salt (LS) (0.05% NaCl) diets. Each animal underwent aortocaval fistula creation for volume-overloaded heart failure or sham surgery. All rats with a fistula received either vehicle or a non-hypotensive dose of spironolactone (200mg/kg/day) by gavage. Two weeks later, the LS diet significantly increased the plasma aldosterone level in the sham-operated and fistula-created rats (2677+/-662pg/ml and 2406+/-422pg/ml) compared with that in rats given the NS diet (518+/-18pg/ml and 362+/-45pg/ml, respectively). In sham-operated rats, the difference in plasma aldosterone level did not affect the extent of myocardial fibrosis (1.8+/-0.1% with LS diet vs. 1.5+/-0.3% with NS diet). However, the increase in myocardial fibrosis in fistula-created rats was more prominent with the LS diet than with the NS diet (4.7+/-0.3% vs. 3.4+/-0.1%). In addition, the fistula-created rats on the LS diet expressed significantly increased oxidative stress and transforming growth factor-beta compared with those on the NS diets (P<0.05). These increases in the fistula-created rats on the LS diet were significantly suppressed by the non-hypotensive dose of spironolactone (P<0.05). These results suggest that increased plasma aldosterone level with strict salt restriction activated the mineralocorticoid receptor signaling in volume-overloaded condition, resulting in increased myocardial fibrosis.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Body Weight; Cell Size; Contraindications; Diet, Sodium-Restricted; Endomyocardial Fibrosis; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Signal Transduction; Spironolactone; Transforming Growth Factor beta; Tyrosine; Ventricular Remodeling

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are circulating hormones secreted predominantly in patients with hypertension or congestive heart failure. To obtain background data on plasma ANP and BNP levels in rats, we investigated the circadian rhythms and effects of anesthesia on these peptides. To determine the circadian rhythms, plasma samples from thirty rats were collected by non-anesthesia (decapitation) at six time points every fourth hour. To determine the effects of anesthesia, plasma samples from thirty-two rats were collected under diethyl ether, pentobarbital or urethane anesthesia. The plasma ANP and BNP levels were determined using a radioimmunoassay. The plasma ANP levels were high from the evening to early morning, while the plasma BNP levels were relatively low at 2:30 AM. The difference in the BNP levels was statistically significant. The plasma BNP levels were relatively high when the rats were anesthetized using urethane. These results suggest that blood collection should be performed between 10:30 AM to 2:30 PM to determine plasma ANP and BNP. The use of pentobarbital is also recommended for toxicological studies in rats.

Topics: Anesthesia; Animals; Atrial Natriuretic Factor; Biomarkers; Circadian Rhythm; Ether; Heart Failure; Hypertension; Male; Natriuretic Peptide, Brain; Pentobarbital; Rats; Rats, Sprague-Dawley; Urethane

To observe the effect of electroacupuncture (EA) of different acupoints on blood pressure (BP), plasma angiotensin (Ang) II, aldosterone (ALD) and atrial natriuretic peptide (ANP) of SHR, so as to observe the relative specificity of effects of acupoints.. A total of 60 SHR were randomly divided into model, Quchi (LI 11), Zusanli (ST 36), Shenmen (HT 7), Jianyu (LI 15) and non-acupoint groups, with 10 cases in each. Other 10 Wistar rats were composed of normal group. EA (2 Hz, 2 mA) was applied to LI 11, ST 36, HT 7, LI 15 and non-acupoint for 30 min, followed by measuring BP with BP-6 system. Plasma Ang II, ALD and ANP contents were assayed by radioimmunoassay.. Compared with control group and pre-treatment, both systolic pressure (SP) and diastolic pressure (DP) of Quchi (LI 11), Zusanli (ST 36) and Shenmen (HT 7) groups lowered significantly (P<0.05). No significant differences were found in the SP and DP of Jianyu (LI 15) and non-acupoint groups (P>0.05). After EA, the SP of Quchi (LI 11) and Shenmen (HT 7) groups were significantly lower than that of Jianyu (LI 15) and non-acupoint groups (P<0.05); and the DP of Quchi (LI 11), Zusanli (ST 36) and Shenmen (HT 7) groups were markedly lower than that of Jianyu (LI 15) and non-acupoint groups (P<0.05). Compared with normal group, the contents of plasma Ang II and ANP of model group decreased significantly, and plasma ALD level of model group increased remarkably (P<0.05). Compared with model group, plasma AngII levels in Quchi (LI 11), Zusanli (ST 36) and Shenmen (HT 7) groups and ALD in Zusanli (ST 36) and Shenmen (HT 7) groups lowered significantly (P<0.05), and plasma ANP content in Shenmen (HT 7) group increased obviously (P<0.05).. EA of LI 11, HT 7 and ST 36 can effectively lowered both DP and SP in SHR, which may be closely related to its effects in regulating the contents of Ang II , ALD and ANP.

Topics: Acupuncture Points; Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Electroacupuncture; Humans; Hypertension; Male; Random Allocation; Rats; Rats, Wistar

Topics: Adrenergic beta-Antagonists; Aging; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cannabinoid Receptor Modulators; Diabetes Complications; Endothelin-1; Genetic Therapy; Heart; Humans; Hypertension; Peptidyl-Dipeptidase A; Pharmacogenetics; Social Class; Sodium Chloride, Dietary; Stress, Physiological

Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage.. We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using

Topics: Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Case-Control Studies; Drug Resistance; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Potassium; Regression Analysis; Renin; Sex Factors; Sodium

Cardiac hypertrophy is common in diabetes and an independent risk factor for cardiac morbidity and mortality. We investigated the effects of pioglitazone on cardiac hypertrophy and hypertrophic signaling in Dahl salt-sensitive hypertensive rats.. Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age and treated with pioglitazone (2.5 mg/kg per day) or vehicle from 7 to 11 weeks.. The vehicle-treated rats developed left ventricular hypertrophy and fibrosis as well as left ventricular diastolic dysfunction. The serum level of adiponectin and the phosphorylation of AMP-activated protein kinase in the myocardium did not differ between the vehicle-treated rats and control rats maintained on a normal diet. The phosphorylation of Akt, mammalian target of rapamycin, and p70S6 kinase as well as the total protein content were increased in the heart of vehicle-treated rats compared with control rats, and these changes were blocked by treatment with pioglitazone. Pioglitazone treatment also ameliorated left ventricular hypertrophy and fibrosis, improved diastolic function, and increased both the serum adiponectin concentration and the level of AMP-activated protein kinase phosphorylation in the heart.. Long-term administration of pioglitazone attenuated left ventricular hypertrophy and fibrosis as well as inhibited phosphorylation of mammalian target of rapamycin and p70S6 kinase in the heart of hypertensive rats. The beneficial cardiac effects of pioglitazone are likely attributable, at least partly, both to the activation of AMP-activated protein kinase signaling through stimulation of adiponectin secretion and to the inhibition of Akt signaling.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Atrial Natriuretic Factor; Collagen; Echocardiography; Fibrosis; Hypertension; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Male; Multienzyme Complexes; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phosphorylation; Pioglitazone; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Dahl; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Thiazolidinediones; Transcription Factors

An increase in arterial stiffness with advancing age is associated with several pathological states, including hypertension and arteriosclerosis. Regular exercise improves the aging-induced increase in arterial stiffness and has a protective effect against these diseases. However, not all individuals respond to exercise to the same extent. Atrial natriuretic peptide (ANP) is involved in the regulation of basal blood pressure, blood flow, and vascular tone. The present study was designed to clarify whether gene polymorphisms in ANP-related genes affect exercise-induced improvements in arterial stiffness. We performed a cross-sectional study of 291 healthy middle-aged and older Japanese subjects (63+/-1 years), examining the relationship between daily physical activity-induced improvements in arterial stiffness, estimated by brachial-ankle arterial pulse wave velocity (baPWV), and the gene polymorphisms of valine32methionine (V32M: 664G>A) in exon 1 of ANP and asparagine521aspartic acid (N521D: 1780A>G) in exon 8 of the ANP clearance receptor (NPR-C). The baseline baPWV was significantly lower in the active group, but no differences were seen in blood pressure. Active subjects with the ANP-VV genotype had significantly lower baPWV and higher plasma ANP levels compared with inactive subjects, but there were no variations related to the VM+MM genotype. Additionally, baPWV and plasma ANP levels were negatively correlated in ANP-VV genotype subjects, but were not correlated in VM+MM individuals. Our results suggest that ANP polymorphism in older Japanese subjects may affect the cardiovascular response to regular exercise.

Topics: Aged; Aging; Asian People; Atrial Natriuretic Factor; Blood Flow Velocity; Brachial Artery; Cross-Sectional Studies; Exercise; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Japan; Life Style; Male; Middle Aged; Motor Activity; Polymorphism, Single Nucleotide; Pulsatile Flow; Risk Factors

Corin is a cardiac serine protease that acts as the pro-atrial natriuretic peptide (ANP) convertase. Recently, 2 single-nucleotide polymorphisms (SNPs) (T555I and Q568P) in the human corin gene have been identified in genetic epidemiological studies. The minor I555/P568 allele, which is more common in African Americans, is associated with hypertension and cardiac hypertrophy. In this study, we examined the effect of T555I and Q568P amino acid substitutions on corin function. We found that corin frizzled-like domain 2, where T555I/Q568P substitutions occur, was required for efficient pro-ANP processing in functional assays. Mutant corin lacking this domain had 30+/-5% (P<0.01) activity compared to that of wild type. Similarly, corin variant T555I/Q568P had a reduced (38+/-7%, P<0.01) pro-ANP processing activity compared to that of wild type. The variant also exhibited a low activity (44+/-15%, P<0.05) in processing pro-brain natriuretic peptide (BNP). We next examined the biochemical basis for the loss of activity in T555I/Q568P variant and found that the zymogen activation of the corin variant was impaired significantly, as indicated by the absence of the activated protease domain fragment. This finding was confirmed in human embryonic kidney (HEK)293 cells and murine HL-1 cardiomyocytes. Thus, our results show that the corin gene SNPs associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity. Our data suggest that corin deficiency may be an important mechanism in hypertensive and heart diseases.

Topics: Atrial Natriuretic Factor; Cardiomegaly; Cell Line; Enzyme Precursors; Genetic Variation; Humans; Hypertension; Kidney; Membrane Proteins; Mutagenesis; Natriuretic Peptide, Brain; Natriuretic Peptides; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Serine Endopeptidases; Substrate Specificity; Transfection

Recent studies suggest that the ANP (atrial natriuretic peptide)/NPRA (type A natriuretic peptide receptor) system modulates ventricular remodelling and cardiac hypertrophy in hypertension in Western populations. In the present study, we tested for any association between two SNPs (single nucleotide polymorphisms) in the ANP gene (one in the promoter and one exonic) with cardiac hypertrophy. We tested the hypothesis in 2118 hypertensive patients, including 945 with LVH [LV (left ventricular) hypertrophy] and 1173 without LVH, as well as 816 healthy control subjects. All subjects were genotyped for the -A2843G and A188G polymorphisms. We found that the GG genotype at position -2843 conferred a 2.2-fold risk for LVH compared with the AA or AG genotypes, including septal wall thickness (11.8+/-1.4 mm for GG compared with 10.9+/-1.4 and 10.7+/-1.3 mm for AA and AG respectively; P<0.01), posterior wall thickness (11.8+/-2.8 mm for GG compared with 10.6+/-1.2 and 10.6+/-1.4 mm for AA and AG respectively; P<0.01), LV mass index (62.7+/-13.6 g/m(2.7) for GG compared with 57.9+/-8.6 and 57.8+/-8.4 g/m(2.7) for AA and AG respectively; P<0.05) and relative wall thickness (50.7+/-10.8% for GG compared with 44.3+/-7.3 and 43.5+/-6.8% for AA and AG respectively; P<0.05). Plasma levels of ANP were significantly lower in the hypertensive patients with LVH carrying the GG genotypes compared with those carrying the AA or AG genotypes (P<0.01). No association of GG genotype with echocardiographic variables and plasma ANP levels was identified in hypertensive patients without LVH and in control subjects (P>0.05). No significant association between the A188G genotype and echocardiographic variables was found in either hypertensive patients or controls (P>0.05). In conclusion, our findings indicate that the -A2843G polymorphism in the ANP gene promoter might be a genetic risk factor for the development of LVH in patients with hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Linkage Disequilibrium; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Ultrasonography

Natriuretic peptides (NP), including atrial natriuretic peptide (ANP), induce potent natriuresis and vasodilation and thereby generate hypotension in vivo. Despite intensive efforts, clinical application of NP as an antihypertensive agent is limited because of their short biological half-life and poor bioavailability. Recently, we have developed a strategy that facilitates slow release of peptides from PEG-peptide inactive conjugates, based on reversible pegylation. Peptides prepared by this approach undergo slow, spontaneous chemical hydrolysis at physiological conditions, releasing the native active peptide/protein drug from the inactive conjugates over prolonged periods. A PEG chain of 30 kDa was linked covalently to the alpha-amino side chain of the hormone via a MAL-Fmoc-NHS spacer, yielding PEG 30-Fmoc-ANP, a prodrug that releases the native hormone upon incubation at physiological conditions. Bolus administration of native ANP to Wistar rats receiving adrenaline yields a short, transitory effect in lowering blood pressure (BP), reaching a maximum at 2 min, and then returning to control values after 12 to 25 min. In contrast, administration of PEG 30-Fmoc-ANP lowered BP following a lag period of 50 min, and maintained low BP for a period exceeding 60 min. Saline or PEG 30-Fmoc-Alanine were not effective in lowering BP in Wistar rats. These results show that the novel compound, PEG 30-Fmoc-ANP, is a reversible pegylated prodrug derivative that facilitates a prolonged BP lowering effect in rats and may be considered as a candidate for development into an antihypertensive drug.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Delayed-Action Preparations; Diuretics; Humans; Hypertension; Polyethylene Glycols; Prodrugs; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Time Factors

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Blotting, Western; Cardiomegaly; Collagen; Hypertension; Male; Mice; Mice, Transgenic; Microscopy, Confocal; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Receptor, Angiotensin, Type 2; RNA, Messenger; Survival Analysis; Ventricular Function, Left

The NPPA gene codes for the precursor of atrial natriuretic polypeptide, suggesting that NPPA may modulate the efficacy of some antihypertensive drugs.. To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (BP) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications.. Post hoc analysis of 38,462 participants with hypertension from ALLHAT, a multicenter randomized clinical trial conducted in the United States and Canada. Genotyping was performed from February 2004 to January 2005.. Participants were randomly assigned to receive a diuretic (chlorthalidone; n = 13,860), a calcium antagonist (amlodipine; n = 8174), an angiotensin-converting enzyme inhibitor (lisinopril; n = 8233), or an alpha-blocker (doxazosin; n = 8195).. The primary outcome measure was coronary heart disease (CHD), defined as fatal CHD or nonfatal myocardial infarction (mean follow-up, 4.9 years). Secondary outcomes were stroke, all-cause mortality, combined cardiovascular disease outcomes, and 6-month systolic and diastolic BP changes. Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly.. Depending on genotype, the event rates per 1000 person-years were 15.3 to 19.7 for CHO, 9.6 to 15.4 for stroke, and 27.4 to 30.7 for all-cause mortality. For the NPPA T2238C variant, lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine (CHD: CC = 0.86; TC = 0.90; TT = 1.09; P = .03 [dominant model]; stroke: CC = 1.18; TC = 0.82; TT = 1.26; P = .01 [additive and dominant models]; all-cause mortality: CC = 0.87; TC = 0.98; TT = 1.12; P = .05 [dominant model]). Combined end points yielded similar results. Consistent with these clinical findings, 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone (-6.5 mm Hg) than with amlodipine (-3.8 mm Hg), lisinopril (-2.4 mm Hg), or doxazosin (-3.8 mm Hg). Among those with the TT genotype, systolic BP differences between drugs were less (range, -5.4 to -7.5 mm Hg; P value, <.001 to .003 for interaction); diastolic BP showed similar results. We found no pharmacogenetic associations with the NPPA G664A variant.. The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP. Minor C allele carriers experienced more favorable cardiovascular disease outcomes when randomized to receive a diuretic, whereas TT allele carriers had more favorable outcomes when randomized to receive a calcium channel blocker.

Topics: Aged; Amlodipine; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Diseases; Chlorthalidone; Diuretics; Doxazosin; Female; Genotype; Humans; Hypertension; Lisinopril; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide

The mechanisms involved in the development and maintenance of hypertension in obstructive sleep apnoea (OSA) are not clear. We hypothesized that OSA patients have an abnormal renal handling of sodium and water during the night.. We studied 29 OSA patients and 19 healthy controls at night with serial determinations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), arginine vasopressin (AVP), aldosterone (Aldo), fractional urinary excretion of sodium (FE(Na)), free water clearance (C(H2O)), urinary excretion of aquaporin 2 (u-AQP2), systolic blood pressure (SBP), diastolic blood pressure (DBP) and oxygen saturation.. OSA patients had a higher FE(Na) (0.6 (0.4-1.0) versus 0.4 (0.3-0.6) %; p = 0.017), SBP (129 (114-145) versus 114 (106-122) mmHg; p = 0.001) and DBP (81 (72-87) versus 71 (65-74) mmHg; p<0.001) than healthy controls at night. In hypertensive OSA patients, the FE(Na) correlated significantly with the change in nocturnal DBP (r (2) = 0.411; p = 0.010). Mean level of AVP during the night was higher in OSA patients compared with healthy controls (1.1 (0.8-1.4) versus 0.8 (0.6-1.1) pmol/L; p = 0.033) and correlated with SBP. ANP, BNP, Aldo, C(H2O) and u-AQP2 were the same in OSA and controls.. We conclude that the higher fractional excretion of sodium in OSA is most likely attributable to pressure natriuresis. The correlation between mean AVP and blood pressure suggests that AVP may be part of the pathogenetic mechanism underlying hypertension in these patients.

Topics: Adult; Age Factors; Aldosterone; Aquaporin 2; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Oxygen; Potassium; Sex Factors; Sleep Apnea, Obstructive; Sodium; Vasopressins; Water

Glucose metabolism in the heart requires oxidation of cytosolic NADH from glycolysis. This study examines shuttling reducing equivalents from the cytosol to the mitochondria via the activity and expression of the oxoglutarate-malate carrier (OMC) in rat hearts subjected to 2 wk (Hyp2, n = 6) and 10 wk (Hyp10, n = 8) of pressure overload hypertrophy vs. that of sham-operated rats (Sham2, n = 6; and Sham10, n = 7). Moderate aortic banding produced increased atrial natriuretic factor (ANF) mRNA expression at 2 and 10 wk, but only at 10 wk did hearts develop compensatory hypertrophy (33% increase, P < 0.05). Isolated hearts were perfused with the short-chain fatty acid [2,4-(13)C(2)]butyrate (2 mM) and glucose (5 mM) to enable dynamic-mode (13)C NMR of intermediate exchange across OMC. OMC flux increased before the development of hypertrophy: Hyp2 = 9.6 +/- 2.1 vs. Sham2 = 3.7 +/- 1.2 muM.min(-1).g dry wt(-1), providing an increased contribution of cytosolic NADH to energy synthesis in the mitochondria. With compensatory hypertrophy, OMC flux returned to normal: Hyp10 = 3.9 +/- 1.7 vs. Sham10 = 3.8 +/- 1.2 muM.g(-1).min(-1). Despite changes in activity, no differences in OMC expression occurred between Hyp and Sham groups. Elevated OMC flux represented augmented cytosolic NADH shuttling, coupled to increased nonoxidative glycolysis, in response to hypertrophic stimulus. However, development of compensatory hypertrophy moderated the pressure-induced elevation in OMC flux, which returned to control levels. The findings indicate that the challenge of pressure overload increases cytosolic redox state and its contribution to mitochondrial oxidation but that hypertrophy, before decompensation, alleviates this stress response.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Butyrates; Cardiomegaly; Carrier Proteins; Cytosol; Disease Models, Animal; Glycolysis; Heart Rate; Hypertension; Ligation; Magnetic Resonance Spectroscopy; Male; Mitochondria, Heart; Mitochondrial Proteins; NAD; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. In recent studies, a decrease in the development or recurrence of AF was found in hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking agents. Hypertension is related to an increased wall tension in the atria, resulting in increased stretch of the individual myocyte, which is one of the major stimuli for the remodeling process. In the present study, we used a model of cultured atrial neonatal rat cardiomyocytes under conditions of stretch to provide insight into the mechanisms of the preventive effect of the angiotensin receptor-blocking agent losartan against AF on a molecular level. Stretch significantly increased protein-to-DNA ratio and atrial natriuretic factor mRNA expression, indicating hypertrophy. Expression of genes encoding for the inward rectifier K(+) current (I(K1)), Kir 2.1, and Kir 2.3, as well as the gene encoding for the ultrarapid delayed rectifier K(+) current (I(Kur)), Kv 1.5, was significantly increased. In contrast, mRNA expression of Kv 4.2 was significantly reduced in stretched myocytes. Alterations of gene expression correlated with the corresponding current densities: I(K1) and I(Kur) densities were significantly increased in stretched myocytes, whereas transient outward K(+) current (I(to)) density was reduced. These alterations resulted in a significant abbreviation of the action potential duration. Losartan (1 microM) prevented stretch-induced increases in the protein-to-DNA ratio and atrial natriuretic peptide mRNA expression in stretched myocytes. Concomitantly, losartan attenuated stretch-induced alterations in I(K1), I(Kur), and I(to) density and gene expression. This prevented the stretch-induced abbreviation of action potential duration. Prevention of stretch-induced electrical remodeling might contribute to the clinical effects of losartan against AF.

Topics: Action Potentials; Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Newborn; Antihypertensive Agents; Atrial Fibrillation; Atrial Natriuretic Factor; Cell Enlargement; Cell Shape; Cell Size; Cells, Cultured; Gene Expression; Heart Atria; Hypertension; Kinetics; Kv1.5 Potassium Channel; Losartan; Mechanotransduction, Cellular; Myocytes, Cardiac; Potassium; Potassium Channels, Inwardly Rectifying; Potassium Channels, Voltage-Gated; Rats; RNA, Messenger; Shal Potassium Channels

Progression of heart failure in hypertensive Dahl rats is associated with cardiac remodeling and increased cardiomyocyte apoptosis. This study was conducted to study whether treatment with a novel inotropic vasodilator compound, levosimendan, could prevent hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.. 6-week-old salt-sensitive Dahl/Rapp rats received levosimendan (0.3 mg kg(-1) and 3 mg kg(-1) via drinking fluid) and high salt diet (NaCl 7%) for 7 weeks, Dahl/Rapp rats on low-salt diet served as controls. Blood pressure, cardiac functions by echocardiography, cardiomyocyte apoptosis by TUNEL technique, tissue morphology, myocardial expression of calcium cycling proteins, and markers of neurohumoral activation were determined.. Untreated Dahl/Rapp rats on high salt diet developed severe hypertension, cardiac hypertrophy and moderate systolic dysfunction. 38% of Dahl/Rapp rats (9/24) survived the 7-week-follow-up period. Cardiomyocyte apoptosis was increased by 6-fold during high salt diet. Levosimendan improved survival (survival rates in low- and high-dose levosimendan groups 12/12 and 9/12, p<0.001 and p=0.05, respectively), increased cardiac function, and ameliorated cardiac hypertrophy. Levosimendan dose-dependently prevented cardiomyocyte apoptosis. Levosimendan normalized salt-induced increased expression of natriuretic peptide, and decreased urinary noradrenaline excretion. Levosimendan also corrected salt-induced decreases in myocardial SERCA2a protein expression and myocardial SERCA2a/NCX-ratio.. Improved survival by the novel inotropic vasodilator levosimendan in hypertensive Dahl/Rapp rats is mediated, at least in part, by amelioration of hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Hydrazones; Hypertension; Male; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Norepinephrine; Osteopontin; Pyridazines; Rats; Rats, Inbred Dahl; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Sodium-Calcium Exchanger; Vasodilator Agents; Ventricular Remodeling

The metabolic syndrome (MS) is associated with left ventricular hypertrophy (LVH). Previous evidence has shown that LVH is favoured by low levels of atrial natriuretic peptide (ANP), independently from blood pressure (BP), in hypertension. Although levels of natriuretic peptides are known to be lower in obesity, plasma ANP levels have not yet been assessed in MS. We aimed to assess the ANP levels and their relationship with left ventricular mass (LVM) in patients affected by MS.. One hundred and twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, echocardiographical and biochemical parameters, and levels of both N-terminal (NT)-proANP and alphaANP were assessed.. Hypertensive patients affected by MS had higher LVM and increased frequency of LVH. NT-proANP levels were significantly lower in MS, independent of waist circumference (WC). Log(NT-proANP) levels were significantly inversely related to left ventricular mass index (LVMI) (beta = -0.360, P < 0.001) and LVM/height (beta = -0.370, P < 0.001) in the whole hypertensive population by multiple linear regression analysis. The relationship of log(NT-proANP) with LVM was more enhanced in patients with MS.. The present study demonstrates that levels of NT-proANP are significantly reduced in hypertensive patients affected by MS, and they are significantly inversely related to the increased LVM observed in these patients. Our findings, while supporting previous experimental and clinical evidence of the antihypertrophic role of ANP in hypertension, may help to identify one of the possible mechanisms directly underlying LVH in MS.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Case-Control Studies; Echocardiography, Doppler; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Male; Metabolic Syndrome; Middle Aged; Predictive Value of Tests; Protein Precursors; Rome; Stroke Volume; Transforming Growth Factor beta

Inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes of patients and experimental animals with congestive heart failure (CHF). Here we show that iNOS expression plays a role in pressure overload-induced myocardial chamber dilation and hypertrophy. In wild-type mice, chronic transverse aortic constriction (TAC) resulted in myocardial iNOS expression, cardiac hypertrophy, ventricular dilation and dysfunction, and fibrosis, whereas iNOS-deficient mice displayed much less hypertrophy, dilation, fibrosis, and dysfunction. Consistent with these findings, TAC resulted in marked increases of myocardial atrial natriuretic peptide 4-hydroxy-2-nonenal (a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) in wild-type mice but not in iNOS-deficient mice. In response to TAC, myocardial endothelial NO synthase and iNOS was expressed as both monomer and dimer in wild-type mice, and this was associated with increased reactive oxygen species production, suggesting that iNOS monomer was a source for the increased oxidative stress. Moreover, systolic overload-induced Akt, mammalian target of rapamycin, and ribosomal protein S6 activation was significantly attenuated in iNOS-deficient mice. Furthermore, selective iNOS inhibition with 1400W (6 mg/kg per hour) significantly attenuated TAC induced myocardial hypertrophy and pulmonary congestion. These data implicate iNOS in the maladaptative response to systolic overload and suggest that selective iNOS inhibition or attenuation of iNOS monomer content might be effective for treatment of systolic overload-induced cardiac dysfunction.

Topics: Amidines; Animals; Aortic Diseases; Atrial Natriuretic Factor; Benzylamines; Cardiomegaly; Chronic Disease; Enzyme Inhibitors; Fibrosis; Heart Failure; Hypertension; Matrix Metalloproteinase 2; Mice; Mice, Knockout; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Protein Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Ribosomal Protein S6; Systole; TOR Serine-Threonine Kinases; Vasoconstriction

The purpose of this study was to evaluate the relationship between natriuretic peptides (NT-proANP and NT-proBNP) and hemodynamic parameters in preeclampsia.. This was a cross-sectional study of 19 preeclamptic, 15 chronic hypertensive, and 26 normotensive women in the third trimester of pregnancy. Stroke index (SI), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and left cardiac work index (LCWI) were derived by whole-body impedance cardiography. Systolic blood pressure (SAP), diastolic blood pressure (DAP), and mean arterial pressure (MAP) were measured. The plasma levels of NT-proANP and NT-proBNP were determined with radioimmunoassays.. NT-proANP and NT-proBNP concentrations were significantly higher in preeclamptic women compared to chronic hypertensive and normotensive pregnancies. Preeclamptic women had lower CI and HR and higher SAP, MAP, and SVRI than the control groups. In preeclampsia NT-proANP correlated significantly with SAP and SVRI; meanwhile, NT-proBNP correlated significantly with SVRI and CI. These correlations persisted in the subgroup of nonmedicated preeclamptic women, except in the case of NT-proBNP and CI.. High NT-proANP and NT-proBNP concentrations in preeclampsia reflect the strain on the heart caused by high afterload, rather than the function of the heart expressed as SI or CI.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Cross-Sectional Studies; Female; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Placental Circulation; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Third; Probability; Reference Values; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index

The aim of the work was to study the maintenance of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1 (ET-1) in patients with idiopathic arterial hypertension and the relationships between cardiac morphological parameters and concentrations of examined peptides in group of patients with left ventricular hypertrophy (LVH).. Seventy-six patients were enrolled in the study: 21 patients with confirmed idiopathic arterial hypertension (group 1), 18 with idiopathic hypertension and eccentric hypertrophy (group 1a), 14 with idiopathic hypertension and concentric hypertrophy (group 1b), and 23 patients without arterial hypertension, organic heart disease, or chronic respiratory tract diseases (group 2 - control group). All subjects were submitted for echocardiographic evaluation. Posterior wall thickness (PWT), interventricular septum thickness (IVST), left ventricular end-diastolic diameter (LVEDd), left atrium diameter (LAD), left ventricular mass index (LVMI), ejection fraction (EF), fractional shortening (FS), midwall shortening fraction (MWS), and relative wall thickness index (RWT) were studied. Concentrations of ANP(1-28), BNP, and ET-1 were determined with the use of radioimmunological kits (RIA). The obtained results were subjected to statistical analysis.. A considerable increase of ANP and BNP was observed in all patients with hypertension (group 1) in comparison to patients without hypertension (group 2). Significant increases of ANP were found in groups 1a and 1b in comparison to group 1 and 2, as well as considerably increase of BNP in group 1b compared to groups 1, 1a, and 2. In the group of patients with hypertension (group 1), a significant increase in the concentration of ET-1 compared to group 2 was found. However, the concentrations of ET-1 in groups 1 and 2 were not statistically different. Significant differences in concentrations of ET-1 between groups 1a, 1b, and 1 and 2 were seen. Significant correlations were found between concentrations of ANP, BNP, ET-1 and morphological parameters: PWT, IVST, LVMI and RWT. In group 1b, a correlation between concentrations of ANP, BNP, MWS, and LAD was found. The multiple regression analysis showed that RWT independently correlates with concentrations of ANP and BNP, and the concentration of BNP is in closer relation to RWT than ANP. In the case of ET-1, the multiple regression analysis did not show that LVMI or RWT had any independent influence on secretion of ET-1 in patients with idiopathic hypertension and LVH.. Increased concentration of ANP in patients with idiopathic hypertension may point to the coexistence of complications with type of LVH. High concentration of BNP may specifically suggest concentric LVH. This is important - especially if there are difficulties in interpretations of results of other clinical examinations. However, increased concentrations of ET-1 in the plasma of patients with hypertension and LVH should not be treated as an indicator of LVH degree.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Echocardiography, Doppler; Endothelin-1; Female; Heart Atria; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Radioimmunoassay; Severity of Illness Index; Stroke Volume

Previous evidence supports a role of atrial natriuretic peptide (ANP) as a candidate gene for hypertension. We characterized an ANP gene promoter variant, which has been associated with lower peptide levels, in a sample of young male subjects from Southern Italy (n=395, mean age=35.2+/-2 years) followed up for 28 years. In this cohort, the ANP gene variant was associated with early blood pressure increase and predisposition to develop hypertension.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Chi-Square Distribution; Cross-Sectional Studies; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Italy; Longitudinal Studies; Male; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Topics: Adenosine Triphosphate; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiomyopathies; Carnitine; Constriction; Echocardiography; Genetic Predisposition to Disease; Heterozygote; Hypertension; Lung; Male; Mice; Mice, Mutant Strains; Mutation; Myocardium; Organ Size; Organic Cation Transport Proteins; Phosphocreatine; RNA, Messenger; Solute Carrier Family 22 Member 5

A cross-sectional study was designed to investigate the association of the levels of plasma renin activity (PRA) and aldosterone (ALDO) and atrial natriuretic hormone (ANH) with the rates of hypertension prevalence in people living at 340 meters below sea level, the Jordan Valley (JV) and those residing at 620 meters above sea level, Irbid City. 1072 natives from the JV and 1402 natives from Irbid City were covered by a questionnaire to estimate hypertension prevalence in the JV and Irbid city (population age: 35-65 years). Male subjects were selected from the JV (24 hypertensives, 46+/-15 years old, and 93 normotensives, 33+/-13 years old) and from Irbid City (31 hypertensives, 47+/-12 years old, and 89 normotensives, 40+/-13 years old) to evaluate the levels of PRA, ALDO and ANH. Hypertension was less common in the JV than in Irbid City (9.9% vs. 13.6%). The levels of PRA in the hypertensive subjects compared to the normotensive subjects were lower in the JV (1.7+/-1.0 vs. 2.6+/-1.4 ng/ml/hr) but were similar in Irbid City (2.9+/-2.7 vs. 3.2+/-2.7). The levels of ALDO in the hypertensive subjects compared to the normotensive subjects were similar in the JV (119+/-58 vs. 139+/-66 pg/ml) but were higher in Irbid City (199+/-112 vs. 146+/-84). The levels of ANH in the hypertensive subjects compared to the normotensive subjects were lower in the JV (13.9+/-9.3 vs. 28.0+/-12.7 ng/ml) and were also lower in Irbid City (21.0+/-12.2 vs. 26.7+/-11.6).

Topics: Adult; Aged; Aldosterone; Altitude; Atrial Natriuretic Factor; Cross-Sectional Studies; Health Surveys; Humans; Hypertension; Jordan; Male; Middle Aged; Prevalence; Renin

To assess hemodynamic and NT-proANP changes in women with chronic hypertension during pregnancy.. Stroke volume index (SI), heart rate (HR), cardiac output index (CI), systemic vascular resistance index (SVRI), pulse wave velocity (PWV), and left cardiac work index (LCWI) were measured using whole-body impedance cardiography. Systolic blood pressure (SAP), mean arterial pressure (MAP), diastolic blood pressure (DAP), and pulse pressure (PP) were also measured. Arterial compliance was defined as the SI-to-PP ratio (SI/PP). Hemodynamic parameters and NT-proANP concentrations were assessed during the early and late second trimester, the third trimester, and after delivery in 20 women with essential hypertension and 30 normotensive women.. Arterial blood pressure, SVRI, and PWV remained higher during the whole study period in chronic hypertensive compared with healthy pregnancies. In the early second trimester, women with chronic hypertension had significantly lower SI and NT-proANP concentrations than did normotensive women.. The hemodynamics of chronic hypertension during pregnancy are characterized by persistent high vascular resistance. Lower SI and NT-proANP values found in chronic hypertensive pregnancies during the early second trimester may suggest a reduced intravascular volume increase during pregnancy.

Topics: Adaptation, Physiological; Adult; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Case-Control Studies; Female; Heart Rate; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Vascular Resistance

The aim was to study the maintenance of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with idiopathic hypertension and relationships between cardiac morphological parameters and concentrations of the peptides in patients with hypertension and left ventricular hypertrophy (LVH).. Seventy-six patients were enrolled: 21 with confirmed idiopathic hypertension (group I), 18 with idiopathic hypertension and eccentric hypertrophy (group Ia), 14 with idiopathic hypertension and concentric hypertrophy (group Ib), and 23 healthy controls (group II). All underwent echocardiographic evaluation. Posterior wall thickness (PWT), interventricular septum thickness (IVST), left ventricular mass index (LVMI), relative wall thickness index (RWT), fractional shortening (FS), midwall shortening fraction (MWS), and left atrium diameter (LAd) were studied.. Considerably increased ANP and BNP were observed in all patients with hypertension (group I) compared with controls (group II). Significant increases in ANP in groups Ia and Ib compared with groups I and II were found as well as considerably increased BNP in group Ib compared with groups I, Ia, and II. Significant correlations were found between ANP and BNP concentrations and PWT, IVST, LVMI, and RWT. In group Ib, correlation between ANP and BNP and MWS and LAd was found. Multiple regression analysis showed that RWT independently correlated with ANP and BNP and that BNP is more closely related to RWT than is ANP.. Increased ANP in patients with idiopathic hypertension may indicate the coexistence of complications with types of LVH. High concentrations of BNP may specifically suggest concentric LVH.

Topics: Atrial Natriuretic Factor; Echocardiography; Female; Heart Atria; Heart Septum; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Organ Size; Regression Analysis

We tested the hypothesis that natriuretic peptide precursor A gene polymorphisms are significantly associated with blood pressure progression and incident hypertension among healthy, middle-aged women. We performed a prospective cohort study among 18 437 white women participating in the Women's Health Study who were free of hypertension at baseline. Two previously characterized single nucleotide polymorphisms within the natriuretic peptide precursor A gene (rs5063 G>A and rs5065 T>C) were genotyped. Blood pressure progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes and inferred haplotypes were assessed by logistic regression and Cox proportional hazards models, respectively. At 48 months, 47.4% of women had blood pressure progression. The odds ratio (95% CIs) for blood pressure progression associated with the rs5063 variant was 0.85 (0.76 to 0.94; P=0.002). For the rs5065 variant, the corresponding odds ratio was 0.94 (0.88 to 1.00; P=0.050). During 9.8 years of follow-up, 29.6% of women developed incident hypertension. Hazard ratios (95% CIs) for incident hypertension were 0.88 (0.80 to 0.96; P=0.005) for the rs5063 variant and 0.95 (0.90 to 1.00; P=0.068) for the rs5065 variant. The odds ratios (95% CIs) of blood pressure progression for the G-T, G-C, and A-T haplotypes were 1.0 (referent), 0.91 (0.85 to 0.98; P=0.007), and 0.80 (0.71 to 0.89; P<0.001), respectively. For incident hypertension, the corresponding hazard ratios were 1.0 (referent), 0.95 (0.90 to 1.01; P=0.095), and 0.90 (0.81 to 0.99; P=0.031), respectively. If corroborated by other large-scale, prospective studies, our findings indicate that the natriuretic peptide precursor A gene plays a significant role in blood pressure regulation and development of hypertension.

Topics: Atrial Natriuretic Factor; Blood Pressure; Female; Haplotypes; Humans; Hypertension; Middle Aged; Polymorphism, Genetic; Prospective Studies; Risk

The renoprotective action of angiotensin I-converting enzyme inhibitors (ACE-Is) is well established, but the role played by bradykinin (BK) remains unclear. We therefore investigated whether an enhanced BK effect on B2 receptor subtype mediated the antifibrotic effect of ACE-Is and whether neutral endopeptidase (NEP) inhibition, which can blunt BK degradation more effectively than ACE inhibition, provided further renoprotection in a rat model of angiotensin (Ang) II-dependent renal damage.. Five-week-old Ren-2 transgenic rats (TGRen2) received, for 8 weeks, a placebo, ramipril (5 mg/kg body weight) or the dual ACE + NEP inhibitor MDL 100,240 (MDL) (40 mg/kg body weight). After 4 weeks, the B2 receptor antagonist icatibant (0.5 mg/kg body weight) was administered on top of active treatment for 4 weeks to 50% of the TGRen2 rats. Blood pressure was measured weekly by a tail-cuff method and, after sacrifice, kidney weight, glomerular volume, density of glomerular profiles were measured; tubulo-interstitial fibrosis, glomerular and perivascular fibrosis were quantified by histomorphometry.. The development of hypertension and tubulo-interstitial fibrosis was prevented by both ramipril and MDL (P = 0.0001 versus placebo); icatibant annulled the latter effect. Glomerular and perivascular fibrosis were unaffected by either ramipril or MDL alone; however, combined treatment with icatibant enhanced glomerular fibrosis (P = 0.0001 versus placebo).. Enhanced BK effect on B2 subtype receptors is essential for the prevention of tubulo-interstitial fibrosis with ACE or dual ACE + NEP inhibition in TGRen2 rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Benzazepines; Creatinine; Fibrosis; Hypertension; Kidney; Male; Neprilysin; Pyridines; Ramipril; Rats; Receptor, Bradykinin B2

The goal of our study was to investigate the relationships between atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type A natriuretic peptide receptor (NPRA) gene polymorphisms and left ventricular structure in human essential hypertension.. Experimental evidence supports a key role for natriuretic peptides in the modulation of cardiac mass. This relationship has not yet been described in human disease.. A total of 203 hypertensive patients were studied by mono-bidimensional echocardiography. Three markers of the ANP gene (-C664G, G1837A, and T2238C polymorphisms) and a microsatellite marker of both NPRA and BNP genes were characterized.. Patients carrying the ANP gene promoter allelic variant had increased left ventricular mass index (117.4 +/- 1.7 g vs. 95.7 +/- 1.7 g, p = 0.005), left ventricular posterior wall thickness (1.14 +/- 0.07 cm vs. 0.96 +/- 0.01 cm, p < 0.0001), left ventricular septal thickness (1.12 +/- 0.10 cm vs. 1.04 +/- 0.01 cm, p = 0.01), and relative wall thickening (47.5 +/- 4.1% vs. 39.4 +/- 5.3%, p = 0.001) as compared with the wild-type genotype. These associations were independent from anthropometric factors and major clinical features and were confirmed in a large subgroup of never-treated hypertensive patients (n = 148). Carrier status of the ANP gene promoter allelic variant was associated with significantly lower plasma proANP levels: 1,395 +/- 104 fmol/ml versus 3,110 +/- 141 fmol/ml in hypertensive patients carrying the wild-type genotype (p < 0.05). A significant association for NPRA gene variants with left ventricular mass index and left ventricular septal thickness was found. The analysis of BNP did not reveal any effect on cardiac phenotypes.. Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.

Topics: Adenine; Adult; Alleles; Atrial Natriuretic Factor; Cytosine; Echocardiography; Female; Genetic Variation; Guanine; Guanylate Cyclase; Heterozygote; Homozygote; Humans; Hypertension; Hypertrophy, Left Ventricular; Introns; Male; Natriuretic Peptide, Brain; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Receptors, Atrial Natriuretic Factor; Thymine; Ventricular Remodeling

Atrial natriuretic peptide receptor types A (NPR-A) and C (NPR-C) binding properties and functional characteristics in renal glomeruli have been investigated in deoxycorticosterone acetate (DOCA)-treated hypertensive Wistar-Kyoto (WKY) rats and their respective controls. We found that DOCA administration had no significant effect on the maximum binding capacity or the affinity of renal NPR-A and NPR-C. NPR-C is involved in the regulation of cAMP production. Our results indicate that the cAMP production by NPR-C is not altered in DOCA-induced hypertension, since ANP(1-28), CNP(1-22) and C-ANP, which specifically bind to NPR-C, show a similar inhibitory effect on cAMP production stimulated by the physiological agonist histamine in glomeruli from DOCA-treated rats and controls. Finally, we have found that DOCA-induced hypertension does not modify NPR-A or NPR-C expression in rat glomerular membranes. These findings indicate that NPR-A and NPR-C binding properties and NPR-C-mediated inhibition of cAMP generation remain unaltered in DOCA-treated rats.

Topics: Animals; Atrial Natriuretic Factor; Binding, Competitive; Cyclic AMP; Desoxycorticosterone; Guanylate Cyclase; Hypertension; Kidney; Kidney Glomerulus; Male; Rats; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor

Although moderate alcohol consumption has been associated with a lower risk of cardiovascular disease, underlying physiologic mechanisms are not fully understood. Data relating alcohol intake to atrial natriuretic peptide (ANP) have been inconsistent. We evaluated whether alcohol consumption was associated with plasma ANP in 1,345 participants from the Hypertension Genetic Epidemiology Network (HyperGEN) study. We used random effect models to estimate the adjusted means of logarithmic transformed ANP. The mean age was 35.8 +/- 8.6 years, 91% were normotensive, 46% were men, and 40% and 60% were African-Americans and whites, respectively. In a model adjusting for age, body mass index, field center, education, gender, race, and serum albumin, alcohol consumption was positively associated with ANP in men (p < 0.0001 for trend) and women (p = 0.0014) and in African-Americans (p = 0.006) and whites (p < 0.0001). The adjusted mean of log-transformed ANP was 3.68, 3.67, 3.77, 3.76, 3.86, and 3.91 pg/ml in lifetime abstainers, former drinkers, and current drinkers of 1 to 6, 7 to 12, 13 to 24, and > 24 g/d, respectively. Controlling for additional factors, including left atrial size, ejection fraction, left ventricular mass, end-diastolic volume, systolic blood pressure, smoking, lipids, and serum creatinine did not change the results. Restriction to normotensive subjects yielded similar results. Alcohol intake was associated positively with systolic and diastolic blood pressure (p < 0.0001 each for trend). In conclusion, our data have shown a positive and linear association between alcohol consumption and ANP in men and women, irrespective of race.

Topics: Adolescent; Adult; Aged; Alcohol Drinking; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cross-Sectional Studies; Female; Humans; Hypertension; Male; Middle Aged; Prognosis; Radioimmunoassay; Risk Factors

The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hypertrophy, remodeling, contractile dysfunction, and induction of molecular markers of hypertrophy (ie, expression of mRNA for atrial natriuretic factor and myosin heavy chain beta). Dahl salt-sensitive rats were fed either a low-fat (10% of total energy from fat) or a high-fat (60% of total energy from fat) diet on either low-salt or high-salt (6% NaCl) chow for 12 weeks. Hearts were analyzed for mRNA markers of ventricular remodeling and activities of the mitochondrial enzymes citrate synthase and medium chain acyl-coenzyme A dehydrogenase. Similar levels of hypertension were achieved with high-salt feeding in both diet groups (systolic pressure of approximately 190 mm Hg). In hypertensive rats fed low-fat chow, left ventricular mass, myocyte cross-sectional area, and end-diastolic volume were increased, and ejection fraction was decreased; however, these effects were not observed with the high-fat diet. Hypertensive animals on low-fat chow had increased atrial natriuretic factor mRNA, myosin heavy chain isoform switching (alpha to beta), and decreased activity of citrate synthase and medium chain acyl-coenzyme A dehydrogenase, which were all attenuated by high-fat feeding. In conclusion, increased dietary lipid intake can reduce cardiac growth, left ventricular remodeling, contractile dysfunction, and alterations in gene expression in response to hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Disease Models, Animal; Gene Expression; Heart; Hypertension; Hypertrophy, Left Ventricular; Myocardial Contraction; Myosin Heavy Chains; Rats; Rats, Inbred Dahl; Ventricular Remodeling

Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. In cardiomyocytes, the hormone is synthesized as a precursor, proatrial natriuretic peptide (pro-ANP), which is proteolytically converted to active ANP. Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established. Here, we show that corin-deficient (Cor-/-) mice develop normally during embryogenesis and survive to postnatal life. Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates. Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP. Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading. Pregnant Cor-/- mice demonstrate late-gestation proteinuria and enhanced high blood pressure during pregnancy. In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life. Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Embryonic Development; Female; Hypertension; Male; Mice; Pregnancy; Pregnancy Complications; Protein Precursors; Proteinuria; Serine Endopeptidases; Sodium Chloride

Topics: Atrial Natriuretic Factor; Hormones; Humans; Hypertension; Serine Endopeptidases

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations-blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P< or =0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Black People; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Case-Control Studies; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Renin; White People

We recently showed that plasma concentration of N-terminal atrial natriuretic peptide (Nt-proANP) is strongly directly related to salt sensitivity. The aims of the present study were to test (i) whether plasma concentration of N-terminal brain natriuretic peptide (Nt-proBNP) is related to salt sensitivity and (ii) whether Nt-proANP, as a marker of salt sensitivity, differs between type 2 diabetes patients and nondiabetic subjects without a history of coronary heart disease.. Nt-proBNP was determined in 30 Swedish normal subjects with heredity for primary hypertension and salt sensitivity was defined as the difference between mean arterial blood pressure after 1 week on a high-salt diet (240 mmol day(-1)) and 1 week on a low-salt diet (10 mmol day(-1)). Nt-proANP was measured in 253 patients with type 2 diabetes and in 230 nondiabetic subjects aged 40-70 years, all without a history of coronary heart disease.. Amongst the 30 subjects, in whom salt sensitivity was directly measured, Nt-proBNP was not correlated with salt sensitivity (R=-0.18, P=0.35). Nt-proANP (median, interquartile range) was lower in patients with type 2 diabetes (505, 387-661 pmol L(-1)) than in nondiabetic subjects (536, 421-696 pmol L(-1)) (P=0.02). In a multiple regression analysis heart rate (P <0.00001), diastolic blood pressure (P=0.02) and diabetes status (P=0.02) were inversely related whereas age (P <0.00001), cystatin C (P=0.0006), hypertension treatment (P=0.002) and female sex (P=0.006) were directly related to ln(Nt-proANP).. In contrast to Nt-proANP, Nt-proBNP is not related to salt sensitivity. Salt sensitivity, as estimated by Nt-proANP, seems to be reduced in type 2 diabetes.

Topics: Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors; Sodium Chloride, Dietary

Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.

Topics: Animals; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Disease Models, Animal; DNA Primers; Gene Expression Profiling; Heart Failure; Hypertension; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Male; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Atrial (ANP) and brain (BNP) natriuretic peptides are hormones of myocardial cell origin. These hormones bind to the natriuretic peptide A receptor (NPRA) throughout the body, stimulating cGMP production and playing a key role in blood pressure control. Because NPRA receptors are present on cardiomyocytes, we hypothesized that natriuretic peptides may have direct autocrine or paracrine effects on cardiomyocytes or adjacent cardiac cells. Because both natriuretic peptides and NPRA gene expression are upregulated in states of pressure overload, we speculated that the effects of the natriuretic peptides on cardiac structure and function would be most apparent after pressure overload. To attenuate cardiomyocyte NPRA activity, transgenic mice with cardiac specific expression of a dominant-negative (DN-NPRA) mutation (HCAT D 893A) in the NPRA receptor were created. Cardiac structure and function were assessed (avertin anesthesia) in the absence and presence of pressure overload produced by suprarenal aortic banding. In the absence of pressure overload, basal and BNP-stimulated guanylyl cyclase activity assessed in cardiac membrane fractions was reduced. However, systolic blood pressure, myocardial cGMP, log plasma ANP levels, and ventricular structure and function were similar in wild-type (WT-NPRA) and DN-NPRA mice. In the presence of pressure overload, myocardial cGMP levels were reduced, and ventricular hypertrophy, fibrosis, filling pressures, and mortality were increased in DN-NPRA compared with WT-NPRA mice. In addition to their hormonal effects, endogenous natriuretic peptides exert physiologically relevant autocrine and paracrine effects via cardiomyocyte NPRA receptors to modulate cardiac hypertrophy and fibrosis in response to pressure overload.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Echocardiography; Gene Expression; Genes, Dominant; Guanylate Cyclase; Hypertension; Ligation; Mice; Mice, Inbred Strains; Mice, Transgenic; Mutation; Myocardium; Receptors, Atrial Natriuretic Factor; Transgenes; Ventricular Remodeling

The crucial functions of atrial natriuretic peptide (ANP) and endothelial nitric oxide/NO in the regulation of arterial blood pressure have been emphasized by the hypertensive phenotype of mice with systemic inactivation of either the guanylyl cyclase-A receptor for ANP (GC-A-/-) or endothelial nitric-oxide synthase (eNOS-/-). Intriguingly, similar levels of arterial hypertension are accompanied by marked cardiac hypertrophy in GC-A-/-, but not in eNOS-/-, mice, suggesting that changes in local pathways regulating cardiac growth accelerate cardiac hypertrophy in the former and protect the heart of the latter. Our recent observations in mice with conditional, cardiomyocyte-restricted GC-A deletion demonstrated that ANP locally inhibits cardiomyocyte growth. Abolition of these local, protective effects may enhance the cardiac hypertrophic response of GC-A-/- mice to persistent increases in hemodynamic load. Notably, eNOS-/- mice exhibit markedly increased cardiac ANP levels, suggesting that increased activation of cardiac GC-A can prevent hypertensive heart disease. To test this hypothesis, we generated mice with systemic inactivation of eNOS and cardiomyocyte-restricted deletion of GC-A by crossing eNOS-/- and cardiomyocyte-restricted GC-A-deficient mice. Cardiac deletion of GC-A did not affect arterial hypertension but significantly exacerbated cardiac hypertrophy and fibrosis in eNOS-/- mice. This was accompanied by marked cardiac activation of both the mitogen-activated protein kinase (MAPK) ERK 1/2 and the phosphatase calcineurin. Our observations suggest that local ANP/GC-A/cyclic GMP signaling counter-regulates MAPK/ERK- and calcineurin/nuclear factor of activated T cells-dependent pathways of cardiac myocyte growth in hypertensive eNOS-/- mice.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Blotting, Western; Cyclic GMP; Gene Deletion; Genotype; Heart Ventricles; Hypertension; Hypertrophy; Mice; Mice, Knockout; Mice, Transgenic; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phenotype; Phosphorylation; RNA, Messenger; Signal Transduction

A reduction of coronary flow reserve has been reported in patients with hypertensive heart disease (HHD), which suggests that myocardial ischemia may contribute to the progression to cardiac failure in HHD. Therefore, we evaluated whether fibroblast growth factor (FGF)-2 and/or heparin, which induce angiogenesis, may affect cardiac function in the setting of HHD. We used Dahl salt sensitive (DS) rats as an HHD model. Direct intramyocardial injection of 100 microg of FGF-2 plus 1.28 microg of heparin (n = 6), 100 microg of FGF-2 (n = 6), 1.28 microg of heparin (n = 6) or saline (n = 6) were performed in 9-week-old rats. Echocardiography was performed to evaluate cardiac function at 9, 11, and 13 weeks of age. Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations were measured at 8 and 13 weeks of age. DS rats were killed 4 weeks after myocardial injection (at 13 weeks of age), and myocardial capillary density was assessed by von Willebrand factor staining. Injection of FGF-2 plus heparin significantly decreased left ventricular end-diastolic diameter (P < 0.0001) and left ventricular end-systolic diameter (P < 0.0001), significantly improved the reduction of left ventricular fractional shortening (P = 0.0005), significantly decreased plasma ANP (P < 0.0001) and BNP (P = 0.016) concentrations, and significantly increased myocardial capillary density (P = 0.0002) compared with injection of saline. These findings indicate that intramyocardial injection of FGF-2 plus heparin suppresses the progression of cardiac failure in DS rats. FGF-2 plus heparin administration may be a new therapeutic strategy for the treatment of HHD.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography; Fibroblast Growth Factor 2; Heart Failure; Heart Rate; Heparin; Hypertension; Hypertrophy, Left Ventricular; Injections; Male; Myocardium; Natriuretic Peptide, Brain; Neovascularization, Pathologic; Rats; Rats, Inbred Dahl; Ventricular Function

To assess relationships between noninvasive ambulatory blood pressure (BP), clinic BP (mean value of three readings in the seated position measured by nurses), structural cardiac indices, intima-media thickness of the common carotid artery and several hormones.. Cross-sectional study of 75 subjects with hypertension and left ventricular hypertrophy (HTH) according to echocardiography, 35 subjects with hypertension and normal left ventricular dimensions (HT) and 23 normotensive subjects (NT).. We found an excellent correlation between mean 24-h ambulatory BP and clinic BP, the r-value for systolic BP being 0.82 and for diastolic levels 0.78 (both P < 0.0001). Clinic and ambulatory BP correlated equally well with left ventricular (LV) mass index (r-values between 0.55 and 0.64, all P < 0.0001) and to intima-media thickness of the carotid artery (r = 0.18-0.34, P < 0.01). The systolic white-coat effect (clinic BP - day-time BP) was higher in the HTH and HT compared with NT and was weakly correlated to LV mass index (r = 0.18, P = 0.04). Nondippers (mean arterial night/day BP ratio of > 0.9) had higher brain (6.1 +/- 7.5 pmol L(-1) vs. 3.7 +/- 3.2 pmol L(-1), P = 0.01) and atrial (14 +/- 3.4 pmol L(-1) vs. 9.3 +/- 5.4 pmol L(-1), P = 0.04) natriuretic peptide levels, and also exhibited a lower ejection fraction (49 +/- 8% vs. 57 +/- 9%, P = 0.006), than dippers.. Clinic BP recordings performed by nurses as three measurements 1 min apart provide excellent relationship to target organ damage. Nondippers exhibited signs of a more advanced hypertensive organ damage than dippers which corresponds well with the poor prognosis linked to this condition.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Carotid Artery, Common; Cross-Sectional Studies; Echocardiography; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin; Male; Middle Aged; Natriuretic Peptide, Brain; Nursing Care

Cardiac mass increases with age and with declining estradiol serum levels in postmenopausal women. Although the non-selective estrogen receptor-alpha and -beta agonist 17beta-estradiol attenuates cardiac hypertrophy in animal models and in observational studies, it remains unknown whether activation of a specific estrogen receptor subtype (ERalpha or ERbeta) might give similar or divergent results. Therefore, we analyzed myocardial hypertrophy as well as cardiac function and gene expression in ovariectomized, spontaneously hypertensive rats (SHR) treated with the subtype-selective ERalpha agonist 16alpha-LE2 or 17beta-estradiol.. Long-term administration of 16alpha-LE2 or 17beta-estradiol did not affect elevated blood pressure, but both agonists efficiently attenuated cardiac hypertrophy and increased cardiac output, left ventricular stroke volume, papillary muscle strip contractility, and cardiac alpha-myosin heavy chain expression. The observed effects of E2 and 16alpha-LE2 were abrogated by the ER antagonist ZM-182780. Improved left ventricular function upon 16alpha-LE2 treatment was also observed in cardiac MRI studies. In contrast to estradiol and 16alpha-LE2, tamoxifen inhibited cardiac hypertrophy but failed to increase alpha-myosin heavy chain expression and cardiac output.. These results support the hypothesis that activation of ERalpha favorably affects cardiac hypertrophy, myocardial contractility, and gene expression in ovariectomized SHR. Further studies are required to determine whether activation ERbeta mediates redundant or divergent effects.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Female; Fulvestrant; Gene Expression; Hemodynamics; Hypertension; In Vitro Techniques; Magnetic Resonance Imaging; Models, Animal; Myocardium; Myosin Heavy Chains; Organ Size; Ovariectomy; Papillary Muscles; Random Allocation; Rats; Rats, Inbred SHR; Tamoxifen; Ventricular Myosins

The antifibrotic effects of the peptide hormone relaxin on cardiac and renal fibrosis were studied in 9- to 10-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rats (n=8 to 9 per group) were allocated into 3 groups: WKY controls, vehicle-treated SHR (SHR-V), and relaxin-treated SHR (SHR-R). Relaxin (0.5 mg/kg per day) was administered via subcutaneously implanted osmotic mini-pumps over 2 weeks before hearts and kidneys were harvested for analysis. Collagen content was analyzed by hydroxyproline assay, gel electrophoresis, and quantitative histology. Zymography was used to determine matrix metalloproteinase (MMP) expression and Western blotting to determine proliferating cell nuclear antigen (PCNA) expression and alpha-smooth muscle actin (alpha-SMA)/myofibroblast expression, whereas cardiac hypertrophy was assessed by myocyte size and real-time polymerase chain reaction of associated genes. The left ventricular (LV) myocardium of SHR-V contained increased collagen levels (by 25+/-1%, P<0.01 using biochemical analysis and 3-fold; P<0.01 using quantitative histology), enhanced expression of PCNA (by 70+/-8%; P<0.01), alpha-SMA (by 32+/-2%; P<0.05), and the collagen-degrading enzyme MMP-9 (by 70+/-6%; P<0.05) versus respective levels measured in WKY controls. The kidneys of SHR-V also contained increased collagen (25+/-2%, P<0.05 using biochemical analysis and 2.4-fold; P<0.01 using quantitative histology). Relaxin treatment significantly normalized collagen content in the LV (P<0.01) and kidney (P<0.05), completely inhibited cell proliferation (P<0.01) and fibroblast differentiation (P<0.05) in the LV, and increased MMP-2 expression (by 25+/-1%; P<0.05) without affecting MMP-9 in the LV compared with that measured in SHR-V. Thus, relaxin is a potent antifibrotic hormone with a rapid-occurring efficacy that may have therapeutic potential for hypertensive disease.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomegaly; Collagen; Fibroblasts; Fibrosis; Heart; Humans; Hypertension; Kidney; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins; Relaxin

Improper functioning of kidneys plays a significant part in the development and further worsening of hypertension. The author aimed at studying the functional and hormonal activity of kidneys in patients with I-III stage essential hypertension under physiological hyperhydratation. 68 patients with essential hypertension and 21 patients of a control group have been observed. The blood content of hormones was detected before and after the physiological water stress consisting 2% of body weight. They are the following: rennin, angiotensin, aldosterone, vasopressin, and atrial sodium-releasing hormone. The observed patients with I stage essential hypertension mostly have their kidneys' ducts apparatus reconstructed with considerable decrease in water reabsorption in ducts apparatus of kidneys. It came along with high level of sodium excretion and moderate activation of rennin-angiotenstin-aldosterone system. Patients with II and III stage essential hypertension responds to the physiological water stress (in contrast to patients with I stage essential hypertension and patients of the control group) with progressive increase in water reabsorption in ducts apparatus of kidneys, decrease in sodium excretion comes along with high level of aldosterone, vasopressin and atrial sodium-releasing hormones.

Topics: Aldosterone; Atrial Natriuretic Factor; Diuresis; Hormones; Humans; Hypertension; Kidney; Kidney Function Tests; Middle Aged; Renin; Vasopressins

Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helper-dependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH/2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN.

Topics: Adenoviridae; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Gene Expression; Gene Expression Regulation; Genetic Therapy; Genetic Vectors; Heart; Hypertension; Mice; Mifepristone; Organ Size

alpha1-Adrenergic receptors mediate several biological effects of catecholamines, including the regulation of myocyte growth and contractility and transcriptional regulation of the atrial natriuretic factor (ANF) gene whose promoter contains an alpha1-adrenergic response element. The nuclear pathways and effectors that link receptor activation to genetic changes remain poorly understood. Here, we describe the isolation by the yeast one-hybrid system of a cardiac cDNA encoding a novel nuclear zinc finger protein, Zfp260, belonging to the Krüppel family of transcriptional regulators. Zfp260 is highly expressed in the embryonic heart but is downregulated during postnatal development. Functional studies indicate that Zfp260 is a transcriptional activator of ANF and a cofactor for GATA-4, a key cardiac regulator. Knockdown of Zfp260 in cardiac cells decreases endogenous ANF gene expression and abrogates its response to alpha1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by alpha1-adrenergic agonists and are elevated in genetic models of hypertension and cardiac hypertrophy. The data identify Zfp260 as a novel transcriptional regulator in normal and pathological heart development and a nuclear effector of alpha1-adrenergic signaling.

Topics: Adenoviridae; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Base Sequence; Blotting, Western; Cell Nucleus; Cell Proliferation; Cloning, Molecular; DNA, Complementary; Down-Regulation; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Gene Expression Regulation, Developmental; Gene Library; Genes, Reporter; Heart; HeLa Cells; Humans; Hypertension; Hypertrophy; Immunohistochemistry; Lac Operon; Molecular Sequence Data; Myocardium; Myocytes, Cardiac; Oligonucleotides, Antisense; Plasmids; Promoter Regions, Genetic; Protein Structure, Tertiary; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Recombinant Proteins; RNA; RNA, Messenger; Sequence Homology, Amino Acid; Signal Transduction; Time Factors; Trans-Activators; Transcription, Genetic; Transcriptional Activation; Zinc Fingers

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having > or =2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (> or =70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density <10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] score=2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD score=3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD score=3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder.

Topics: Atrial Natriuretic Factor; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 11; Female; France; Genetic Linkage; Genome, Human; Genotype; Humans; Hypertension; Male; Middle Aged; Obesity; Pedigree; Quebec; Receptors, Tumor Necrosis Factor, Type II

We have previously shown that the partial disruption of the gene for atrial natriuretic peptide (ANP) results in a salt-sensitive phenotype. The present study examined the possibility that alterations in either the ANP natriuretic pathway or endothelin (ET) system in the kidney of the salt-challenged ANP +/- mouse was responsible for its salt-sensitive phenotype. Plasma ANP levels and renal cGMP activity were increased in response to a salt load in both ANP +/+ and +/- mice. However, the mRNA expression of proANP was found to be increased only in the ANP +/- kidney along with its guanylyl cyclase-linked receptor, NPRA; the upregulation of NPRA mRNA was limited to the renal medulla. This suggests that the renal ANP pathway remains capable of responding to a salt load in the ANP +/- animal, but may be compensating for other dysfunctional pathways. We also report a significant increase in renal ET-1 mRNA and ETA receptor protein expression in medulla and cortex of the salt-treated, ANP +/- mouse, but not its wild-type counterpart. In fact, ETA expression decreased in the renal cortex of the ANP +/+ salt-treated animal. The ETB receptor expression was not affected by diet in either genotype. We hypothesize that the salt-sensitive hypertension in the ANP +/- mouse is exacerbated, and possibly driven by the vasoconstrictive effects resulting from an upregulated ET-1/ETA pathway.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Cyclic GMP; Disease Models, Animal; Guanylate Cyclase; Heterozygote; Homozygote; Hypertension; Kidney; Mice; Mice, Knockout; Receptor, Endothelin A; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium, Dietary; Up-Regulation

CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured.. Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period.. The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently.. The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Benzazepines; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-Converting Enzymes; Hypertension; Indoles; Male; Metalloendopeptidases; Neprilysin; Nitric Oxide; Organophosphonates; Phenylalanine; Protease Inhibitors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species

Individual variations in the pharmacokinetics and pharmacodynamics of antihypertensive drugs are influenced by genetic and environmental factors. The ANP gene, which encodes the precursor of atrial natriuretic peptide (ANP), is among the candidate genes for genetic susceptibility to hypertension.. This study examined the relationship between ANP Val7Met polymorphism (Single Nucleotide Polymorphism database ID: rs5063) and baseline blood pressure (BP), plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension.. Patients with essential hypertension who had taken no antihypertensive medications within 4 weeks of study initiation received oral irbesartan 150 mg/d for 4 weeks. Genotyping was performed for all patients. BP was measured before dosing on the 1st and 28th days of treatment. Plasma irbesartan concentrations were measured using high-performance liquid chromatography with fluorescent detection. Antihypertensive efficacy was defined as attainment of a diastolic BP (DBP) <90 mm Hg (DBP analysis), a systolic BP (SBP) <140 mm Hg (SBP analysis), and a DBP <90 mm Hg and SBP <140 mm Hg (DBP and SBP analysis).. The study included 756 patients, 621 with the Val/Val genotype and 135 with the Val/Met+Met/Met genotypes. There were no significant differences in age, body mass index, sex, education level, occupation, alcohol consumption, or smoking status between the 2 groups. Patients with the Val/Met+Met/Met genotypes had a significantly lower mean baseline DBP compared with those with the Val/Val genotype (adjusted regression coefficient [SE]: -2.5 [1.0] mm Hg; P = 0.012) and significantly lower mean steady-state plasma trough irbesartan concentrations (adjusted regression coefficient: -12.6 [4.1]; P = 0.002). No significant association was found between antihypertensive efficacy and Val7Met polymorphism in the overall population, but in an analysis by baseline DBP status, patients with the Val/Met+Met/Met genotype a baseline DBP > or =100 mm Hg had significantly smaller reductions in DBP (adjusted regression coefficient: -5.7 [1.4] mm Hg; P < 0.001) and SBP compared with those with the Val/Val genotype and a baseline DBP > or =100 mm Hg (adjusted regression coefficient: -9.8 [2.9] mm Hg; P < 0.001).. The findings of this study suggest that in these rural Chinese patients with essential hypertension, ANP Val7Met polymorphism may be a genetic marker for baseline DBP, plasma irbesartan concentrations, and the antihypertensive efficacy of short-term irbesartan therapy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Asian People; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; China; Female; Genotype; Humans; Hypertension; Irbesartan; Male; Middle Aged; Polymorphism, Single Nucleotide; Rural Population; Tetrazoles

The synergistic effects of the combined ACE and NEP inhibition is based both on the blockade of angiotensin II synthesis and degradation of vasoactive peptides and NEP substrates (ANP, arginine, endothelial cells, guanylat cyclase etc.), including bradykinine and the natriuretic peptides, which contribute to vasodilatation, diuresis and improvement of myocardial function.. This study was undertaken to asses the hypotensive effect of a dual ACE/NEP inhibitor (omapatrilat) in comparison to a NEP inhibitor (candoxatril) and ACE inhibitor (enalapril) in SHRS.. The study was performed in 130 male spontaneously hypertensive rats (SHRS) that were divided into 4 groups and treated orally by a gastric tube for 14 days according to the following dosage regimen: omapatrilat (40 mg/kg b.w./24 h); candoxatril (30 mg/kg b.w./24 h); enalapril (20 mg/kg b.w./ 24 h) and control (water). Systolic blood pressure values were determined at the beginning of the study by the tail-cuff pletysmographic method, at the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration. For evaluation of the effect of omapatrilat, candoxatril and enalapril on the investigated parameters (plasma atrial natriuretic peptide and serum ACE), 10 animals from the control group were sacrificed at the beginning of the study, and afterwards 10 animals from each group were also sacrificed on the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration (28th day).. The dual ACE/NEP inhibitor, omapatrilat and the ACE inhibitor, enalapril lowered SBP more effectively than the NEP inhibitor, candoxatril at all time points of the experiment (p < 0.01). Omapatrilat was slightly more effective than the enalapril treatment.. Two-week treatment with the dual ACE/NEP inhibitor omapatrilat caused a significant decrease of the SBP, inhibition of the serum ACE activity and increase of the plasma ANP values, and therefore it should be considered as a new potential therapeutic agent in blood pressure management (Tab. 3, Fig. 2, Ref. 20).

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Drug Combinations; Enalapril; Hypertension; Indans; Male; Neprilysin; Propionates; Pyridines; Rats; Rats, Inbred SHR; Thiazepines

We assessed the effect of nitric oxide (NO) synthase inhibition on plasma atrial natriuretic peptide (ANP) concentration and content in some brain structures [neurohypophysis (NH), adenohypophysis (AH), medial basal hypothalamus (MHB) and olfactory bulb (OB)] in rats before and after blood volume expansion (BVE). Male Wistar rats were injected i.p. with N(pi)-nitro-L-arginine (L-NNA), 25 mg/kg of body weight, 40 min before the experiment (acute treatment) or L-NNA at a dose of 25 mg/kg body weight, twice a day, for 4 days (chronic treatment). The acute treatment caused an increase in the blood pressure and plasma ANP concentration in rats under basal conditions and after BVE. A decrease in ANP content was observed in the OB and NH, whereas no significant changes were found in the AH or MBH. In chronically treated rats, we also found an increase in blood pressure and in plasma ANP concentration under basal conditions and after BVE. The ANP content increased in the OB, NH and AH. These results indicate that systemic NO synthase inhibition increases ANP concentration in plasma and in areas of the central nervous system. We hypothesize that ANP participates in the hypertension-induced by NO synthesis blockade acting by baroreceptors input to the brain to stimulate ANP release and synthesis that reduces NO prival hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Hypertension; Male; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar

The mechanisms linking obesity to hypertension have not been established, but sodium retention and excessive sympathetic tone are key contributors. The natriuretic peptides are important regulators of sodium homeostasis and neurohormonal activation, raising the possibility that obese individuals have an impaired natriuretic peptide response.. We examined the relations of plasma B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide (N-ANP) to body mass index in 3389 Framingham Study participants (1803 women) without heart failure. Multivariable regression analyses were performed, adjusting for clinical and echocardiographic covariates. BNP levels below the assay detection limit and N-ANP levels in the lowest sex-specific quartile were categorized as low. Multivariable-adjusted mean plasma BNP levels in lean (<25 kg/m2), overweight (25 to 29.9 kg/m2), and obese (> or =30 kg/m2) men were 21.4, 15.5, and 12.7 pg/mL, respectively (trend P<0.0001). Corresponding values in women were 21.1, 16.3, and 13.1 pg/mL (trend P<0.001). A similar pattern was noted for plasma N-ANP. Obese individuals had higher odds of having low plasma BNP (multivariable-adjusted odds ratios: men, 2.51; 95% CI, 1.71 to 3.68; women, 1.84; 95% CI, 1.32 to 2.58) and low plasma N-ANP (odds ratios: men, 4.81; 95% CI, 2.98 to 7.76; women, 2.85; 95% CI, 2.01 to 4.04) compared with lean individuals. Diabetes also was associated with low plasma natriuretic peptide levels, and the negative effects of obesity and diabetes on natriuretic peptide levels were additive.. Obese individuals have low circulating natriuretic peptide levels, which may contribute to their susceptibility to hypertension and hypertension-related disorders.

Topics: Atrial Natriuretic Factor; Body Constitution; Body Mass Index; Diabetes Complications; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Obesity; Protein Precursors

A-type (atrial) natriuretic peptide (ANP) levels in heart and plasma were examined by immunohistochemistry, electron microscopy, and radioimmunoassay (RIA) in hypertensive transgenic mice (Tsukuba hypertensive mice; THM). Additionally, the ANP mRNA level in the heart was measured using real-time polymerase chain reaction (PCR) assay. The blood pressure and the ratio of heart weight to body weight in THM was significantly higher than those in the control mice (C57BL/6J). The number of ANP-granules and ANP immunoreactivity in the auricular cardiocytes were significantly lower in THM than in the control. Ultrastructurally, the ventricular cardiocytes in the THM occasionally had ANP-like granules, which were not present in the controls. Using RIA, the plasma, auricular, and ventricular ANP concentrations were significantly higher in THM than in the control, but there was no significant difference in plasma cyclic guanosine monophosphate (GMP) concentration between THM and the control. The ANP mRNA levels of the auricular and ventricular cardiocytes in the THM were siginificantly higher than those in the controls. The present study suggested that the ANP release system of the auricular cardiocytes in these transgenic mice is different from normal (control mice).

Topics: Angiotensins; Animals; Atrial Natriuretic Factor; Cyclic GMP; Disease Models, Animal; DNA Primers; Hypertension; Immunohistochemistry; Mice; Mice, Transgenic; Microscopy, Electron; Myocardium; Polymerase Chain Reaction; Radioimmunoassay; RNA, Messenger

Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Body Weight; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Fosinopril; Hypertension; Kidney; Male; Models, Cardiovascular; Neprilysin; Pyridines; Rats; Renin; Statistics as Topic; Survival Analysis; Systole; Thiazepines; Time Factors; Treatment Outcome

Patients with hypertrophic cardiomyopathy (HCM) or hypertensive heart disease (HHD) have increased concentrations of various neurohumoral factors. Thus, the aim of the present study was to evaluate the differences in the neurohumoral profiles of HCM and HHD.. Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II and endothelin-1 were measured in 40 patients with HCM, 35 with HHD, and 15 controls. Additionally, the concentrations of these neurohumoral factors in the coronary sinus and aortic root were measured in 12 HCM patients and 10 controls. Plasma concentrations of norepinephrine, ANP and BNP were significantly higher in HCM than HHD and controls. In HCM, there was no significant correlation between the left ventricular mass index and any neurohumoral factor. The plasma BNP concentration significantly correlated with left intraventricular pressure gradient in HCM. There were significant differences in the plasma concentrations of ANP and BNP between HCM with and without left ventricular diastolic dysfunction. Transcardiac production of BNP was significantly higher in patients with obstructive HCM than in those with non-obstructive HCM.. The significant neurohumoral differences between HCM and HHD were the plasma concentrations of norepinephrine, ANP and BNP. In HCM patients, the plasma BNP concentration may reflect the intraventricular pressure gradient and left ventricular diastolic dysfunction whereas the plasma ANP concentration reflects only the left ventricular diastolic dysfunction.

Topics: Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Coronary Vessels; Echocardiography; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Pressure; Ventricular Dysfunction, Left; Ventricular Function

Greater change of postural blood pressure (BP) is often seen in elderly hypertensives and is recognized as a risk factor for cognitive decline and poorer cerebrovascular outcome, but its clinical significance still remains to be clarified. We performed a head-up tilting test, ambulatory BP monitoring, and brain MRI in 59 hypertensives and 27 normotensive subjects. We measured plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels at rest to assess cardiac burden. The 59 hypertensive patients were classified into 3 groups: an orthostatic hypertension (OHT) group with orthostatic increase in systolic BP (SBP) > or = 10 mmHg (n=16); an orthostatic hypotension (OHYPO) group with orthostatic SBP decrease < or = -10 mmHg (n=18); and an orthostatic normotension (ONT) group with neither of these two patterns (n=25). A group of 27 normotensive subjects (NT) was also included as a control. Plasma BNP (72 +/- 92 vs. 29 +/- 24 pg/ml, p < 0.05) and BNP/ANP ratio (4.6 +/- 3.3 vs. 2.4 +/- 1.5, p < 0.05) were significantly higher in the OHYPO than in the NT group. The BNP/ANP ratio was also higher in the OHT than in the NT group (5.1 +/- 3.9 vs. 2.4 +/- 1.5, p < 0.01). The number of silent cerebral infarct (SCI), prevalence of SCI and number of multiple SCIs was the highest in the OHT group, followed in order by the OHYPO, ONT and NT groups. Blood pressure and left ventricular mass index were not significantly different among the 3 hypertensive groups. In conclusion, hypertensive patients with greater change of postural BP (OHT and OHYPO) were shown to have increased risk of advanced silent brain lesions and greater cardiac burden.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Cerebral Infarction; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Hypotension, Orthostatic; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Stroke Volume; Ventricular Dysfunction, Left

Aim of the study was to evaluate the role of atrial (ANP) and brain natriuretic peptides (BNP) as markers of preclinical cardiac disease in obesity.. We selected 26 obese (BMI > 29 kg m(-2)) never-treated hypertensives (24-h BP > 140 and/or 90 mmHg), 26 obese normotensives (24-h BP < 130/80 mmHg) and 25 lean (BMI < or = 25 kg m(-2)) never-treated hypertensives. Each subject underwent measurements of ANP and BNP plasma levels, 24-h ambulatory blood pressure (BP) monitoring, digitized M-mode and Doppler echocardiography.. Mean values of ANP and BNP were similar among the three groups. All the subjects had normal left ventricular (LV) systolic function. Within each group ANP levels were higher in patients with LV diastolic dysfunction than in patients with normal diastolic function, and BNP levels were higher in patients with LV hypertrophy and in patients with LV diastolic dysfunction. Within each group, ANP levels were inversely correlated with LV diastolic indices, whereas BNP levels were directly correlated with LV mass index and inversely correlated with LV diastolic indices. ANP and BNP levels were not correlated with other echocardiographic parameters, age, BMI or 24-h BP values.. In normotensive and hypertensive obese subjects the relationships of ANP and BNP levels with LV morpho-functional characteristics follow the same trend as in lean hypertensives, with ANP mainly influenced by diastolic dysfunction and BNP influenced by both LV hypertrophy and LV diastolic dysfunction. Therefore ANP and BNP can be considered useful markers of preclinical cardiac disease in obesity.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Female; Heart Diseases; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptides; Obesity; Ventricular Dysfunction, Left; Ventricular Function, Left

Long-term nitric oxide (NO) blockade is known to induce a severe and progressive hypertension. The influence of the salt-intake on atrial natriuretic peptide (ANP) system in this hypertension model is unknown. The aim of this study was to evaluate ANP plasma levels, content and mRNA in atria of male Wistar rats chronically treated with oral Nomega-nitro-L-arginine methyl ester (L-NAME) after 4 weeks of high-salt diet. The high-salt diet induced an increase (P < 0.05) in ANP plasma levels in normotensive rats and no significant changes in hypertensive animals. We observed a significant increase in the ANP content in the left and right atria of hypertensive rats (P < 0.001) when compared to normotensive ones. However, no significant changes were observed during high-salt diet in normotensive and hypertensive animals. Northern blot analysis revealed that ANP gene expression is higher in the right and left atria of hypertensive rats when compared to normotensive rats. However, we found no significant changes in ANP mRNA of rats treated with high-salt diet in normotensive and hypertensive rats when compared to low-salt diet. The present observations indicate no interaction between salt-intake and activation of the ANP system during chronic nitric oxide synthase (NOS) inhibition.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Enzyme Inhibitors; Heart Atria; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary

The success of any gene-therapy approach depends on the survival of the genetically engineered cells that are implanted in the patient to deliver the therapeutic product. Immunoisolation of nonautologous cells within a microcapsule is a unique approach for gene therapy.. We employed an immunoisolation device that protects nonautologous cells from destruction, to implant human atrial natriuretic peptide (hANP)-producing Chinese hamster ovary (CHO) cells in two-kidney, one-clip (2K1C) hypertensive rats. CHO cells transfected with the plasmid CMV-cANP were encapsulated in biocompatible polycaprolactone (PCL) capsules, and then the PCL capsules were implanted into 2K1C hypertensive rats intraperitoneally.. The implantation of encapsulated hANP-producing cells caused a significant delay of blood pressure (BP) increase 2 weeks post-implantation and the effect lasted for more than 5 months. The implantation of encapsulated hANP-producing cells also caused significant increases in renal blood flow (RBF), glomerular filtration rate (GFR), sodium output, urine excretion, and urinary cGMP levels. These beneficial effects were reflected morphologically by an attenuation of the glomerular sclerotic lesions, reduction in cardiomyocyte size, tubular injury and renal arterial thickening. Immunoreactive hANP can be detected in the blood of 2K1C rats after implantation of the PCL capsules containing hANP-producing cells.. This study demonstrates the usefulness of encapsulated ANP gene transfected cells as a new tool for ANP gene delivery in studying renovascular hypertension and cardiovascular diseases. Thus, our results may have important implications for clinical use of transgene cells as therapeutic agents in the treatment of cardiovascular diseases.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; CHO Cells; Cricetinae; Hypertension; Kidney; Kidney Function Tests; Male; Microscopy, Confocal; Myocardium; Rats; Rats, Wistar; Transfection; Transgenes

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48 U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P < 0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P < 0.01). Compared with U, UH has lower HW/BW and LV/BW (P < 0.05) and UE has normal HW/BW but lower LV/BW than U (P < 0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal a- actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta1, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure-overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.

Topics: Actins; Anemia; Animals; Atrial Natriuretic Factor; Erythropoietin; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

To dissect the tissue-specific functions of atrial natriuretic peptide (ANP), we recently introduced loxP sites into the murine gene for its receptor, guanylyl cyclase-A (GC-A), by homologous recombination (tri-lox GC-A). For either smooth-muscle or cardiomyocyte-restricted deletion of GC-A, floxed GC-A mice were mated to transgenic mice expressing Cre-recombinase under the control of the smooth-muscle SM22 or the cardiac alphaMHC promoter. As shown in these studies, Cre-mediated recombination of the floxed GC-A gene fully inactivated GC-A function in a cell-restricted manner. In the present study we show that alphaMHC-Cre, but not SM22-Cre, with high frequency generates genomic recombinations of the floxed GC-A gene segments which were transmitted to the germline. Alleles with partial or complete deletions were readily recovered from the next generation, after segregation of the Cre-transgene. We took advantage of this strategy to generate a new mouse line with global, systemic deletion of GC-A. Doppler-echocardiographic and physiological studies in these mice demonstrate for the first time the tremendous impact of ANP/GC-A dysfunction on chronic blood volume homeostasis.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Blotting, Southern; DNA Primers; Echocardiography, Doppler; Gene Components; Gene Silencing; Guanylate Cyclase; Heart; Hypertension; Integrases; Mice; Mice, Transgenic; Microfilament Proteins; Models, Animal; Muscle Proteins; Muscle, Smooth; Myosin Heavy Chains; Promoter Regions, Genetic; Receptors, Atrial Natriuretic Factor; Reverse Transcriptase Polymerase Chain Reaction

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Blood Volume; Cohort Studies; Cross-Sectional Studies; Diet, Reducing; Disease Susceptibility; Humans; Hypertension; Natriuretic Peptide, Brain; Obesity; Protein Precursors; Thinness

Hypertension is associated with changes in concentrations of vasoactive peptides and procollagen propeptides, but their relationships with left ventricular hypertrophy and cardiac function are unclear.. We measured plasma levels of atrial natriuretic peptide (ANP), its amino terminal propeptide (NT-proANP), B-type natriuretic peptide (BNP), endothelin-1 (ET-1), and serum levels of the aminoterminal propeptide of type I procollagen (PINP) and the aminoterminal propeptide of type III procollagen (PIIINP) and echocardiographic parameters in 97 patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial.. Median values (reference values) of the peptides were: ANP 11.2 (6.9-14.9) pmol/l, NT-proANP 351 (143-311) pmol/l, BNP 1.1 (0.4-7.2) pmol/l, ET-1 8.7 (1.2-5.0) pmol/l, PIIINP 2.8 (1.7-4.2) microg/l and PINP 29 (19-84) microg/l. Plasma BNP levels in patients with left ventricular hypertrophy (1.2 pmol/l) and patients with echocardiographic signs of diastolic dysfunction (1.5 pmol/l) were greater than those in patients without hypertrophy (0.7 pmol/l) and normal diastolic parameters (0.9 pmol/l) (p<0.05). BNP was the only biochemical parameter that independently predicted interventricular septal diastolic diameter (p<0.05), left ventricular mass index (p<0.01) and ratio of the velocity-time integrals of the E and A waves of the mitral inflow in a stepwise logistic regression analysis (p<0.05).. The results show that BNP reflects the remodelling process in hypertension.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Diastole; Endothelin-1; Humans; Hypertension; Hypertrophy, Left Ventricular; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Procollagen; Protein Precursors; Ultrasonography; Ventricular Dysfunction, Left

Electron microscopy and stereomorphometric analysis of hypertrophic cardiomyocytes in the right atrium of NISAG rats revealed signs of activation of biosynthetic processes: increased relative volume of euchromatin (compared to Wistar rats), high density of nuclear pores, presence of large numerous Golgi complexes, and well-developed endoplasmic reticulum. The numerical density of secretory granules in the cytoplasm of cardiomyocytes in NISAG rats significantly surpassed that in Wistar rats. However, these granules in NISAG rats were smaller than in Wistar rats. The presence of numerous secretory granules and increased ratio of forming and dissolving structures suggest that this pool is characterized by high turnover rate, i.e., intensive synthesis and rapid elimination (consumption) of natriuretic peptide. Hypertrophy and hyperactivity of endocrine function in atrial cardiomyocytes of NISAG rats can be considered as a compensatory reaction to hypertension.

Topics: Animals; Atrial Natriuretic Factor; Cytoplasmic Granules; Heart Atria; Hypertension; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Inbred Strains; Rats, Wistar

In order to investigate the contribution of the atrial natriuretic factor (ANF) gene in pathogenesis of essential arterial hypertension (EAH), we analyzed the ScaI gene polymorphism of the ANF gene in a group of children with EAH. Fifty-eight children, aged 8-19 years, with the diagnosis of EAH were included in the association study and were compared to 57 subjects with normal blood pressure (the control group). Arterial hypertension was defined as systolic/diastolic blood pressure higher than the 95th age-gender-height percentile of the adopted reference values. We failed to demonstrate an association between the ScaI ANF gene polymorphism and EAH in childhood (OR = 2; 95% CI 0.9-4.2; p = 0.07), however, we provided evidence of an interaction between the ScaI ANF gene polymorphism and obesity defined as BMI over the 85th percentile (OR = 13.1; 95% CI 1.6-106; p < 0.001).

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Case-Control Studies; Child; Female; Genetic Predisposition to Disease; Humans; Hypertension; Male; Polymorphism, Genetic

Hypertension produced by chronic inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME) was used to determine the effect of severe pressure overload with or without left ventricular (LV) hypertrophy on the transcriptional activation of the cardiac fetal genes encoding for the natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and for beta-myosin heavy chain (MHC) in both atrial and ventricular muscle. A previously reported association of LV hypertrophy with the activation of cardiac renin and angiotensin-converting enzyme (ACE) in this hypertension model was also investigated.. Male Sprague-Dawley rats received L-NAME (75 mg/kg/day) or were left untreated for 4 (n=12) or 8 (n=12) weeks.. L-NAME-treated rats became severely hypertensive in both treatment groups but only five out of 12 8-week treatment animals showed a significantly increased LV weight to body weight (BW) ratio (LVW/BW). LV ANF mRNA, but not LV BNP mRNA, correlated significantly with LVW/BW only in animals showing LV hypertrophy. No changes were observed in atrial gene expression or plasma concentration of ANF or BNP. A significant correlation was found between LVW/BW and LV renin mRNA and LV ACE activity in rats with LV hypertrophy. LV beta-MHC mRNA levels were significantly increased in the LV of rats with or without LV hypertrophy at both 4 and 8 weeks of treatment.. It is concluded that pressure overload per se does not promote NP or cardiac renin-angiotensin system gene expression while increased beta-MHC expression is a marker of LV pressure overload even in the absence of LV hypertrophy. It is apparent that L-NAME causes a disruption in the coordinated transcriptional activation of cardiac fetal genes expected of hypertrophic stimuli acting on the LV.

Topics: Animals; Atrial Natriuretic Factor; Enzyme Inhibitors; Gene Expression Regulation; Heart Ventricles; Hypertension; Male; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (r=0.72, r=0.79, and r=0.70, respectively; all P<0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Calcitonin Receptor-Like Protein; Disease Progression; Heart Failure; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Peptides; Rats; Rats, Inbred Dahl; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Transcription, Genetic

In case-control studies, polymorphisms at the atrial natriuretic peptide gene (ANP) locus have been associated with presence of albuminuria in Type 1 and Type 2 diabetes. We evaluated the relationship between the ScaIand BstxI polymorphisms and albuminuria in the general population of the Mexico City Diabetes Study.. Allele/genotype frequencies were analysed by PCR-RFLP analysis using ScaI (wild, A(2) vs mutated, A(1)) and BstxI (wild, C(708) vs mutated, T(708)) enzyme.. Among 1288 subjects, hypertension was present in 112 subjects, Type 2 diabetes in 191 and impaired glucose tolerance in 136; microalbuminuria was present in 464 subjects, and clinical proteinuria in 199. General frequencies were 0.93 and 0.96 for the wild alleles, and 0.07 and 0.04 for the mutated alleles, respectively for ScaI and BstxI. Frequency of A(1)was 0.08 in normoalbuminuric, 0.05 in microalbuminuric, and 0.05 in proteinuric patients (chi(2)=7.3, p=0.025). Frequency of T(708) was 0.06 in normoalbuminuric and 0.03 microalbuminuric and 0.03 in proteinuric subjects (chi(2)=8.1, p=0.017). By multivariate analysis, the associations between A(1)or T(708) allele and albuminuria were independent of age, sex, BMI, diabetes, and hypertension, (odds ratio (OR) 0.60, p=0.01, (OR) 0.51, p=0.004, respectively).. In the general population of Mexico City, both polymorphisms of ANP are associated with albuminuria independently of hypertension, and could play a role in protecting subjects against development of albuminuria.

Topics: Adult; Albuminuria; Alleles; Atrial Natriuretic Factor; Deoxyribonucleases, Type II Site-Specific; Diabetes Complications; Diabetes Mellitus; Female; Gene Frequency; Glucose Intolerance; Humans; Hypertension; Male; Mexico; Middle Aged; Polymorphism, Genetic; Population; Proteinuria; Reverse Transcriptase Polymerase Chain Reaction

We Investigated a gene therapy delivery system based on microcapsules enclosing recombinant Chinese hamster ovary (CHO) cells engineered to secrete a therapeutic peptide-atrial natriuretic peptide (ANP).. Human atrial natriuretic peptide gene transfecting Chinese hamster ovary (CHO) cells were encapsulated in non-antigenic biocompatible polycaprolactone (PCL) capsules prior to their implantation into rats, then, the PCL-tubes were implanted into hypertensive DSS rats intraperitoneally.. The PCL-tubes 2 d post implantation caused a significant delay of blood pressure increase. The effect lasted for more than 5 months. The PCL-tubes also caused significant increases in renal blood flow, glomerular filtration rate, sodium output, urine excretion. Plasma levels of ANP in rats implanted with the PCL-tubes containing engineering cells is higher than that of the control rats.. This study demonstrates encapsulated engineering cells have significant potential in treatment of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; CHO Cells; Cricetinae; Drug Compounding; Drug Delivery Systems; Drug Evaluation; Genetic Therapy; Humans; Hypertension; Polyesters; Rats; Transfection

In patients with chronic heart failure plasma levels of N-terminal proatrial natriuretic peptide (Nt-proANP) correlate to cardiac filling pressures. The aim of the present study was to examine the relation between Nt-proANP plasma levels and echocardiographic indices of cardiac dysfunction in patients recruited from primary care.. After clinical examination by the primary care physician, the patients were referred to one of two centres for echocardiography and blood sampling. In patients with mild to moderate symptoms of heart failure (n=52) and in asymptomatic patients with long-standing hypertension (n=46) or previous myocardial infarction (n=97), peptide levels were most closely related to parameters of left atrial wall stress. Patients who according to echocardiographic predefined criteria had diastolic or systolic dysfunction had two- and three-fold higher Nt-proANP than controls. According to receiver operating curve (ROC) analysis, Nt-proANP measurements were helpful in ruling out left ventricular systolic dysfunction, but not diastolic dysfunction.. In patients with mild to moderate cardiac disease, Nt-proANP plasma concentration was related to increased atrial wall stress. Peptide measurement could assist in ruling out the presence of LV systolic dysfunction, but was otherwise of limited value when used for diagnostic subgrouping into echocardiographically determined function categories.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Echocardiography; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Primary Health Care; Protein Precursors; Systole; Ventricular Dysfunction, Left

The effects of low-dose oral spironolactone (SPIRO) in a rat model of hypertensive heart failure (spontaneously hypertensive heart failure rat) were compared with its effects when combined with captopril (CAP). Twenty-six spontaneously rats with hypertensive heart failure were treated with either placebo (CON), SPIRO (20 mg/kg/d by mouth), CAP (100 mg/kg/d by mouth), or both SPIRO and CAP for 12 weeks. This dose of oral SPIRO did not affect blood pressure, left ventricular end-diastolic diameter, left ventricular ejection fraction, plasma atrial natriuretic peptide concentration, or cardiac fibrosis; however, in combination with CAP, it exerted a significant depressor effect after 12 weeks of treatment that was accompanied by increased urine output and decreased urinary protein excretion. These effects were significantly greater than those with CAP treatment alone. A significant increase in plasma aldosterone level was observed only in CON (174 +/- 21%). These data suggest that the addition of low-dose SPIRO to angiotensin I-converting enzyme inhibitor treatment may prevent progression into end-stage congestive heart failure through synergistic effects on diuresis and renoprotection.

Topics: Administration, Oral; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Captopril; Diuresis; Drug Therapy, Combination; Fibrosis; Heart Failure; Heart Ventricles; Hypertension; Hypertrophy; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Spironolactone; Time Factors; Ultrasonography

We investigated the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand, receptor and amidating activity in the hypertrophied heart in severe hypertension.. We studied the following four groups: control Wistar-Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), 8 weeks captopril-treated SHR-SP, and 8 weeks trichlormethiazide-treated SHR-SP. AM precursor is converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly is converted to active mature AM (AM-m) by enzymatic amidation. We measured AM-m, AM-total (AM-T; AM-T = AM-m + AM-Gly), and atrial natriuretic peptide (ANP) in the plasma and left ventricle (LV) by immunoradiometric assay. We also measured gene expression of AM and ANP was and gene expression and protein levels of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor-activity modifying protein (RAMP) 2 and RAMP3.. At 7 weeks old, SHR-SP had higher blood pressure and ANP mRNA levels and lower plasma AM-T compared with WKY, however, there were no differences in other indices between the two groups. At 17 weeks old, SHR-SP had increased blood pressure, LV weight, plasma and LV ANP levels and mRNA levels of ANP compared with WKY. AM-m and AM-T levels in plasma (AM-m: + 31%; AM-T: + 56%) and the LV (AM-m: + 84%; AM-T: + 31%) were significantly higher in SHR-SP than in WKY. The LV tissue AM-m/AM-T ratio was significantly higher in SHR-SP (93.2%) than in WKY. The mRNA levels of AM, CRLR, and RAMP2 in the LV were significantly higher in SHR-SP than in WKY. Captopril and trichlormethiazide similarly decreased blood pressure and LV hypertrophy with the reduction of the LV AM-m and AM-T levels and mRNA abundance of AM and its receptor component.. These results suggest that cardiac AM system is upregulated in the hypertrophied heart in this hypertension model. Considering that AM acts as an anti-remodeling autocrine and/or paracrine factor, upregulation of the AM system may modulate the pathophysiology in LV hypertrophy.

Topics: Adrenomedullin; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcitonin Receptor-Like Protein; Captopril; Diuretics; Drug Therapy, Combination; Gene Expression; Hypertension; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Ligands; Male; Membrane Proteins; Myocardium; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; RNA, Messenger; Sodium Chloride Symporter Inhibitors; Trichlormethiazide; Up-Regulation

Atrial natriuretic peptide (ANP) has vasodilating and diuretic/natriuretic properties, both of which contribute to lower blood pressure. These effects are mediated by binding of ANP to a cell-surface receptor [type A guanylyl cyclase (GC-A)]. It has been demonstrated by studies in monogenetic mouse models that the ANP/GC-A system participates in the maintenance of blood pressure homeostasis.. In male patients with essential hypertension (EH; n = 36) as the only cardiovascular risk factor and normotensive controls (n = 12), blood flow was measured in the forearm circulation in response to i.a. infusion of synthetic human ANP, acetylcholine, orciprenaline, and sodium nitroprusside by strain-gauge venous plethysmography. In blood samples, cyclic guanosine'5-monophosphate (cGMP) and ANP concentrations were measured at resting conditions and during exogenous ANP infusion. In 200 patients with EH, genomic DNA was screened for an inhibitory deletion mutation of the GC-A gene, which has been recently linked to EH in a Japanese cohort.. The vasodilatations in response to ANP and acetylcholine were impaired in the forearm circulation of patients with EH, whereas the responses to orciprenaline and nitroprusside were preserved. Plasma ANP and cGMP concentrations were increased in the patients with EH both at resting conditions and during ANP infusion; the resting plasma cGMP levels correlated significantly with the plasma ANP levels (r = 0.68). A specific deletion mutation of the GC-A gene did not account for the diminished relaxant effects of ANP in our study population.. The vascular ANP/GC-A pathway is altered in patients with EH, in addition to the known defects on the nitric oxide/cGMP pathway. Attenuation of the vasodilative responses to ANP suggests impaired receptor or postreceptor responsiveness of GC-A. It is possible that this dysfunction participates in the pathomechanism of EH.

Topics: Atrial Natriuretic Factor; Blood Flow Velocity; Blood Pressure; Body Mass Index; Forearm; Gene Deletion; Guanylate Cyclase; Humans; Hypertension; Male; Middle Aged; Mutation; Vasodilator Agents

To assess the accuracy of B-type natriuretic peptide (BNP) plasma levels for the diagnosis of left ventricular hypertrophy (LVH) in hypertensive patients.. We studied a sample of 409 adults aged 45 years or older, recruited from residents of Porto by random digit dialing. Data were collected by clinical interview and physical examination, ECG, echocardiogram and venous blood sampling for the measurement of plasma concentrations of BNP. Hypertension (HT) was defined as blood pressure > or = 140/90 mmHg on the day of interview and/or self-reported HT if treated with any antihypertensive medication; LVH was defined as left ventricular mass index (LVMI) > or = 125 g/m2 in men and 110 g/m2 in women. The participants were further classified in four strata according to left ventricular morphology--normal, concentric remodeling, eccentric LVH or concentric LVH.. Two hundred and thirty-two (56.7%) individuals were hypertensive, and among these 73 (31.5%) had LVH. BNP levels were significantly higher in these individuals (median [P25-P75] = 55.8 pg/ml [22.6-88.4]) than in hypertensive patients without LVH (29.9 pg/ml [10.0-62.8]), p = 0.003. BNP levels also differed significantly across strata of left ventricular geometry, the main difference depending on the presence or absence of LVH. There was a positive correlation between plasma BNP levels and LVMI (Spearman's P 0.185, p = 0.005). The area under the ROC curve--a parameter for diagnostic accuracy quantification--was 0.62 (95% confidence interval 0.54-0.70), indicating low discriminatory power between normal and abnormal LVMI.. In the assessed population, BNP levels were higher in hypertensive patients with LVH than in the absence of LVH. However, BNP did not perform well in discriminating between the presence or absence of LVH.

Topics: Aged; Atrial Natriuretic Factor; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain

Proinflammatory cytokines are capable of modulating cardiovascular function by a various mechanisms. The aim of the study was to evaluate the influence of the selected cytokines: tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (L-6), endothelin 1 (ET-1) on the remodeling of the heart in patients with congestive heart failure (1-year follow-up). The study was made in 45 patients with congestive heart failure treated in the Department of Cardiology. Of these, 31 were men aged from 44 to 77 and 14 were women aged from 48 to 79. Ischaemic heart disease was diagnosed in 22 patients and ischaemic heart disease and hypertension in 10 patients, dilated cardiomyopathy was diagnosed in 6 patients and postinflammatory cardiomyopathy in 7 patients. Blood samples for determination of TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels were obtained prior to the treatment and in 3 and 6 and 12 month follow-up. At the same time were estimated: NYHA functional class, structure, systolic and diastolic left ventricle function of the heart using echocardiography and 24-hour ECG Holter monitoring (HR, supraventricular and ventricular arrhythmias). TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, BNP and ANP plasma levels were determined with radioimmunological assay. In patients with progression of congestive heart failure (worsening of NYHA class and ejection fraction of left ventricle) the plasma concentrations of TNF-alpha and ET-1 significantly increased in following observations. In this group patients we determined a correlation between ejection fraction of the left ventricle and serum concentration of TNF-alpha and ET-1. In patients with improving of NYHA functional class and ejection fraction of left ventricle the plasma concentrations of cytokines were not altering. In all patients the plasma concentration of TNF-alpha correlated with ANP and BNP concentrations.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Catecholamines; Cytokines; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Interleukin-1; Interleukin-2; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Radioimmunoprecipitation Assay; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Left ventricular hypertrophy, in particular concentric, accompanying hypertension is an independent risk factor of sudden death and other serious cardiovascular complications. It is still not clear how ANP and BNP are related to various types of left ventricular geometry and whether BNP is a better predictor of left ventricular hypertrophy and dysfunction than ANP. The aim of the study was estimation of plasma ANP and BNP levels in patients with hypertension in relation to the changes of left ventricular geometry. Investigations were carried out in 80 patients aged 52.5 +/- 12.6. In every patient plasma levels of ANP and BNP were estimated, blood pressure was measured and echocardiographic study was performed. Based on echocardiographic measurements every patient was classified into one of four left ventricular geometric patterns. It was found that in patients with left ventricular concentric hypertrophy plasma level of ANP and BNP was increased whereas in patients with concentric remodeling and eccentric hypertrophy only plasma level of ANP was elevated. In patients with concentric hypertrophy higher levels of ANP and BNP were found compared to patients with concentric remodeling and eccentric hypertrophy.

Topics: Atrial Natriuretic Factor; Electrocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain

A technique based on the release of atrial natriuretic peptide (ANP) from encapsulated ANP cDNA transfected Chinese hamster ovary (CHO) cells for potential therapeutic approach to hypertension or congestive heart failure (CHF) was investigated.. ANP cDNA transfected CHO cells were encapsulated in polycaprolactone (PCL) tubes and the levels of ANP secreted from PCL tubes were detected. Circadian rhythm of ANP secreted by encapsulated transfected cells was also studied by regulation with melatonin.. During culturing, the encapsulated cells remained viable and the mean level of ANP reached 246.1 pg/ml/24 h in 2 ml medium containing one PCL tube (20 mm in length and 3 mm in diameter), whereas the secretion by the control was negative. The secretion of ANP showed a circadian variation: higher at night, but lower at day. The acrophase of circadian rhythm was 4:18 and shifted to 7:56 after melatonin was given.. The above results demonstrated a potential use of the encapsulation technique of gene transfected cells implanted into human body for treatment of hypertension or CHF.

Topics: Animals; Atrial Natriuretic Factor; Caproates; CHO Cells; Circadian Rhythm; Cricetinae; Drug Delivery Systems; Drug Design; Heart Failure; Hypertension; Immunohistochemistry; Lactones; Melatonin; Transfection

1. The aim of the present studies was to determine the role of proANP (1-30) in the regulation of arterial pressure. It was hypothesized that blocking endogenous proANP (1-30) would exacerbate the hypertension in susceptible animal models. 2. Pentobarbital-anaesthetized spontaneously hypertensive rats (SHR) were pretreated i.v. with 1.2 mL rabbit serum containing an antibody directed specifically against rat proANP (1-30) (SHR-AB group; n = 7) or an equal volume of normal rabbit serum as a control (SHR-NRS group; n = 5). 3. Following a 1 h equilibration period and two 30 min baseline periods, rats were volume expanded with 3 mL of 6% albumin in Krebs' solution and observed for an additional 3 h to determine the effects of the anti-proANP on arterial pressure. 4. Arterial pressure increased in both groups compared with their own baselines with volume expansion, but was significantly greater in the anti-proANP SHR group compared with the SHR-NRS group throughout the volume expansion period. A maximum difference of 21 mmHg between the anti-proANP SHR group and the NRS-SHR group was observed at 150 min of the study (183 +/- 5 vs 162 +/- 3 mmHg, respectively; P < 0.005. 5. These results suggest a protective role for proANP (1-30) in the SHR model of hypertension.

Topics: Animals; Antibodies; Atrial Natriuretic Factor; Blood Pressure; Hypertension; Male; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred SHR

The precise function of angiotensin II type 2 receptor (AT2-R) in the mammalian heart in vivo is unknown. Here, we investigated the role of AT2-R in cardiac pressure overload.. Rats were infused with vehicle, angiotensin II (Ang II), PD123319 (an AT2-R antagonist), or the combination of Ang II and PD123319 via subcutaneously implanted osmotic minipumps for 12 or 72 hours. Ang II-induced increases in mean arterial pressure, left ventricular weight/body weight ratio, and elevation of skeletal alpha-actin and beta-myosin heavy chain mRNA levels were not altered by PD123319. In contrast, AT2-R blockade resulted in a marked increase in the gene expression of c-fos, endothelin-1, and insulin-like growth factor-1 in Ang II-induced hypertension. In parallel, Ang II-stimulated mRNA and protein expression of atrial natriuretic peptide were significantly augmented by AT2-R blockade. Moreover, PD123319 markedly increased the synthesis of B-type natriuretic peptide. Furthermore, the expression of vascular endothelial growth factor and fibroblast growth factor-1 was downregulated by Ang II only in the presence of AT2-R blockade.. Our results provide evidence that AT2-R plays a functional role in the cardiac hypertrophic process in vivo by selectively regulating the expression of growth-promoting and growth-inhibiting factors.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Hypertrophic; Fibroblast Growth Factor 1; Gene Expression Regulation; Genes, fos; Heart Rate; Hypertension; Imidazoles; Infusion Pumps, Implantable; Losartan; Male; Natriuretic Peptide, Brain; Proto-Oncogene Proteins c-fos; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; RNA, Messenger; Vascular Endothelial Growth Factor A

Gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from proopiomelanocortin (POMC) in the pituitary neurointermediate lobe (NIL); its plasma concentration in rats doubles after ingestion of a high (HSD; 8% NaCl) compared with a low sodium diet (LSD; 0.07%). Because NIL function is regulated through dopaminergic pathways, we asked whether dopaminergic stimulation with bromocriptine (5 mg/kg IP daily for 1 week) or inhibition with haloperidol (5 mg/kg IP for 1 week) alters the gamma-MSH response to a HSD. In vehicle-treated rats, plasma gamma-MSH and NIL gamma-MSH content on the HSD were both markedly elevated over values in rats on the LSD (P<0.001); no difference in mean arterial pressure (MAP) occurred. In haloperidol-treated rats on the LSD, both plasma gamma-MSH and NIL gamma-MSH content were greater than in vehicle-treated rats (P<0.05) and did not increase further on the HSD; MAP was also no different. In bromocriptine-treated rats, neither plasma gamma-MSH nor NIL gamma-MSH content increased on the HSD versus LSD, and MAP was markedly elevated on the HSD (132+/-3 versus 106+/-3 mm Hg, P<0.001). Intravenous infusion of gamma-MSH (0.4 pmol/min) to bromocriptine-treated rats on the HSD restored plasma gamma-MSH concentration to a level appropriate for the HSD and lowered MAP from 131+/-6 to 108+/-5 mm Hg (P<0.01). These results demonstrate that the increases in NIL content and plasma concentration of gamma-MSH normally occurring during ingestion of the HSD are prevented by dopaminergic suppression of NIL function. This results in deficiency of gamma-MSH on the HSD and is accompanied by elevated blood pressure, which is corrected by infusion of the peptide. gamma-MSH may be an important component in the normal response to a HSD; interruption of this response leads to salt-sensitive hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Bromocriptine; Dopamine Agonists; Dopamine Antagonists; gamma-MSH; Haloperidol; Hypertension; Infusions, Intravenous; Male; Pituitary Gland, Posterior; Rats; Rats, Sprague-Dawley; Renin; Sodium; Sodium Chloride

In hypertensive patients, diminished nocturnal blood pressure (BP) fall is associated with poor prognosis for cardiovascular events. However, the relation of insulin resistance with the etiology of nondipper essential hypertension remains unclear. The aim of the present study was to assess the role of insulin resistance in diminished nocturnal BP fall, left ventricular hypertrophy (LVH), and increased plasma atrial (ANP) and brain natriuretic peptides (BNP) in essential hypertensive patients. One hundred and three patients with essential hypertension were divided into dippers (n = 57; age: 57 +/- 5 years, mean +/- SD) or age-matched nondippers (n = 46; 57 +/- 4 years), based on ambulatory BP (ABP) monitoring. Although the systolic and diastolic ABP values were similar during the day, those at night were higher in nondippers than in dippers ( p < 0.0001 for each). Echocardiographic findings revealed that the left ventricular mass index (LVMI) was higher in nondippers (p < 0.0001). Plasma ANP and BNP were also higher in nondippers (p < 0.0001 for each). Fasting plasma concentrations of glucose and insulin (p < 0.0001 for each) and the homeostasis model assessment (HOMA) index (p < 0.0001) were also higher in nondippers. Multivariate analysis revealed that systolic ABP at night was a significant factor for LVMI, ANP and BNP. In addition, the HOMA index was a significant factor for LVMI and BNP. These observations suggest that diminished nocturnal BP fall is closely related to the development of LVH with concomitant increase in BNP in essential hypertensive patients, and that insulin resistance may play a key role in these processes.

Topics: Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Case-Control Studies; Circadian Rhythm; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin Resistance; Male; Middle Aged; Natriuretic Peptide, Brain

Natriuretic peptide receptor-A (NPR-A) functional characteristics in the hypothalamus and olfactory bulb (OB) have been investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Autoradiographic studies demonstrate a decreased number of atrial natriuretic peptide (ANP) binding sites in the olfactory bulb and hypothalamus in SHR compared to WKY rats. We found that NPR-A showed a lower maximal binding capacity (B(max)) and higher affinity in SHR than in WKY rats both in the olfactory bulb and hypothalamus. However, despite the lower B(max) in SHR, both ANP(1-28) and ANP(5-25) stimulated similar or greater cGMP production than in WKY rats. These differences were found even before the development of hypertension. NPR-A in the olfactory bulb and hypothalamus from 3-week-old SHR showed a lower B(max) and K(d) and a higher cGMP production rate than in WKY rats, suggesting that these characteristics are intrinsic of NPR-A in SHR, instead of being a result of hypertension itself. The present study provides evidences for altered NPR-A receptor properties and function in the olfactory bulb and hypothalamus from SHR, which might be involved in the pathogenesis of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Autoradiography; Binding, Competitive; Cyclic GMP; Hypertension; Hypothalamus; Olfactory Bulb; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor

Moxonidine, an imidazoline receptor agonist that acts centrally to inhibit sympathetic activity, has been shown to reduce effectively blood pressure, fasting insulin levels, and free fatty acids. In this study, we investigated the long-term effects of moxonidine treatment on cardiac natriuretic peptides (ANP and BNP) in Spontaneously Hypertensive Obese Rats (SHROBs), a rat model that resembles human Syndrome X. SHROBs expressing spontaneous hypertension, insulin resistance, and genetic obesity (weight 590 +/- 20 g, at 30 weeks) received moxonidine in chow at 4 mg/kg/day for 15 days. Moxonidine significantly reduced not only systolic blood pressure (187 +/- 6 versus 156 +/- 5 mm Hg, P < 0.05) but also plasma ANP (1595 +/- 371 versus 793 +/- 131 pg/mL, P < 0.05) and BNP (22 +/- 3 versus 14 +/- 1 pg/mL, P < 0.04), without influencing cardiac content of either peptide. Semi-quantitative PCR revealed that atrial ANPmRNA/GAPDHmRNA decreased to 39% 6 10% of pair-fed controls, P < 0.03. In left ventricles, moxonidine also decreased ANP mRNA to 69% +/- 7% and BNP mRNA to 74% +/- 6% of control, P < 0.02, but right ventricular ANP and BNP mRNA were not affected. These findings indicate that chronic inhibition of sympathetic activity with moxonidine in SHROB is associated with decreased ventricular natriuretic peptide transcription, consistent with the cardioprotective effects of moxonidine given the role of ANP and BNP as markers of cadiac disease. Moxonidine also improves the metabolic profile in these rats, thus it may be considered the drug of choice in treatment of metabolic syndrome X.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Female; Heart Atria; Heart Ventricles; Humans; Hypertension; Imidazoles; Male; Natriuretic Peptide, Brain; Obesity; Rats; Rats, Inbred SHR

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Embryo, Mammalian; Female; Fibrosis; Guanylate Cyclase; Heart Ventricles; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Receptors, Atrial Natriuretic Factor; Reference Values; RNA, Messenger

The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We recently characterized the exon/intron organization of the human type A NP receptor (hNPRA) gene. The aim of this study was to isolate the genetic markers according to the organization of this gene, and to study the association between this gene and essential hypertension. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we identified a novel missense mutation, M3411, consisting of a methionine (ATG) to isoleucine (ATC) substitution at nucleotide 1023 in exon 3. Computer-aided three-dimensional structural analysis suggested that M341 exists in the loop between two alpha-helices, and that the mutation may influence receptor activities by altering the conformation of the alpha-helices. We performed an association study of the mutation in 210 essential hypertension (EH) patients and 210 normotensive controls. The overall distribution of alleles was not significantly different between the control and EH groups. However, the C/C homozygous genotype was found only in the EH group. The ratio of plasma brain natriuretic peptide (BNP)/mean blood pressure of the C/C genotype was significantly higher than that of the G/G genotype or the G/C genotype. We conclude that the significance of homozygous M3411 mutation in exon 3 is worth investigating for its possible association with EH.

Topics: Adult; Aged; Atrial Natriuretic Factor; Dimerization; Exons; Genotype; Guanylate Cyclase; Humans; Hypertension; Male; Middle Aged; Mutation, Missense; Natriuretic Peptide, Brain; Receptors, Atrial Natriuretic Factor

The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Cilazapril; Dihydropyridines; Drug Therapy, Combination; Heart Failure; Hypertension; Kidney; Natriuretic Peptide, Brain; Organ Size; Rats; Receptor, Angiotensin, Type 1; RNA, Messenger; Survival Rate; Systole; Transforming Growth Factor beta

This study examined the role of angiotensin II in the increase of blood pressure, activation of cardiac natriuretic peptide gene expression, left ventricular hypertrophy, and vascular changes in nitric oxide-deficient hypertension. N(G)-nitro->L-arginine methyl ester (>L-NAME, 20 mg/kg/d), angiotensin II type 1 receptor (AT ) antagonist losartan (20 mg/kg/d), or their combination were administered orally for 8 weeks in Wistar rats. >L-NAME elevated systolic blood pressure, which reached its maximum within 4 weeks (200 +/- 4 mm Hg). Despite hypertension, >L-NAME administration for 8 weeks did not induce left ventricular hypertrophy. Losartan treatment significantly decreased the development of hypertension induced by >L-NAME and decreased left ventricular hypertrophy in untreated rats. In contrast, losartan did not prevent the hypertrophic remodeling of the mesenteric resistance arteries induced by >L-NAME. >L-NAME treatment increased ventricular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) mRNA levels and immunoreactive BNP levels significantly. Losartan therapy decreased the >l-NAME-induced ventricular ANP gene expression by 69% (p < 0.05) and also reduced ventricular BNP mRNA levels so that it did not differ from control. Losartan treatment alone decreased ventricular immunoreactive ANP and BNP levels by 30% (p < 0.05). These results show that ventricular ANP and BNP gene expression are dissociated from the increased ventricular mass in nitric oxide deficiency-induced hypertension. Results suggest that >l-NAME-induced hypertension and the associated activation of ventricular ANP and BNP gene expression are, at least in part, mediated by angiotensin II, whereas the resistance vessel hypertrophy following nitric oxide synthase inhibition is angiotensin II independent.

Topics: Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Enzyme Inhibitors; Gene Expression Regulation; Hypertension; In Vitro Techniques; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.. We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.. These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Fibrosis; Gene Targeting; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Imidazoles; Mice; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Organ Size; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Ventricular Remodeling

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 micromol/kg over 10 minutes) reduced peak left ventricular pressure (171+/-6 versus 130+/-6 mm Hg immediately after infusion, P<0.01) through arterial vasodilation (arterial elastance, 9.8+/-0.8 to 5.8+/-1.6 mm Hg/mL, P<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1+/-6.8 to 46.0+/-6.9 mL, P<0.01). At 60 minutes, preload decreased further (40.5+/-5.9 mL, P<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2+/-9.6 versus 72.3+/-15 pg/mL, P<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.

Topics: Adrenomedullin; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Dogs; Fosinopril; Hemodynamics; Hypertension; Kinetics; Male; Neprilysin; Peptides; Protease Inhibitors; Pyridines; Thiazepines; Vasoconstrictor Agents

Salt-sensitive hypertension represents a major cause of left ventricular (LV) dysfunction. We therefore explored the potential effects of the selective endothelin-A (ETA) receptor antagonist darusentan on the development of hypertension, LV hypertrophy (LVH), and dysfunction in a genetic rat model of salt-sensitive hypertension.. Animals from the salt-sensitive Sabra rat strain (SBH/y) and the salt-resistant strain (SBN/y) were treated with either normal diet (SBH/y and SBN/y) or with deoxycorticosterone-acetate (DOCA) and salt (SBN/y-DOCA and SBH/y-DOCA). Additional groups were treated with 50 mg x kg(-1) x d(-1) of darusentan (SBH/y-DOCA-DA and SBN/y-DOCA-DA). Systolic blood pressure and LV weight increased in response to DOCA only in the SBH/y strain (+75 mm Hg and +30%; P<0.05). LV end-diastolic pressure increased and -dP/dtmax decreased in SBH/y-DOCA compared with SBH/y (P<0.05). This was paralleled by a 5-fold upregulation of LV mRNA expression of atrial natriuretic factor (ANF) and a significant reduction of sarcoplasmic reticulum (SR) Ca2+-reuptake and the SR Ca2+-ATPase to phospholamban protein ratio (-30%). Whereas treatment with darusentan in SBH/y-DOCA-DA reduced the SBP increase by 50%, LVH elevation of ANF mRNA and LV dysfunction were completely prevented (P<0.05); this was associated with a normalization of SR Ca2+-reuptake and SR Ca2+-ATPase to phospholamban ratio by darusentan (P<0.05). A moderate elevation of interstitial fibrosis in SBH/y-DOCA (P<0.05) remained unaffected by darusentan treatment.. In the Sabra model of salt-sensitive hypertension, ETA-receptor blockade demonstrated striking effects on the prevention of LVH and LV dysfunction beyond its considerable antihypertensive effect.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium-Binding Proteins; Calcium-Transporting ATPases; Desoxycorticosterone; Disease Models, Animal; Endothelin Receptor Antagonists; Fibrosis; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Male; Organ Size; Phenylpropionates; Pyrimidines; Rats; Rats, Inbred Strains; Receptor, Endothelin A; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium Chloride; Ventricular Dysfunction, Left

A positive correlation has been previously documented between B-type natriuretic peptide (BNP) levels and left ventricular mass index (LVMI) in hypertensive patients. We evaluated 8 cycling athletes, 8 healthy age-matched controls; 17 hypertensive patients and 7 age-matched controls. LVMI was significantly higher in athletes and hypertensive patients than in their controls. Plasma levels of BNP in hypertensive patients were significantly higher than in athletes and their age-matched controls. No significant difference was found between athletes and their controls. Cycling athletes had significantly larger LVMI than hypertensive patients and controls, without elevated BNP levels. These results suggest that BNP levels are elevated in patients with increased LVM due to hypertension but not in physiologically increased LVM. Whether elevated BNP levels in athletes is a sign of structural heart disease merits further investigation.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Sports; Statistics as Topic

To study the inhibitive effect of subcutaneous implantation of capsule filled with fibroblasts engineered to secrete the mutant human atrial natriuretic peptide (mhANP) on blood pressure in young spontaneously hypertensive rats (SHR) and to explore the feasibility of gene therapy for the treatment of hypertension.. A recombinant retroviral vector pLHY24 bearing mhANP cDNA was constructed. Primary fibroblasts derived from the skin of new born SHR were cultured and transfected with the vector pLHY24 to establish a genetically modified fibroblast line or transfected with the blank vector pLNCX. Then the two kinds of cell culture were put into specially made capsules with microholes. The capsules filled with the genetically modified allogenic fibroblasts and those with blank vector were implanted into the dorsal subcutaneous tissues of two groups of 10 young SHR respectively. The plasma ANP, blood pressure, urine volume, potassium and sodium concentrations in urine, and body weight were determined every week for 7 weeks.. After delivery of retroviral vector bearing mhANP gene into the packaging cell PA317 and the primary fibroblasts, immunoreactive mhANP were detected in the cell culture medium at the concentration of (5.84 +/- 0.07) and (13.37 +/- 2.36) ng.10(-6) cells.24 h(-1) respectively. One week after implantation of the genetically modified allogenic fibroblasts the plasma level of mhANP was 131 pg/ml +/- 8 pg/ml, significantly higher than that in control group (104 pg/ml +/- 7 pg/ml, t = 8.62, P < 0.001). Although the blood pressure increased along with aging after the gene transfer, an obvious delay of blood pressure increase was seen significantly lower in test group [from (129 +/- 9) to (169 +/- 9) mm Hg] than that in the control group [from (145 +/- 10) to (181 +/- 9) mm Hg, P < 0.05 or 0.01]. A maximal blood pressure reduction of 28 mm Hg in young SHR was observed 7 days after transplantation as compared with controls. In addition, there was an obvious increase in urine volume of test group 2 weeks after transplantation and the effect lasted for more than 2 weeks. However, there were no statistical differences in body weight and the concentrations of K(+) and Na(+) in urine.. Subcutaneous implantation of the encapsulated genetically modified fibroblasts engineered to secrete mutant ANP causes a lowering effect of blood pressure in young SHR.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Capsules; Fibroblasts; Gene Expression; Genetic Therapy; Humans; Hypertension; Male; Mutation; Rats; Rats, Inbred SHR; Time Factors; Transfection

We examined the effects of aging and hypertensive left ventricular hypertrophy on the plasma level of brain natriuretic peptide (BNP), and assessed BNP as a risk marker for incident hypertensive cardiovascular events. One hundred and eighty-five hypertensive patients were echocardiographically divided into a hypertensive group with normal left ventricular mass (n=96; age range, 37-86 years; left ventricular mass, 97+/-14 g/m2) and a hypertensive group with left ventricular hypertrophy (n=89; 37-90 years; 140+/-20 g/m2). Forty-four normotensive subjects served as the normotensive group (32-84 years; 91+/-15 g/m2). We examined the association of age with BNP in the three groups and also evaluated BNP as a risk marker for incident cardiovascular events by following up all patients for 40 months. All three groups demonstrated a significant positive relationship between age and BNP. The slope of the relation between age and BNP was steepest in the hypertensive group with left ventricular hypertrophy (p<0.0001 vs. the other two groups). Multiple regression analysis revealed that age, pulse pressure and left ventricular mass index were significantly associated with the increase in BNP. Multivariate Cox proportional hazards regression analysis, which was used to assess the potential association of age, pulse pressure, left ventricular mass index and BNP with the cardiovascular events during follow-up, revealed the highest correlation between BNP and incident cardiovascular events (risk ratio=1.011; p=0.0011). BNP, which is synergistically increased with aging and left ventricular hypertrophy, may be an important risk marker for hypertensive cardiovascular events.

Topics: Aged; Aging; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Catecholamines; Disease-Free Survival; Female; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Incidence; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Renin; Risk Factors

Although a variety of techniques have been devised to assess salt sensitivity, most have proven cumbersome from a methodological perspective. We therefore attempted to develop a 2-week method by which participants could be tested in an outpatient setting without requirement of a strict dietary regimen. In this method, subjects take 140 mEq of an NaCl supplement per day for 1 week and 25 mg of hydrochlorothiazide daily for another week while maintaining their customary diet. In our first trial, 8 healthy volunteers submitted to this method, as well as to a widely-used rapid volume expansion and contraction protocol. Blood pressure measurements, blood sampling and 24-h urine collection were performed before, in the middle of, and after each intervention. There was a fair correlation (r = 0.69) between the two protocols with respect to the changes in mean blood pressure (deltaMBP), a measure of salt sensitivity. In our second trial, we tested the method on 82 Japanese subjects who had never been treated with antihypertensive drugs. DeltaMBP was significantly correlated with plasma renin activity (PRA) during salt loading (r = 0.52, p < 0.0001) and with the changes in atrial natriuretic peptide (deltaANP) (r = -0.34, p = 0.0018). When total subjects were divided into two subgroups by age, a similar tendency of correlation was observed. Age, PRA during salt loading, deltaANP, and delta norepinephrine were proven to be significant predictors of salt sensitivity and accounted for 46% of the deltaMBP variances. Based on these results, the dietary method presented here seems to be applicable for a population-based survey. Our preliminary data also suggest that PRA and ANP would be of predictive value in the salt sensitivity test.

Topics: Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Diet; Feasibility Studies; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Methods; Middle Aged; Norepinephrine; Predictive Value of Tests; Renin; Sodium Chloride

A fructose-enriched diet induces an increase in blood pressure associated with metabolic alterations in rats. Our hypothesis was that an increase in protein kinase C (PKC) activation, reported in the acute period of fructose overload, and an impaired vessel's response to vasoactive substances contribute to maintain elevated blood pressure levels in the chronic period. The aims of this study were to investigate in this animal model of hypertension: (1) if the increase in PKC activation was also found in the chronic stage; (2) the involvement of nitric oxide and insulin in the vessel's response; and plasma atrial natriuretic factor and nitrites/nitrates (nitric oxide metabolites) behavior. We evaluated the effects of: PKC-stimulator 12,13-phorbol dibutyrate, phenylephrine, insulin, nitric oxide synthase-inhibitor NG-nitro-L-arginine methyl esther (L-NAME) and PKC-inhibitor Calphostin C on aortic rings responses of Sprague-Dawley rats: fructose-fed and control. The fructose-fed group showed higher contractility to 12,13-phorbol dibutyrate than the control group in aortic rings pre-incubated with insulin, and this difference disappeared with L-NAME. The response to phenylephrine in rings pre-incubated with Calphostin C was decreased in the fructose-fed group and increased with Calphostin C plus L-NAME. Fructose-fed rats showed higher levels of plasma atrial natriuretic factor and nitrites/nitrates than controls. In conclusion, chronic fructose feeding seems to develop an impaired response to insulin, dependent on nitric oxide, suggesting a PKC alteration. Vasorelaxant agents, such as atrial natriuretic factor and nitric oxide, would behave as compensatory mechanisms in response to high blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Enzyme Activators; Enzyme Inhibitors; Fructose; Hypertension; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Muscle Contraction; Muscle, Smooth, Vascular; Naphthalenes; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phorbol 12,13-Dibutyrate; Protein Kinase C; Rats; Rats, Sprague-Dawley

Increased physical activity is followed by a stimulation of the sympathetic nervous system and this effect is probably more pronounced in patients with chronic renal failure and hypertension than in healthy controls. The role of sustained exercise in hypertensive patients with chronic renal failure, with and without antihypertensive therapy, is unclear, as is hormonal regulation of the renal hemodynamics. We hypothesized that prolonged low-intensity bicycle exercise would have a greater effect in patients with chronic renal failure than in controls, and that antihypertensive treatment would ameliorate these effects.. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), mean arterial blood pressure (MAP), norepinephrine (NE) and atrial natriuretic peptide (ANP) were measured in the upright position before and during low-intensity exercise for 2 h in healthy controls (n = 8) and in hypertensive patients with moderately reduced renal function who were not taking antihypertensives (n = 7) or who were receiving treatment with captopril (n = 10), enalapril (n = 6) or verapamil (n = 9).. GFR tended to decrease and ERPF decreased significantly in healthy individuals when exercise duration was prolonged from 1 to 2 h. An earlier decline in GFR and ERPF was seen in the renal failure patients compared with the controls. Filtration fraction (FF) increased during exercise in all groups except the group taking enalapril. MAP increased in the captopril group during exercise but was unchanged in the other groups. Treatment with captopril produced a more pronounced and earlier fall in exercise-induced GFR than in untreated controls, while verapamil treatment completely blunted the decline in GFR, with a concomitant increase in plasma ANP. No significant changes were seen in plasma NE levels, but urinary NE excretion increased in controls and captopril-treated patients during exercise.. The results suggest that prolonged low-intensity exercise has a substantially greater effect on renal hemodynamics in hypertensive renal failure patients than in healthy controls, with negligible changes in plasma NE levels. Verapamil treatment seems to ameliorate the renal effects of exercise on GFR in these patients, and this may in part be mediated via a stimulatory effect on ANP.

Topics: Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Captopril; Enalapril; Exercise; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Renal Circulation; Renal Plasma Flow, Effective; Verapamil

Atrial natriuretic peptide (ANP) has negative modulatory effects on a variety of pathophysiological mechanisms; i.e., it inhibits hypoxia-induced pulmonary vasoconstriction and vascular remodeling and facilitates natriuresis and vasorelaxation in NaCl-supplemented subjects. We have previously demonstrated organ-selective potentiation of ANP in the pulmonary circulation of hypoxia-adapted animals by local downregulation of its clearance receptor (NPR-C; Li H, Oparil S, Meng QC, Elton T, and Chen Y-F. Am J Physiol Lung Cell Mol Physiol 268: L328-L335, 1995). The present study tested the hypothesis that NPR-C expression is attenuated selectively in kidneys of NaCl-supplemented subjects. Adult male wild-type (ANP+/+) and homozygous mutant (ANP-/-) mice were studied after 5 wk of normal or high-salt diets. Mean arterial pressure (MAP) and left (LV) and right ventricular (RV) mass were greater in ANP-/- mice than in ANP+/+ mice fed the normal-salt diet; salt supplementation induced increases in plasma ANP in ANP+/+ mice and in MAP and LV, RV, and renal mass in ANP-/- mice but not in ANP+/+ mice. NPR-C mRNA levels were selectively and significantly reduced (>60%) in kidney, but not in lung, brain, LV, or RV, by dietary salt supplementation in both genotypes. NPR-A mRNA levels did not differ among diet-genotype groups in any organ studied. cGMP content was significantly increased in kidney, but not in lung or brain, by dietary salt supplementation in both genotypes. These findings suggest that selective downregulation of NPR-C in the kidney in response to dietary salt supplementation may contribute to local elevation in ANP levels and may be functionally significant in attenuating the development of salt-sensitive hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Down-Regulation; Female; Gene Expression; Genotype; Guanylate Cyclase; Hypertension; Kidney; Male; Mice; Mice, Knockout; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Sodium Chloride, Dietary

We investigated the effect of long-term in vivo blockade of the ET-1 receptor subtype B (ET(B)) with A-192621, a selective ET(B) antagonist, on atrial and ventricular natriuretic peptide (NP) gene expression in deoxycorticosterone acetate (DOCA)-salt hypertension. In this model, stimulation of the cardiac natriuretic peptide (NP) and the endothelin system and suppression of the renin-angiotensin system is observed. DOCA-salt induced significant hypertension, cardiac hypertrophy and increased NP plasma and left atrial and right and left ventricular NP gene expression. ET(B) blockade per se produced hypertension and left ventricular hypertrophy but induced little change on the levels of ventricular NP and only increased left atrial natriuretic factor (ANF) mRNA levels. Combined ET(B) blockade/DOCA-salt treatment worsened hypertension, increased left ventricular hypertrophy and induced right ventricular hypertrophy. All animals so treated had increased ventricular NP gene expression. Collagen III and beta-myosin heavy chain gene expression were enhanced in both the right and the left ventricle of DOCA-salt hypertensive rats. The results of this study suggest that the ET(B) receptor does not participate directly in the modulation of atrial or ventricular NP gene expression and that this receptor mediates a protective cardiovascular function. ET(B) blockade can induce significant ventricular hypertrophy without an increase in ANF or brain NP gene expression.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Desoxycorticosterone; Endothelin Receptor Antagonists; Gene Expression Regulation; Heart Ventricles; Hypertension; Natriuretic Peptide, Brain; Organ Size; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Sodium, Dietary; Transcription, Genetic

Sexual dimorphism may occur during the development of hypertension and congestive heart failure (CHF). Male and female spontaneous hypertension heart failure (SHHF) rats with established hypertension, but before CHF (age 5-8 mo) and during cardiac decompensation leading to CHF (age 18-20 mo in male rats and 22-24 mo in female rats), were studied. At 5-8 mo, male SHHF rats showed early activation of the renin-angiotensin system (RAS), as indicated by increased plasma renin activity (PRA) and higher serum angiotensin-converting enzyme activity compared with female rats. The increase in PRA in female rats was delayed compared with males rats, but it reached comparable levels just before CHF. Urinary endothelin excretion was significantly greater in 5- to 8-mo-old female rats compared with age-matched male rats. Urinary endothelin excretion increased in both male and female rats as CHF developed. Plasma atrial natriuretic peptide (ANP) was comparable at both time points, and both genders showed similar, marked increases as CHF developed. In conclusion, male rats show early activation of the RAS, whereas female rats show early activation of the endothelin vasopressor system. During cardiac decompensation, generalized activation of the RAS, endothelin, and ANP systems occurs and is similar in male and female SHHF rats.

Topics: Aging; Animals; Animals, Newborn; Atrial Natriuretic Factor; Endothelins; Female; Heart Failure; Hypertension; Male; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Sex Characteristics

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Chlorides; Desoxycorticosterone; Diuresis; Hypertension; Injections, Intraventricular; Kidney; Male; Mineralocorticoid Receptor Antagonists; Potassium; Rats; Rats, Wistar; Receptors, Mineralocorticoid; RNA, Messenger; Sodium; Sodium Chloride, Dietary; Spironolactone; Time Factors; Transcription, Genetic

B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II-induced hypertension by injecting DNA constructs containing the BNP promoter (-2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (P<0.001) at 2 hours and peaked at 12 hours (5.2-fold, P<0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, P<0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (P<0.05) at 2 hours and remained upregulated up to 2 weeks (2.8-fold, P<0.05) during Ang II infusion, except at 12 hours. These results indicate that posttranscriptional control plays a major role in the regulation of ventricular BNP gene expression in Ang II-induced hypertension.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography; Gene Expression Regulation; Heart Rate; Heart Ventricles; Hypertension; Male; Natriuretic Peptide, Brain; Organ Size; Promoter Regions, Genetic; Protein Binding; Rats; Rats, Sprague-Dawley; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcription Factor AP-1

Midwall fractional shortening (MFS) is a useful index to evaluate left ventricular myocardial function in patients with essential hypertension. The study investigated the prevalence and characterization of low MFS in hemodialysis patients.. MFS was calculated from M-mode echocardiograms in 67 patients (34 males, 33 females) receiving maintenance hemodialysis in whom fractional shortening was normal. Plasma levels of atrial and brain natriuretic peptides were also measured in these patients before and after hemodialysis. MFS was evaluated by stress-corrected MFS (ratio of observed to predicted MFS). The relationship of MFS to circumferential end-systolic stress in 122 healthy subjects was used to calculate the predicted MFS.. Stress-corrected MFS was depressed in 18 of the 67 patients (26.9%). In the low MFS group, duration of hypertension was significantly longer (p < 0.05), wall thickness was significantly greater (p < 0.001), left ventricular dimension was significantly smaller (p < 0.0001), and relative wall thickness was significantly greater (p < 0.0001) than in the normal MFS group. Reduction of brain natriuretic peptide level by hemodialysis in the low MFS group was significantly higher (p < 0.05) than in the normal MFS group.. Depression of stress-corrected MFS may be common in hemodialysis patients. Long duration of hypertension and concentric geometry of the left ventricle occur in patients with low MFS.

Topics: Aged; Atrial Natriuretic Factor; Female; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Renal Dialysis; Renal Insufficiency; Ventricular Function, Left

We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg/kg/day) from 12 to 24 weeks of age. Systolic blood pressure (BP) and heart rate were measured every week after the treatment using the tail-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BP, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcineurin Inhibitors; Calcium Channel Blockers; Calcium Channels, L-Type; Cardiomegaly; Fibrosis; Gene Expression; Heart Rate; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Nifedipine; Rats; Rats, Inbred SHR

The alpha1-adrenergic receptors (alpha1-ARs) play a key role in cardiovascular homeostasis. However, the functional role of alpha1-AR subtypes in vivo is still unclear. The aim of this study was to evaluate the cardiovascular influences of alpha1b-AR.. In transgenic mice lacking alpha1-AR (KO) and their wild-type controls (WT), we evaluated blood pressure profile and cardiovascular remodeling induced by the chronic administration (18 days via osmotic pumps) of norepinephrine, angiotensin II, and subpressor doses of phenylephrine. Our results indicate that norepinephrine induced an increase in blood pressure levels only in WT mice. In contrast, the hypertensive state induced by angiotensin II was comparable between WT and KO mice. Phenylephrine did not modify blood pressure levels in either WT or KO mice. The cardiac hypertrophy and eutrophic vascular remodeling evoked by norepinephrine was observed only in WT mice, and this effect was independent of the hypertensive state because it was similar to that observed during subpressor phenylephrine infusion. Finally, the cardiac hypertrophy induced by thoracic aortic constriction was comparable between WT and KO mice.. Our data demonstrate that the lack of alpha1b-AR protects from the chronic increase of arterial blood pressure induced by norepinephrine and concomitantly prevents cardiovascular remodeling evoked by adrenergic activation independently of blood pressure levels.

Topics: Angiotensin II; Animals; Aorta; Arterioles; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiovascular System; Echocardiography; Heart Rate; Heart Ventricles; Hypertension; Male; Mesentery; Mice; Mice, Transgenic; Norepinephrine; Organ Size; Phenylephrine; Receptors, Adrenergic, alpha-1; RNA, Messenger; Vasoconstrictor Agents; Ventricular Remodeling

This study was designed to examine whether aldosterone is produced from the hearts of patients with essential hypertension without left ventricular systolic dysfunction (LVSD). The study population consisted of 20 patients with essential hypertension without LVSD and 22 control subjects. Plasma levels of aldosterone, serum ACE activity, and B-type natriuretic peptide levels were measured in the anterior interventricular vein (AIV), coronary sinus, and aortic root during cardiac catheterization. The plasma aldosterone levels were significantly higher in AIV and coronary sinus than in aortic root (99+/-11 versus 88+/-10 pg/mL, P<0.01, and 100+/-12 versus 88+/-10 pg/mL, P<0.01, respectively) in the hypertension group. On the other hand, there were no significant differences in aldosterone levels for these sites in the control group. There were no significant differences in ACE activity levels between aortic root, AIV, and coronary sinus in either the hypertension or control group. The levels of B-type natriuretic peptide were significantly higher in AIV than in aortic root in both groups. The difference in aldosterone levels between AIV and aortic root (Delta Aldo[AIV-Ao]) had a significant positive correlation with the difference in ACE activity between AIV and aortic root (DeltaACE[AIV-Ao]) (r=0.501, P<0.05) in the hypertension group. Both Delta Aldo[AIV-Ao] and DeltaACE[AIV-Ao] had a significant positive correlation with diastolic blood pressure (r=0.498, P<0.05; r=0.577, P<0.01, respectively) in the hypertension group. We conclude that production of aldosterone is activated in the left ventricles in patients with essential hypertension without LVSD in proportion to the severity of hypertension.

Topics: Aldosterone; Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Female; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptidyl-Dipeptidase A

Epidemiological studies have produced evidence that unfavorable intrauterine environments during fetal life may lead to adverse outcomes in adulthood. We have previously shown that a low-sodium diet, given to pregnant rats over the last week of gestation, results in intrauterine growth restriction (IUGR). We hypothesize that pups born with IUGR are more susceptible to the development of hypertension in adulthood. IUGR fetuses and rats aged 1 wk were characterized for organ growth and renal morphogenesis. The adults (12 wk) were evaluated for weight, systolic blood pressure, activity of the renin-angiotensin-aldosterone system (RAAS), and renal function; hearts and kidneys underwent a histological examination. Brain and cardiac ventricle-to-body ratios were increased in IUGR fetuses compared with age-matched controls, whereas the kidney-to-body ratio was unchanged. Systolic blood pressure was elevated in both IUGR male and female adults. Plasma aldosterone levels were not correlated with increased plasma renin activity. Moreover, urinary sodium was decreased, whereas plasma urea was elevated in both males and females, and creatinine levels were augmented only in females, suggesting a glomerular filtration impairment in IUGR. In our model of IUGR induced by a low-sodium diet given to pregnant rats, high blood pressure, alteration of the RAAS, and renal dysfunction are observed in adult life. Differences observed between male and female adults suggest the importance of gender in outcomes in adulthood after IUGR.

Topics: Aging; Angiotensins; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Corticosterone; Female; Fetal Growth Retardation; Heart Ventricles; Hypertension; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Male; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger

Topics: Animals; Atrial Natriuretic Factor; Hypertension; Kidney; Male; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To explore the mechanism of conducting physical exercise to lower blood pressure of hypertensive patients, relieve their symptoms and influence the cardiovascular endocrine hormone.. One hundred and twenty-five patients with II or III stage hypertension were divided into the experimental group and the control group and observed. The comparison of conditions before and after treatment, and between experimental and control groups was carried out.. The effect in lowering blood pressure and relieving symptoms in the experimental group were obviously better than those in the control group, P < 0.05. Angiotensin-II (AT-II) level much reduced after the exercise experiment, P < 0.05. Peripheral renin activity (PRA) level had a tendency of reduction, but atrial natriuetic factor (ANF) and 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) showed a tendency of increasing.. Physical exercise combined with medical treatment could control the symptoms of hypertensive patients, in some of them could gradually using the way of doing physical exercise to replace the hypotensive medicament, the effect of the combined treatment can be obtained within a month. The change of cardiovascular endocrine hormone indicated that the physical exercise can be helpful in lowering blood pressure and improving blood circulation in hypertensive patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Captopril; Exercise; Female; Humans; Hypertension; Male; Middle Aged

To assess the activity of the human fetal atrial natriuretic peptide system in hypertensive pregnancies with and without signs of increased fetal systemic venous pressure and in pregnancies complicated by fetal acidemia during labor.. Umbilical artery plasma N-terminal peptide of proatrial natriuretic peptide concentrations were measured in neonates by radioimmunoassay. The control group consisted of 50 neonates with uncomplicated gestation and labor. In group 1, there were 22 newborns of hypertensive pregnancies. Doppler ultrasonography showed abnormal umbilical artery blood velocity waveform in five cases and normal nonpulsatile umbilical vein blood velocity profile in every case. Group 2 consisted of five newborns of pregnancies complicated by maternal hypertensive disorder. Atrial pulsations in the umbilical vein and retrograde diastolic blood velocity pattern in the umbilical artery were detected in every case. Group 3 was composed of 27 newborns of uncomplicated pregnancies with fetal acidemia (pH 7.10 or less) during labor.. In groups 1-3, N-terminal peptide of proatrial natriuretic peptide concentrations were higher (P <.001) than in the control group. In group 1, neonates with abnormal umbilical artery blood velocity pattern had higher N-terminal peptide of proatrial natriuretic peptide concentrations than neonates with normal umbilical artery Doppler findings (P <.006). N-terminal peptide of proatrial natriuretic peptide concentrations were higher in group 2 (P <.002) than in groups 1 and 3. CONCLUSIONS Maternal hypertensive disorder and fetal acidemia during labor stimulate fetal atrial natriuretic peptide production, which was greatest in fetuses with severe placental insufficiency and signs of congestive heart failure.

Topics: Adult; Atrial Natriuretic Factor; Blood Flow Velocity; Female; Fetal Diseases; Humans; Hypertension; Infant, Newborn; Placental Insufficiency; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Precursors; Umbilical Arteries

The present study determined cardiac chamber-specific alterations of the expression of the atrial and brain natriuretic peptide (ANP and BNP) genes with a small increase in age beyond adulthood and with systemic hypertension of intermediate duration. The expression distributions of these genes was determined using in situ hybridization in the right and left atria (RA and LA), and the right and left ventricles (RV and LV) in Wistar Kyoto rats (WKY) and age-matched Spontaneously Hypertensive rats (SHR) at ages 6 months (adult) and 8 months (advanced-age beyond adulthood). In all rat groups, both genes were expressed (ANP > BNP) in the LA and LV, and were not expressed in the RA and RV. The genes were expressed in the LA in all rat groups; the ANP, but not the BNP, expression increased with advancing age and with superimposed hypertension. They were expressed in the LV of the advanced-age WKY, adult and advanced-age SHR, but not in the adult WKY. The ANP mRNA labeling in the LA was diffuse and interspersed with dense accumulations, whereas BNP labeling was diffuse. The labeling of both genes in the form of sparse clusters was seen in the LV of the advanced-age SHR. Our study showed that ANP and BNP expression in left heart chambers increased with a small increase in age, with hypertension of intermediate duration, and with modest left ventricular hypertrophy. The chamber-specific expression distribution could be due to special groups of cardiac cells, or to local chamber-specific factors.

Topics: Age Factors; Aging; Animals; Atrial Natriuretic Factor; Heart Atria; Heart Ventricles; Hypertension; In Situ Hybridization; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

In the ventricles of adult mammalian hearts, production of atrial natriuretic peptide (ANP) is negligible, restricted to the impulse-conducting cells, the papillary muscles, and a minority of subendocardial myocytes. ANP expression is reinduced in the ventricles of pressure-overloaded and failing hearts and is frequently used as a marker for myocyte hypertrophy. Using an immunohistochemical approach, we have characterized the size distribution of ANP-containing myocytes in the left ventricle of the spontaneously hypertensive rat (SHR) before and after chronic antihypertensive therapy and compared the results to age-matched normotensive Wistar rats (WR). Our findings show that in SHR the frequency of cells presenting ANP granularity is positively correlated with myocyte size (r=0.746, P<0.02). The highest proportion of ANP-positive myocytes (55-57%) was measured among cells of diameters 30-34 microm. In any corresponding cell size, the proportion of ANP-presenting myocytes was five- to tenfold higher in SHR than in the normotensive WR. We studied the effects of the antihypertensive drugs captopril, hydralazine, and nifedipine and found that, regardless of their effect on blood pressure or hypertrophy, all three eliminated ANP immunoproducts from the majority of the left ventricular myocytes and reduced the level of ANP mRNA, captopril being the most effective. The positive correlation between myocyte size and ANP expression was not maintained in the hearts of drug-treated SHR. Myocytes on the border of fibrotic areas or in regions of ANP presentation within the normal heart resisted the suppressive effect of the antihypertensive therapy, indicating that blood pressure or hypertrophy are not the sole correlates for ANP expression.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Captopril; Cell Size; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Immunohistochemistry; Male; Muscle Fibers, Skeletal; Myocardium; Nifedipine; Organ Size; Rats; Rats, Inbred SHR; Rats, Wistar; RNA, Messenger; Vasodilator Agents; Ventricular Function

The cardiac state and the prevalence of high blood pressure (BP) were analyzed in 21 pediatric patients (mean age 5.3 +/- 5.3 years) on chronic peritoneal dialysis (CPD), the aim being to specify the impact of hypervolemia in the etiology of hypertension. C- and N-terminal atrial natriuretic peptide (ANP-C, ANP-N) were measured as possible additional markers of hypervolemia. Baseline investigations were carried out 0.2 years after initiation of PD, and repeated after 0.9 +/- 0.2 years. Fifty-two percent of the patients had high BP, and in 40% the nocturnal BP decline was decreased. Left ventricular hypertrophy was present in 45%, but the systolic and diastolic functions of the heart were not impaired. Left ventricular mass correlated significantly with the severity of hypertension and with ANP-N (r = 0.79, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). Significant correlations were also found between the severity of hypertension and ANP-N and ANP-C (r = 0.82, P < 0.01 and r = 0.66, P < 0.01, Spearman rank correlation). High BP and cardiac impairment were more frequent in the younger and nephrectomized patients in whom volume overload seemed to be the most-important etiological factor. Our results suggest further that an ANP-N over 3.0 nmol/l combined with hypertension is strongly indicative of volume overload in patients on PD.

Topics: Atrial Natriuretic Factor; Biomarkers; Child; Child, Preschool; Echocardiography; Heart; Humans; Hyperemia; Hypertension; Nephrectomy; Peritoneal Dialysis; Prevalence

Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).. SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups.. Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05).. These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Topics: Acrylates; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Heart Rate; Hypertension; Imidazoles; Kidney; Magnetic Resonance Imaging; Male; Myocardium; Natriuresis; Organ Size; Peptide Fragments; Protein Precursors; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Survival Rate; Thiophenes; Ventricular Remodeling

Topics: Acid-Base Imbalance; Atrial Natriuretic Factor; Blood Flow Velocity; Constriction; Female; Fetal Blood; Fetal Distress; Humans; Hypertension; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular; Prognosis; Respiratory Distress Syndrome, Newborn; Umbilical Arteries; Umbilical Cord

Variants of atrial natriuretic peptide (ANP) are reported to be more common in blacks with hypertension than in normotensive controls and constitute an independent risk factor for cerebral infarction. The purpose of the present study was to investigate the role of ANP in the pathogenesis of essential hypertension (EH) in the Japanese. We investigated 2 previously reported ANP gene markers, G1837A and T2238C, for their possible associations with EH. A total of 233 individuals with EH and 213 age-matched normotensive (NT) control subjects were studied. The frequencies of the G and A alleles were 0.09 (42/466) and 0.91 (424/466), respectively, for the NT group and 0.11 (47/426) and 0.89 (379/426), respectively, for the EH group. These frequencies did not differ significantly between the two groups. The frequencies of the T and C alleles were 0.024 (11/466) and 0.97 (455/466), respectively, for the NT group and 0.03 (13/426) and 0.97 (413/426), respectively, for the EH group. These frequencies also did not differ significantly between the two groups. Neither G1837A nor the T2238C polymorphism of the ANP gene was associated with EH. Our findings do not support the hypothesis that the G1837A and T2238C polymorphisms of the ANP gene are markers for EH in the Japanese.

Topics: Adult; Atrial Natriuretic Factor; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

Pioneer studies have proposed that multiple metabolic abnormalities, such as insulin resistance, increased Na(+)-H(+) exchanger activity and abnormal intracellular calcium homeostasis, are frequently associated with a subset of essential hypertensive patients with low plasma renin activity (PRA). However, it is unclear whether insulin resistance is related to the low renin status in the very early phase of genetical hypertension. Besides, there is controversy on the subject of the in vivo effect of acute hyperinsulinaemia on sodium-related factors. We investigated the relationship between sodium-related parameters and insulin sensitivity, and the effects of euglycaemic hyperinsulinaemia on cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) levels in 17 young, lean, normotensive male subjects, who displayed extreme predispositions for the development of hypertension. PRA was significantly lower in the positive than in the negative family history group (P < 0.05). Insulin sensitivity (M-value) was correlated with PRA before euglycaemic hyperinsulinaemic clamping (r = 0.577, P < 0.05), and was also inversely correlated with fractional excretion of sodium (FE(Na)) before clamping (r = -0.51, P < 0.05). Euglycaemic hyperinsulinaemia significantly decreased PRA (P < 0.0001) and increased cGMP (P < 0.05) and ANP levels (P < 0.01). In conclusion, insulin sensitivity may be partially determined by PRA levels and FE(Na) before clamping in young, lean, normotensive male subjects. Acute euglycaemic hyperinsulinaemia decreases PRA, and increases cGMP and ANP levels from the fasting condition.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Glucose Clamp Technique; Homeostasis; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Male; Predictive Value of Tests; Renin; Sensitivity and Specificity; Sodium; Thinness

We examined whether measurement of the plasma BNP concentrations might be useful for the early diagnosis of the existence and severity of disease in patients with heart disease in daily clinical practice.. The plasma BNP and ANP concentrations in 415 patients with heart disease and hypertension and 65 control subjects were measured. Patients with heart disease had higher plasma BNP and ANP concentrations than did those with hypertension or control subjects. Among the etiology of cardiac diseases, specifically dilated cardiomyopathy and hypertrophic cardiomyopathy, was associated with the highest plasma BNP concentrations, whereas dilated cardiomyopathy was associated with the highest plasma ANP concentrations. Plasma BNP concentrations showed an increase as the severity of the heart disease, as graded according to the NYHA classification of cardiac function, increased. In both patients with heart disease and hypertension, the plasma BNP values were higher in those who had abnormalities in their echocardiogram and electrocardiogram as compared to those without any abnormalities. The plasma BNP levels also showed a significant correlation with left ventricular wall thickness and left ventricular mass. On the other hand, the plasma ANP levels showed significant correlations with left ventricular dimension. Receiver operative characteristic analysis revealed that plasma BNP levels showed substantially high sensitivity and specificity to detect the existence of heart diseases.. Measurements of the plasma BNP concentrations is useful to detect the existence of the diseases, and abnormalities of left ventricular function and hypertrophy in patients with heart disease in daily clinical practice.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Heart Diseases; Humans; Hypertension; Natriuretic Peptide, Brain; ROC Curve; Sensitivity and Specificity

We evaluated the effects of angiotensin II subtype 1 (AT1) receptor antagonism on cardiac fibrosis and sarcoplasmic (SR) Ca2+ handling in a transgenic rat model of renin-dependent left ventricular (LV) hypertrophy (LVH).. Hypertensive transgenic rats overexpressing the Ren2 gene (TGR(mRen2)27) were treated between 10 and 30 weeks of age with the angiotensin II subtype 1 (AT1) receptor antagonist, eprosartan, in an antihypertensive (Ren2-E60, 60 mg/kg per day) and a non-antihypertensive (Ren2-E6, 6 mg/kg per day) dose applied intraperitoneally via osmotic-mini-pumps. They were compared to age-matched Ren2 and Sprague-Dawley (SD) control rats receiving 0.9% NaCl as vehicle via osmotic mini-pumps (Ren2-Vehicle, SD-Vehicle, respectively).. Systolic blood pressure (SBP), LV weight, LV end-diastolic pressure (LVEDP), and cardiac fibrosis were elevated in Ren2-Vehicle, while diastolic function (-dP/dt(max)) and sarcoplasmic reticulum (SR) Ca2+ uptake were decreased in Ren2-Vehicle compared to SD-Vehicle (P < 0.05, respectively). SBP was not altered in Ren2-E6, but reduced to normotensive levels in Ren2-E60 compared to Ren2-Vehicle and SD-Vehicle (P < 0.0001). In both Ren2-E6 and Ren2-E60, LV weights were reduced and LVEDP and -dP/dt(max)normalized compared to Ren2-Vehicle (P < 0.05). SR Ca2+ uptake was normalized in both Ren2-E6 and Ren2-E60. Cardiac fibrosis did not change in Ren2-E6, but perivascular LV fibrosis and hydroxyprolin content were reduced in Ren2-E60 compared to Ren2-Vehicle (P < 0.05, respectively).. Normalization of LV SR Ca2+ uptake is an important mechanism by which AT1 receptor antagonism improves LV diastolic dysfunction independent from a reduction of SBP and cardiac fibrosis in the TGR (mRen2)27 model.

Topics: Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Calcium; Fibrosis; Heart Ventricles; Hypertension; Mice; Myocardium; Organ Size; Protein Isoforms; Rats; Receptor, Angiotensin, Type 2; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Ventricular Function, Left

Polyamines (putrescine, spermidine and spermine) play an important role in the development of hypertension and in the expression of atrial natriuretic peptide (ANP), a cardiac hormone involved in the regulation of blood pressure. Wistar Kyoto normotensive (WKY) and spontaneously hypertensive rats (SHR) were given spermine in drinking water (0.5%) for 15 days. The spermine intake elevated the blood pressures of both SHR and WKY rats and reduced the expression of ANP (Northern blotting) in the ventricles. ANP levels in the plasma determined by enzyme immunoassay (EIA) showed no changes in the levels of plasma ANP after spermine intake. An analysis of polyamines by high-pressure liquid chromatography showed that the levels of spermine and spermidine were elevated in SHR hearts. It was in SHR hearts alone that spermine intake was associated with increases in the levels of putrescine. The results suggest that spermine-induced increases in blood pressure may involve mechanisms other than ANP.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Heart Ventricles; Hypertension; Myocardium; Polyamines; Putrescine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spermidine; Spermine

The majority of women with a history of preeclampsia have either an underlying thrombophilic disorder or a vascular disorder. In this study, we tested the hypothesis that only the latter condition predisposes for abnormal hemodynamic adaptation to pregnancy.. Thirty-seven formerly preeclamptic subjects were subdivided into a hypertensive (HYPERT, N = 10), a normotensive thrombophilic (THROMB, N = 13) and a normotensive nonthrombophilic subgroup (NONTHROMB, N = 14). In these women and in 10 normal parous controls, the following variables were measured at least five-months postpartum at day 5 (+/-2) of the menstrual cycle and again at five- and seven-weeks amenorrhea in the next pregnancy: mean arterial pressure, heart rate, cardiac output, central cardiovascular dimensions, plasma volume, glomerular filtration rate, effective renal plasma flow, 17-beta estradiol, progesterone, the hormones of the renin-angiotensin-aldosterone (RAAS) axis, catecholamines and alpha-atrial natriuretic peptide.. The early pregnancy rise in cardiac output, renal variables, RAAS activity, and plasma volume was comparable in all groups. However, the HYPERT and NONTHROMB subgroups differed from controls by a lower plasma volume in the prepregnant state. In addition, only the women in these two subgroups responded to pregnancy by a rise in circulating alpha-atrial natriuretic peptide. In addition, at seven weeks, in the subjects belonging to the HYPERT and NONTHROMB subgroups, plasma volume was the lowest and correlated inversely with the concomitant circulating level of alpha-atrial natriuretic peptide.. The hemodynamic adaptation to pregnancy in the HYPERT and NONTHROMB subgroups differs from that in THROMB and controls by an early pregnancy rise in alpha-atrial natriuretic peptide. As a consequence, the early pregnancy plasma volume expansion in the NONTHROMB and HYPERT subgroups is less than in normal parous controls.

Topics: Adaptation, Physiological; Adult; Atrial Natriuretic Factor; Blood Volume; Female; Hemodynamics; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thrombophilia

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Carboxylic Acids; Endothelin Receptor Antagonists; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Indans; Male; Myocardium; Protein Precursors; Rats; Rats, Inbred SHR; Survival Rate; Ventricular Remodeling

Brain natriuretic peptide (BNP) is a strong predictor of left ventricular (LV) hypertrophy (LVH) and dysfunction. However, our recent studies suggested that LVH is not necessarily associated with enhanced production of BNP in hypertension. This study aimed to clarify the relation of the characteristics of hypertrophy with the degree of gene expression of BNP in the developmental process of hypertensive heart failure.. Serial changes in LV geometry, histology and atrial natriuretic peptide (ANP) and BNP mRNA levels, were assessed in a hypertensive heart failure model using Dahl salt-sensitive rats (n = 24). We further studied effects of alpha1-receptor antagonist (doxazosin: 1 mg/kg per day, n = 5) and angiotensin II type 1 receptor (AT1R) antagonist (candesartan cilexetil: 1 mg/kg per day, n = 5).. The BNP mRNA level was not elevated at the compensatory hypertrophic stage when ANP mRNA level was elevated. BNP mRNA level was increased with further progression of hypertrophy and development of fibrosis. AT1R blockade prevented such fibrosis and further progression of hypertrophy with normalization of BNP mRNA levels. Compensatory hypertrophy was not suppressed; therefore, ANP mRNA level, although decreased, was still beyond the normal level. The alpha1-receptor blockade slightly attenuated LV hypertrophy with a slight decrease in ANP mRNA levels. LV fibrosis was not prevented, and the BNP mRNA level was not decreased.. BNP gene expression is not enhanced by initial compensatory hypertrophy, but is enhanced by LV fibrosis and late stage progression of hypertrophy dependent on AT1R-mediated signaling pathway.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Echocardiography; Fibrosis; Heart Ventricles; Hemodynamics; Hypertension; Male; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Rats; Rats, Inbred Dahl; RNA, Messenger; Ventricular Remodeling

To identify the mechanisms that couple hemodynamic stress to alterations in cardiac gene expression, DNA constructs containing the rat B-type natriuretic peptide (BNP) promoter were injected into the myocardium of rats, which underwent bilateral nephrectomy or were sham-operated. Ventricular BNP mRNA levels were induced about 4-fold; and the BNP reporter construct containing the proximal 2200 bp, 5-fold, in response to 1-d nephrectomy. Deletion of sequences between bp -2200 and -114 did not affect basal or inducible activity of the BNP promoter. An activator protein-1-like site and two tandem GATA elements are located within this 114-bp sequence. Both deletion and mutation of the AP-1-like motif decreased basal activity but did not abolish the response to nephrectomy. In contrast, mutation or deletion of -90 bp GATA-sites abrogated the response to hemodynamic stress. The importance of these GATA elements to BNP promoter activation was further confirmed by the corresponding 38-bp oligonucleotide conferring hemodynamic stress responsiveness to a minimal BNP promoter. In gel mobility shift assays, nephrectomy increased left ventricular BNP GATA4 binding activity significantly. In conclusion, GATA elements are necessary and sufficient to confer transcriptional activation of BNP gene in response to hemodynamic stress.

Topics: Amino Acid Motifs; Animals; Atrial Natriuretic Factor; DNA-Binding Proteins; GATA4 Transcription Factor; GATA6 Transcription Factor; Gene Expression Regulation; Heart; Heart Ventricles; Hemodynamics; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological; Transcription Factors; Transcriptional Activation; Up-Regulation

Topics: Amlodipine; Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Bendroflumethiazide; Cardiomegaly; Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Perindopril; Procollagen; Randomized Controlled Trials as Topic

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure. 3. The lowest dosages of both drugs had non-significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt-loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor-beta1. 4. The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine. 5. Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. 6. We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

Topics: Actins; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Collagen Type I; Dihydropyridines; Dose-Response Relationship, Drug; Fibrosis; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypertrophy; Kidney; Male; Muscle, Skeletal; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Atrial Natriuretic Factor; Gene Transfer Techniques; Humans; Hypertension; Rats; Research Design

The renal functional consequences of an activated sympathetic nervous system and plasma atrial natriuretic hormone (ANP) in various renal diseases are not well described. We hypothesize that norepinephrine (NE) and ANP have antagonizing effects on renal hemodynamics in diseased kidneys.. Plasma NE, ANP. glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and mean arterial pressure (MAP) were measured in the upright position in healthy controls (n = 9) and hypertensive patients with reduced GFR (n =11). The same parameters were compared between healthy controls (n = 6) and hypertensive patients with reduced GFR (n = 6) in upright and supine positions.. Upright plasma NE and ANP were significantly elevated in the patients compared with the controls (4.4 +/- 0.4 vs 2.1 +/- 0.2 nmol/l (p < 0.001) and 1.3.5 +/- 2.1 vs 6.9 +/- 1.0 nmol/l (p < 0.01) respectively). With change from upright to supine position plasma NE decreased in the controls (2.2 +/- 0.3 vs 1.7 +/- 0.3 nmol/l) (p < 0.01) and patients (3.8 +/- 0.4 vs 2.6 +/- 0.4) (p < 0.01). Supine ANP increased in controls (5.5 +/- 1.0 vs 8.3 +/- 1.1) (p < 0.01) but not in patients (14.3 +/- 3.8 vs 16.1 +/- 3.8 nmol/l) (p > 0.10). Plasma NE correlated positively with MAP (p < 0.001) and negatively with GFR (p < 0.01) in the upright but not supine position. A positive correlation between NE and ANP was observed in upright (p < 0.001) but not in supine position. ANP correlated negatively with GFR in the upright (p < 0.01) but not supine position. No position dependent changes were seen in GFR and ERPF, but supine filtration fraction (FF) increased insignificantly in the patient group (0.23 +/- 0.02 vs 0.24 +/- 0.02) (p < 0.05).. Hypertensive patients with reduced GFR have elevated levels of plasma NE and ANP in the upright body position. When the upright and supine positions are compared, plasma NE declines in the supine position in controls and hypertensive renal failure patients. and plasma ANP levels are elevated only in the upright position in hypertensive renal failure patients where the sympathetic nervous system is activated. A significant positive relationship between plasma NE and ANP was observed only in the upright position. The upright body position seems superior to recumbency in the characterization of these hormonal changes in hypertensive chronic renal failure patients.

Topics: Atrial Natriuretic Factor; Blood Pressure; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Posture; Renal Plasma Flow, Effective; Sympathetic Nervous System; Sympathomimetics

The objective of this study was to determine the primary event that occurs in Ca2+-regulatory sarcoplasmic-reticular (SR) proteins during subacute transition from concentric/mechanically-compensated left ventricular (LV) hypertrophy to eccentric/decompensated hypertrophy. Using Dahl salt-sensitive rats with hypertension, changes of myocardial contraction, intracellular Ca2+ transients, SR Ca2+ uptake, protein levels of SR Ca2+ ATPase (SERCA2), phospholamban, and calsequestrin (CSQ), and mRNA levels of SERCA2 and CSQ were serially determined and compared between the established stage of LV hypertrophy (LVH) and the subsequent stage of overt LV dysfunction (CHF). In LVH, isolated LV papillary muscle preparations showed an equal peak-tension level and a mild prolongation of the isometric tension decay compared to those of age-matched controls. The Ca2+ transients as measured by aequorin were unchanged. The Ca2+ uptake of isolated SR vesicles and the protein/mRNA levels of SR proteins were also equivalent to those of the controls. In contrast, in CHF, the failing myocardium showed a further prolongation of the contraction time course and a 39% reduction of the peak-tension development. The Ca2+ transients showed changes consisting of a decrease in the peak level and a prolongation of the time course. In addition, the SR Ca2+ uptake was decreased by 41%. Despite these functional changes, the protein and mRNA levels of the SR components remained equivalent to those of the age-matched controls. Thus, in this hypertensive animal, 1) at the LVH stage, myocardial contractility and intracellular capability to regulate Ca2+ remained normal; 2) at the CHF stage, impaired SR Ca2+ handling and the subsequent reduction of myocardial contraction were in progress; and 3) impairments of SR function occurred at the post-translational protein level rather than at the transcriptional/translational levels. Our findings support the role of SR proteins as the primary determinant of the contractile dysfunction that occurs during the heart-failure transition; however, post-translational modulators of these SR elements may also be critical.

Topics: Aequorin; Animals; Atrial Natriuretic Factor; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Calsequestrin; Heart Failure; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Rats; Rats, Inbred Dahl; RNA, Messenger; Ryanodine; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Dysfunction, Left

Our previous study demonstrated that human adrenal medulla is a site of atrial natriuretic peptide (ANP) synthesis. To further evaluate the role of adrenal ANP in body fluid homeostasis, we investigated the changes in adrenal ANP in rats receiving deoxycorticosterone acetate (DOCA)-salt treatment. In situ hybridization and immunohistochemical study showed that adrenal ANP messenger RNA (mRNA) and ANP-like immunoreactivities (ANP-LI) were mainly localized in the zona glomerulosa and medulla of vehicle-treated rats. DOCA-salt treatment activated ANP mRNA and peptide expression in all adrenal zones, especially in the zona fasciculata/reticularis from 12 h to the entire 8-day study period. Using a semiquantitative RT-PCR technique, the relative quantities of ANP mRNA in the adrenals of the DOCA-salt-treated group were significantly increased from 1 to 8 days, whereas the adrenal weights of DOCA-salt-treated rats were significantly decreased from day 2 to day 8. Our results are the first to indicate that ANP is synthesized not only in the adrenal medulla but also in the adrenal cortex and their syntheses are markedly increased in DOCA-salt-treated rats. These results imply that adrenal ANP may participate in the intraadrenal regulation of adrenal function on water-electrolyte homeostasis in an autocrine or paracrine manner.

Topics: Adrenal Cortex; Adrenal Medulla; Animals; Atrial Natriuretic Factor; Blotting, Southern; Desoxycorticosterone; Hypertension; Immunohistochemistry; In Situ Hybridization; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA Probes; RNA, Messenger; Sodium Chloride; Up-Regulation

Atrial natriuretic peptide (ANP) plays an important role in the regulation of blood pressure through sodium-water homoeostasis. Accordingly, several investigators have raised the question of whether the gene encoding ANP is involved in the aetiology of essential hypertension or related phenotypes such as salt sensitivity. Most of the studies have used anonymous polymorphic markers of the gene, and made inconclusive claims about the disease relevance of ANP. Therefore, in order to find sequence variations with potential functional significance and to characterize the pattern of linkage disequilibrium between polymorphisms, we screened a 3368-bp genomic fragment of ANP. Subsequently we tested the association of detected polymorphisms with plasma ANP levels and with hypertension status. Two new polymorphisms were identified, in the 5'-untranslated region and exon 1 respectively, as well as three previously reported polymorphisms in intron 2 and exon 3. When analysed in 102 healthy normotensive subjects, none of the polymorphisms appeared to significantly affect plasma ANP levels. A case-control study in a Japanese population (255 hypertensive and 225 normotensive individuals) revealed a marginally significant association (P=0.026) between an ANP polymorphism located in the 5'-untranslated region (C-664G) and hypertension, but no association for the other polymorphisms. Each of the uncommon variants has an allele frequency of less than 10% in Japanese people, which may have hampered our detection of a significant association between ANP variants and hypertension status (and plasma ANP levels). The pathophysiological relevance of ANP, however, needs to be further defined in relation to hypertension-associated phenotypes, and also should be examined in different ethnic groups.

Topics: Aged; Alleles; Analysis of Variance; Atrial Natriuretic Factor; Case-Control Studies; Chi-Square Distribution; Female; Humans; Hypertension; Japan; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Genetic

Thiorphan, a neutral endoprotease (NEP) enzyme inhibitor, has been shown to enhance the effects of atrial natriuretic peptide (ANP) in vivo. In this study, we examined the effects of an intravenous (iv) infusion of thiorphan on cardiovascular hemodynamics and excretion of urine volume (UV), sodium (U(Na)V) and potassium (UKV) in four different models of experimental hypertension, namely: 1) SHR, 2) two-kidney, one clip (2K1C),3) one-kidney, 1 clip (1K1C) and. 4) 70% reduced renal mass-salt (RRM-S) hypertensive rats. SHR has normal plasma renin activity, 2K1C is renin dependent, and 1K1C and RRM-S are low renin volume dependent models of hypertension. Rats were divided into experimental and control groups. Under inactin (120 mg/kg, body weight) anesthesia, rats were instrumented to record blood pressure and dP/dt (Millar catheter) and urine was collected through a suprapubic urinary bladder catheter. Experimental animals received an iv infusion of thiorphan, 0.5 mg/kg/min for 120 minutes. Control animals received vehicle only. In some animals, vascular smooth muscle cell membrane potentials (Em) was measured in vivo. In another series of experiments, using the identical protocol, cardiac output was recorded. The thiorphan infusion produced a similar progressive decrease in blood pressure in all models of hypertension. Cardiac output did not change relative to vehicle infused control animals. Thus pressure decreased because of a decrease in total peripheral resistance. The contractility index (dP/dt/P, where P = left ventricular pressure) did not change but vascular smooth muscle cells in tail arteries hyperpolarized in all four models. In spite of a significant decrease in blood pressure, thiorphan infusion either increased or produced no change in urinary volume (UV) and sodium (U(Na)V) excretion. These data show that thiorphan, an NEP inhibitor, decreases the blood pressure of hypertensive rats due to a decrease in total peripheral resistance, perhaps by hyperpolarizing vascular smooth muscle cells. These effects are independent of the mechanism of the hypertension. Increased UV and U(Na)V in the face of decreased pressure suggests a direct renal effect.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cyclic GMP; Hypertension; Infusions, Intravenous; Kidney; Male; Potassium; Protease Inhibitors; Rats; Rats, Inbred SHR; Sodium; Thiorphan; Urodynamics

The contributions of arterial baroreceptor and Bezold-Jarisch reflexes, and atrial natriuretic factor (ANF) to the anti-hypertensive effect of the diuretic chlorthalidone were investigated in rats with deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Chlorthalidone (8 mg rat(-1)day(-1)added to food) was given to one group during all 20 days of DOCA (8 mg kg(-1)s.c. twice per week) administration (preventive regimen) and, to another group, 20 days after DOCA treatment was initiated until the 40th day (therapeutic regimen). DOCA caused a significant increase in mean arterial pressure, reduced arterial baroreflex, and increased both the Bezold-Jarisch reflex and pro-ANF converting enzyme activity. Chlorthalidone reversed or prevented the DOCA-salt-induced hypertension, which was accompanied by the normalization of both the arterial baroreflex and the Bezold-Jarisch reflex. Additionally, both preventive and therapeutic regimens with chlorthalidone did cause normalization of the plasma sodium concentration and pro-ANF converting enzyme activity in the left atrium that follows DOCA-salt hypertension. Although it is difficult to determine the relative importance of each of the above regulatory mechanisms altered by chlorthalidone treatment, these data indicate that they may account for the prevention or decrease of DOCA-salt-induced hypertension in rats.

Topics: Animals; Atrial Natriuretic Factor; Baroreflex; Biguanides; Blood Pressure; Chlorthalidone; Desoxycorticosterone; Diuretics; Heart Rate; Hypertension; Male; Myocardium; Potassium; Pressoreceptors; Rats; Rats, Wistar; Serotonin Receptor Agonists; Sodium

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Calcium; Calcium Channel Blockers; Drug Therapy, Combination; ErbB Receptors; Gene Expression; Heart Ventricles; Hypertension; Myocardium; Organ Size; Perindopril; Phosphorylation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, Platelet-Derived Growth Factor; RNA, Messenger; Stroke; Tetrazoles

To evaluate blood pressure in a population-based cohort with urographic renal scarring after childhood urinary tract infection.. Follow-up investigation 16-26 years after the first recognized urinary tract infection.. University out-patient clinic for children with urinary infections serving the local area.. From the original cohort of 1221 consecutive children with first urinary tract infection diagnosed during 1970-1979, 57 of 68 with non-obstructive renal scarring participated as well as 51 matched subjects without scarring.. 24 h ambulatory blood pressure.. Acceptable blood pressure monitorings were obtained from 53 individuals with and 47 without scarring. There were no significant differences between the two groups even when only patients with the most extensive scarring (individual kidney clearance < 30 ml/min per 1.73 m2) or patients with bilateral scarring were compared with the non-scarring group. Mean systolic or diastolic blood pressure above +2 SD were found in 5/53 (9%) and 3/47 (6%) in the scarring and non-scarring group, respectively. Plasma renin activity, angiotensin II and aldosterone concentrations were not significantly different, but atrial natriuretic protein was significantly higher in the scarring group (P = 0.004).. This study demonstrates a low risk of hypertension two decades after childhood urinary tract infection. It should be stressed that the patients with renal scarring were under close supervision throughout childhood. Those with scarring had higher concentrations of atrial natriuretic protein which might indicate a counter-regulation mechanism.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cicatrix; Cohort Studies; Female; Follow-Up Studies; Humans; Hypertension; Kidney Diseases; Male; Risk Factors; Time Factors; Urinary Tract Infections

The natriuretic peptide (NP) family is involved in the regulation of blood pressure and fluid volume. We isolated the 5'-flanking region of the type A human NP receptor gene and identified an insertion/deletion mutation in this region. We then assessed whether there is a genetic association between this mutation and essential hypertension (EH). The deletion allele lacks 8 nucleotides and alters binding sites for the activator protein-2 (AP-2) and Zeste transcriptional factors. We genotyped 200 EH and 200 normotensive (NT) individuals and found 9 subjects with the deletion (8 in the EH group and 1 in the NT group). All 9 individuals were heterozygous. The NT subject with the mutation had left ventricular hypertrophy without hypertension. Transcriptional activity of the deletion allele was <30% that of the wild-type allele. The plasma levels of brain NP in EH patients with the deleted allele were significantly higher than the levels in the EH patients with the wild-type allele, and plasma brain NP levels were significantly higher in subjects with the deleted allele than in subjects with the wild-type allele, despite comparable blood pressures. These findings suggest that in Japanese individuals, this deletion in the human NP receptor gene reduces receptor activity and may confer increased susceptibility to developing EH or left ventricular hypertrophy.

Topics: Adult; Aged; Atrial Natriuretic Factor; Base Sequence; DNA, Complementary; Female; Gene Expression Regulation; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Molecular Sequence Data; Receptors, Atrial Natriuretic Factor; Sequence Deletion

Among women with a history of preeclampsia the prevalence of hemodynamic and clotting disorders is elevated. In this study we tested the hypothesis that the normal cyclic variation in hemodynamic and renal function parameters with the menstrual cycle that is seen among healthy women would be preserved in women with a history of preeclampsia irrespective of whether they had an underlying hemodynamic or clotting disorder.. We compared the hemodynamic and volume cyclic variations during the menstrual cycle among women with a history of preeclampsia (n = 39) with those among healthy parous control women (control group, n = 10). The participants with a history of preeclampsia were subdivided into groups of women with hypertension with or without thrombophilia (hypertension group, n = 10), women with a normotension and a thrombophilic disorder (thrombophilia group, n = 17), and women without either of these abnormalities (symptom-free group, n = 12). We measured > or =5 months post partum, once during the follicular phase of the menstrual cycle (day 5 +/- 2) and once during the luteal phase (day 22 +/- 2), the following variables: body weight and length, mean arterial pressure, heart rate, cardiac output, plasma volume, glomerular filtration rate, effective renal plasma flow, and concentrations of renal volume homeostatic hormones, reproductive hormones, and catecholamines. From the measured data we calculated body mass index, cardiac index, left ventricular work, total peripheral and renal vascular resistances, effective renal blood flow, and renal filtration fraction.. The hypertension group differed from the control group in having higher baseline (follicular phase) values for cardiac output, cardiac output, left ventricular work, renal vascular resistance, and atrial natriuretic peptide and norepinephrine levels. The symptom-free group differed from the control group in having a lower baseline plasma volume and higher baseline cardiac output and left ventricular work values. Women in the thrombophilia group were comparable to those in the control group with respect to baseline hemodynamic and renal function variables except for a higher renal vascular work value. In the control group heart rate, plasma volume, effective renal plasma volume, effective renal blood flow, and concentrations of renin-angiotensin-aldosterone system hormones and norepinephrine were increased during the luteal phase with respect to values during the follicular phase, whereas the renal vascular resistance and atrial natriuretic peptide values were decreased. In the three subgroups of women with a history of preeclampsia this cyclic pattern with the menstrual cycle was preserved for most of these parameters.. Although baseline hemodynamic and volume status among women with a history of preeclampsia differed from that among healthy parous control subjects, the cyclic variation with the menstrual cycle was largely preserved.

Topics: Atrial Natriuretic Factor; Blood Flow Velocity; Blood Pressure; Blood Volume; Cardiac Output; Female; Follicular Phase; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Homeostasis; Humans; Hypertension; Kidney; Luteal Phase; Menstrual Cycle; Norepinephrine; Pre-Eclampsia; Pregnancy; Thrombophilia; Vascular Resistance

Previous studies have shown that short-term high salt intake unmasks blunted plasma aldosterone suppression in stroke-prone spontaneously hypertensive rats (SHRsp). The aim of this study was to evaluate the response of aldosterone biosynthesis and production to a sustained exposure to the stroke-permissive Japanese-style diet (JD) in young stroke-prone and stroke-resistant SHRs. For this purpose, 6-week old male rats from both strains were divided into 2 dietary groups and received regular diet (SHR = 37, SHRsp = 32) or the JD and 1% saline to drink (SHR = 34, SHRsp = 30) for 4 weeks. All measurements were carried out at the end of the dietary periods. After JD, plasma aldosterone levels were significantly decreased in SHR (from 357.8 +/- 57 to 163.3 +/- 31.5 pg/ml, p < 0.05) but markedly increased in SHRsp (from 442 +/- 56.5 to 739 +/- 125.7 pg/ml, p < 0.05). Consistently, the adrenal aldosterone synthase expression was reduced by JD in SHR (p < 0.05), whereas it was even slightly raised by JD in SHRsp so that, at the end of JD, aldosterone synthase mRNA was 5-fold higher in SHRsp than in SHR. Urinary sodium excretion (mEq/24h) achieved lower levels in SHRsp, so that fractional excretion of sodium was 80.2 +/- 9% in SHR and 40.3 +/- 8% in SHRsp (p < 0.05) in balance studies performed at the end of JD. These different responses of mineralocorticoid biosynthesis and urinary sodium excretion to JD were not accounted for by different adaptations of the renin-angiotensin and atrial natriuretic peptide systems, of serum potassium levels, or of adrenal 11beta-hydroxylase expression in the two strains. Systolic blood pressure was comparable in both strains throughout the experiment. These results demonstrate enhanced aldosterone biosynthesis, associated with reduced urinary excretion of sodium in response to JD in SHRsp before the onset of stroke. This abnormality may play a role in the higher susceptibility to stroke of this model.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Hypertension; Japan; Male; Rats; Rats, Inbred SHR; Renin; Sodium Chloride, Dietary; Stroke

We tested the hypothesis that hypertension in atrial natriuretic peptide (ANP) knockout mice is caused in part by disinhibition of angiotensin II-mediated vasopressin release. Inactin-anesthetized F(2) homozygous ANP gene-disrupted mice (-/-) and wild-type (+/+) littermates were surgically prepared for carotid arterial blood pressure measurement (ABP) and background intravenous injection of physiological saline or vasopressin V(1)-receptor antagonist (Manning compound, 10 ng/g body wt) and subsequent intracerebroventricular (left lateral ventricle) injection of saline (5 microl) or ANP (0.5 microg) or angiotensin II AT(1)-receptor antagonist losartan (10 microg). Only (-/-) showed significant decrease in ABP after intracerebroventricular ANP or losartan. Both showed significant hypotension after intravenous V(1) antagonist, but there was no difference between their responses. We conclude that 1) vasopressin contributes equally to ABP maintenance in ANP-disrupted mice and wild-type controls; 2) permanently elevated ABP in ANP knockouts is associated with increased central nervous angiotensin II AT(1)-receptor activation; 3) disinhibition of central nervous angiotensin II AT(1) receptors in ANP-deficient animals does not lead to a significant increase in the importance of vasopressin as a mechanism for blood pressure maintenance.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Female; Hormone Antagonists; Hypertension; Injections, Intravenous; Losartan; Male; Mice; Mice, Knockout; Paraventricular Hypothalamic Nucleus; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Vasopressins

This study analysed the regulation of cardiac mineraloreceptor (MR) and glucoreceptor (GR) in aldosterone-salt treatment (AST). AST causes hypertension, left ventricle (LV) hypertrophy and decreases plasma corticosterone level. Ribonuclease protection assay and Western blot analysis showed a rise of MR mRNA (1.5- and 1.4-fold at day 15 and 30, respectively) and protein levels (1.8- and 4.1-fold at day 30 and 60, respectively) in the LV, but not in either the right ventricle (RV) or in kidney of treated rats. Addition of MR antagonist spironolactone (20 mg/kg/day) for 30 days failed to prevent these changes but was able to reduce AST-induced cardiac fibrosis. Similar hypertension-induced MR upregulations were observed in the LV of AngII-hypertensive rats and of 12-week-old SHR when compared to 4-week-old prehypertensive SHR. AST also enhanced left ventricular GR mRNA (2.0- and 3.0-fold at day 7 and 15, respectively) and protein contents (2.0- and 1.7-fold at day 30 and 60, respectively). In contrast to MR, GR levels were also upregulated in both RV and kidney. Such an upregulation was equally observed at mRNA and protein levels in LV, RV and kidney after adrenalectomy (15 days) and was prevented in both tissues after glucocorticoid replacement (adrenalectomy + dexamethasone at 100 micro g/kg/day for 15 days). Therefore, MR level may be controlled by hemodynamical factors whereas that of GR depends upon glucocorticoids level.

Topics: Adrenalectomy; Age Factors; Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blotting, Western; Collagen; Glucocorticoids; Heart; Hypertension; Kidney; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Steroid; RNA, Complementary; Sodium Chloride; Spironolactone; Time Factors

Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease.. This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension.. Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy.. Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005).. Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiac Volume; Diastole; Echocardiography, Doppler, Pulsed; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Perindopril; Ventricular Function, Left

To determine the role of endothelin-1 (ET-1) in the upregulation of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) observed in deoxycorticosterone acetate (DOCA)-salt hypertension, the selective ET-1 type-A receptor (ET(A)) antagonist ABT-627 was chronically administered to normal controls and hypertensive rats. Chronic ET(A) blockade in DOCA-salt-treated rats prevented the increase in blood pressure and circulating natriuretic protein (NP) levels and partially prevented left ventricular hypertrophy. The changes observed in NP gene expression in the atria were not affected by ABT-627. In the ventricles, ABT-627 reduced NP gene expression. Rats receiving the ET(A) antagonist alone showed reduced left ventricular NP gene expression. ABT-627 did not affect ventricular collagen III gene expression but enhanced left ventricular alpha-myosin heavy chain expression. These findings suggest that in vivo, ventricular but not atrial NP production is regulated by ET-1. This difference in response between atrial and ventricular NP gene expression to ET(A) receptor blockade is similar to that observed by us after applying angiotensin-converting enzyme inhibitors in other hypertensive models. In general therefore, atrial NP gene expression may not be as sensitive to the endocrine environment as is ventricular NP gene expression.

Topics: Animals; Atrasentan; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Endothelin Receptor Antagonists; Gene Expression Regulation; Heart; Heart Ventricles; Hypertension; Male; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; Organ Size; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium, Dietary; Transcription, Genetic

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.

Topics: Animals; Atrial Natriuretic Factor; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Infarction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta

The atrial natriuretic peptide (ANP) family is a complex system consisting of at least three polypeptides and at least three types of receptor. Each peptide interacts with different types of receptor at varying degrees of affinity. To determine if natriuretic peptide levels influence natriuretic peptide receptor expression and regulation, we examined the expression of guanylyl cyclase linked GC-A, GC-B and C-receptor in the lungs of mice with a mutation that inactivates the ANP gene (Nppa).. The mRNA level of GC-A, GC-B and C-receptor in the lung were studied by ribonuclease protection assays (RPA).. Results of RPA showed that although the mRNA level of GC-A and GC-B of heterozygous ANP+/- was not different from wild type ANP+/+ mice, they were significantly higher in the homozygous mutant ANP-/- mice. In addition, C-receptor mRNA level in ANP+/- and ANP-/- was significantly lower than ANP+/+ mice. The C-receptor results were confirmed by receptor binding assays and affinity cross-linking studies.. Taken together these data suggest that permanent removal of ANP from the natriuretic peptide system results in an up-regulation of GC-A and GC-B, and a corresponding down-regulation of C-receptor in the lung of proANP gene disrupted mice. We postulated that changes in the natriuretic peptide receptor population may result in chronic hypertension and cardiac hypertrophy in the ANP-/- mice.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Autoradiography; Gene Expression; Guanylate Cyclase; Hypertension; Lung; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptors, Atrial Natriuretic Factor; RNA, Messenger

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca(2+)](i)) is still unknown. Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains. Measuring [Ca(2+)](i) by imaging analysis of fura-2-loaded cells, we demonstrated that alpha-thrombin (3-180 U l(-1)) induced a superimposable dose-dependent calcium transient in ECs from both strains. In WKY ECs, S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose-dependently (10 - 100 microM) and 0.1 microM atrial natriuretic factor (ANF) reduced the maximum and the decay time of alpha-thrombin-induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP-dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of alpha-thrombin-induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. In SHR ECs, alpha-thrombin-induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 9. 3 and 51 fold respectively. In WKY ECs, SNAP dose-dependently (10 - 100 microM) reduced also bradykinin-induced calcium transient, while in SHR ECs was ineffective. We concluded that in SHR ECs, the cyclic GMP-dependent regulation of calcium transient is lost.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Calcium; Cyclic GMP; Drosophila Proteins; Endothelium, Vascular; Hypertension; Insect Proteins; Myocardium; Nitric Oxide; Nitric Oxide Donors; Penicillamine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA-Binding Proteins; Thrombin

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Body Weight; Cardiotonic Agents; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardial Contraction; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Serine Proteinase Inhibitors; Vasodilator Agents

There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.. Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg x kg(-1) x d(-1)) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.. Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcineurin Inhibitors; Disease Models, Animal; Drug Administration Schedule; Echocardiography; Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Myocardium; Organ Size; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium Chloride; Tacrolimus

A genetic linkage study of young-onset hypertension was performed on data from 59 nucleus families of Han Chinese residing in Taiwan. Thirty seven microsatellite markers near 18 hypertension candidate genes were genotyped. In a nonparametric identity-by-descent sibpair analysis, a positive linkage signal (defined as P<0.05) was found for four microsatellite markers, viz., D1S1612 (P=0.0162), D1S547 (P=0.0263), D8S 1145 (P= 0.0284), and D17S2193 (P=0.0256), which were located near genes for atrial natriuretic peptide (NPPA)/glucose transporter 5 (SLC2A5), angiotensinogen (AGT), lipoprotein lipase (LPL), and angiotensin-conveting enzyme (DCP1), respectively. Marker D5S1480 located near beta-2-adrenergic receptor (ADRB2) had a borderline P value (P=0.0785) for the positive signal. Comprehensive genotyping with further markers in these regions is underway to confirm whether these genes are linked to young-onset hypertension.

Topics: Adult; Age Factors; Age of Onset; Angiotensinogen; Atrial Natriuretic Factor; Genetic Linkage; Genetic Markers; Genotype; Glucose Transporter Type 5; Humans; Hypertension; Lipoprotein Lipase; Microsatellite Repeats; Monosaccharide Transport Proteins; Nuclear Family; Peptidyl-Dipeptidase A; Statistics, Nonparametric; Taiwan

To investigate the effects of hypoxemia, hypercapnia, and cardiovascular hormones (norepinephrine, endothelin-1, and atrial natriuretic factor) on blood pressure during acute respiratory failure.. Patients with chronic obstructive pulmonary disease and acute respiratory failure were divided into four groups of 10 patients each: hypoxemia-normocapnia, hypoxemia-hypercapnia, hypoxemia-hypocapnia, and normoxemia-hypercapnia. Plasma norepinephrine levels were determined by high-performance liquid chromatography with electrochemical detection. Plasma endothelin-1 and atrial natriuretic factor levels were radioimmunoassayed after chromatographic preextraction.. Systolic blood pressure and cardiovascular hormone levels were greater in patients with hypercapnia (whether or not they also had hypoxemia) than in those with normocapnia and hypoxemia. For example, in patients with hypercapnia and normoxemia, the mean (+/- SD) systolic blood pressure was 183+/-31 mm Hg and the mean norepinephrine level was 494+/-107 pg/mL, as compared with 150+/- 6 mm Hg and 243+/-58 pg/mL in those with normocapnia and hypoxemia (both P<0.05). Similar results were seen for endothelin-1 and atrial natriuretic factor levels, and for the comparisons of hypoxemic patients who were hypercapnic with those who were normocapnic.. These results suggest that blood carbon dioxide levels, rather than oxygen levels, are responsible for hypertension during acute respiratory failure, perhaps as a result of enhanced sympatho-adrenergic activity.

Topics: Acute Disease; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Carbon Dioxide; Endothelin-1; Female; Heart Rate; Humans; Hypercapnia; Hypertension; Hypocapnia; Hypoxia; Lung Diseases, Obstructive; Male; Middle Aged; Norepinephrine; Oxygen; Respiratory Insufficiency; Severity of Illness Index

We examined the effect of a hypocaloric diet on adrenomedullin (AM), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) in 12 obese patients with essential hypertension (age, 48-81 years; body mass index, 26-34 kg/m2). For the initial week, a standard diet of 2000 kcal/day was given, followed by 3 weeks of a hypocaloric diet of 850 kcal/day, with a constant intake of sodium. The patients lost 3.7 +/- 0.2 kg body weight during the hypocaloric diet period (p < 0.0001). The decrease in blood pressure during the study period was 10.3 +/- 3.6 mmHg systole (p = 0.017) and 4.2 +/- 3.2 mmHg diastole (NS). Plasma AM concentration was decreased significantly from 4.88 +/- 0.46 to 3.97 +/- 0.38 pmol/l by the hypocaloric diet (p = 0.004). Plasma ANP and BNP concentrations were also decreased significantly by the hypocaloric diet (p = 0.042 for each). These results demonstrate, for the first time, that plasma AM concentration as well as plasma ANP and BNP concentrations are decreased by a hypocaloric diet in obese patients with essential hypertension. These vasodilator peptides may act against further elevation in blood pressure in obese patients with essential hypertension.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Energy Intake; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Obesity; Peptides

The effect of moderate left atrial (LA) hypertension on alveolar liquid clearance (ALC) was investigated in anesthetized, ventilated sheep, surgically prepared to measure lung lymph flow as well as hemodynamics. To simulate alveolar edema, 3-4 ml/kg of isosmolar 5% albumin in Ringer lactate were instilled into each lower lobe, and ALC was measured. After 4 h of LA hypertension (24 cmH2O), ALC was similar to that in control sheep (31 +/- 3% with LA hypertension vs. 34 +/- 10% with normal LA pressure). Because plasma epinephrine levels were moderately elevated in the presence of LA hypertension, ALC was then studied in the presence of LA hypertension following bilateral adrenalectomy. Without endogenous release of epinephrine, ALC was significantly reduced compared with normal LA pressure (20 +/- 7% compared with 34 +/- 10%, P < 0.05). Thus endogenous catecholamines caused a submaximal stimulation of ALC in the presence of LA hypertension. Exogenous administration of aerosolized beta2-agonist therapy with salmeterol increased ALC in the presence of normal LA pressure but had no stimulatory effect in the presence of moderate LA hypertension. Therefore, we tested the hypothesis that endogenous release of atrial natriuretic factor (ANF) may downregulate alveolar epithelial Na+ and fluid transport in the presence of LA hypertension. There was a modest twofold increase in plasma ANF levels after LA hypertension. Additional in vitro studies demonstrated that, in the presence of beta2-agonist stimulation, ANF decreased Na+ pump activity (Na+-K+-ATPase) in isolated rat alveolar epithelial type II cells. ANF may downregulate vectorial Na+ and fluid transport stimulated by endogenous or exogenous beta-adrenergic agonist stimulation in the presence of LA hypertension. In summary, ALC continues even in the presence of moderate LA hypertension. Aerosolized beta2-adrenergic agonist therapy significantly increased ALC, but only when LA pressure was normal.

Topics: Adrenalectomy; Adrenergic alpha-Agonists; Anesthesia; Animals; Atrial Natriuretic Factor; Blood Proteins; Capillary Permeability; Epinephrine; Hemodynamics; Hypertension; In Vitro Techniques; Lymph; Male; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Respiration, Artificial; Sheep; Sodium-Potassium-Exchanging ATPase

-Previous studies suggested that atrial natriuretic peptide gene (Anp) and brain natriuretic peptide gene (Bnp) are plausible candidate genes for susceptibility to stroke and for sensitivity to brain ischemia in the stroke-prone spontaneously hypertensive rat (SHRSP). We performed structural and functional analyses of these 2 genes in SHRSP from Glasgow colonies (SHRSPGla) and Wistar-Kyoto rats from Glasgow colonies (WKYGla) and developed a radiation hybrid map of the relevant region of rat chromosome 5. Sequencing of the coding regions of the Anp and Bnp genes revealed no difference between the 2 strains. Expression studies in brain tissue showed no differences at baseline and at 24 hours after middle cerebral artery occlusion. Plasma concentrations of atrial natriuretic peptide (ANP) did not differ between the SHRSPGla and WKYGla, whereas concentrations of brain natriuretic peptide were significantly higher in the SHRSPGla as compared with the WKYGla (n=11 to 14; 163+/-21 pg/mL and 78+/-14 pg/mL; 95% confidence interval 31 to 138, P=0.003). We did not detect any attenuation of endothelium-dependent relaxations to bradykinin or ANP in middle cerebral arteries from the SHRSPGla; indeed the sensitivity to ANP was significantly increased in arteries harvested from this strain (WKYGla: n=8; pD2=7. 3+/-0.2 and SHRSPGla: n=8; pD2=8.2+/-0.15; P<0.01). Moreover, radiation hybrid mapping and fluorescence in situ hybridization allowed us to map the Anf marker in the telomeric position of rat chromosome 5 in close proximity to D5Rat48, D5Rat47, D5Mgh15, and D5Mgh16. These results exclude Anp and Bnp as candidate genes for the sensitivity to brain ischemia and pave the way to further congenic and physical mapping strategies.

Topics: Amino Acid Substitution; Animals; Atrial Natriuretic Factor; Base Sequence; Brain; Brain Ischemia; Cells, Cultured; Cerebrovascular Disorders; Chromosome Mapping; DNA Primers; Exons; Genetic Markers; Genetic Predisposition to Disease; Hypertension; Introns; Male; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Point Mutation; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley

The expression of the natriuretic peptide clearance receptor is abundant in human and rat adipose tissue, where it is specifically inhibited by fasting. In obese hypertensives, plasma atrial natriuretic peptide (ANP) levels were found to be lower than in obese normotensives. Therefore, the increased adipose mass might influence ANP levels and/or its biological activity. The aim of the present study was to evaluate whether the humoral, hemodynamic, and renal effects of exogenous ANP in obese hypertensives might be enhanced by a very low calorie diet. Eight obese hypertensives received a bolus injection of ANP (0.6 mg/kg) after 2 weeks of a normal calorie/normal sodium diet, and blood pressure (BP), heart rate, ANP, cGMP, plasma renin activity, and aldosterone were evaluated for 2 hours before and after the injection. Diuresis and natriuresis were measured every 30 minutes. The patients then started a low calorie/normal sodium diet (510 kcal/150 mmol/d) for 4 days, and then the ANP injection protocol was repeated. The low calorie diet induced a slight weight loss (from 90.6+/-1.1 to 87. 7+/-1.2 kg; P<0.01), which was accompanied by increase of cGMP excretion (from 146.0+/-10.1 to 154.5+/-9.5 nmol/24 h; P<0.05) together with a reduction of BP (P<0.01 versus basal levels). ANP injection after diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis, and natriuresis increased significantly only after diet. Similarly, the decrease of BP after ANP administration was significantly higher after diet (change in mean arterial pressure, -6.4+/-0.7 versus -4. 0+/-0.6 mm Hg; P<0.05) as well as that of aldosterone (P<0.01). These data show that a low calorie diet enhances the humoral, renal, and hemodynamic effects of ANP in obese hypertensives and confirm the importance of caloric intake in modulating the biological activity of ANP, suggesting that the natriuretic peptide system can play a role in the acute changes of natriuresis and diuresis associated with caloric restriction.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Diet; Diuresis; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Obesity; Rats; Renin

Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect which is mediated by a reduction in total peripheral resistance (TPR). Mice with a homozygous disruption of the pro-ANP gene (-/-) fail to synthesize ANP and develop chronic hypertension in comparison to their normotensive wild-type (+/+) siblings. In order to determine whether alterations in basal hemodynamics underlie the hypertension associated with lack of endogenous ANP activity, we used anesthetized mice to measure arterial blood pressure (ABP) and heart rate (HR), as well as cardiac output (CO) by thermodilution technique. -/- (n = 7) and +/+ (n = 10) mice of comparable weight and age were used. Stroke volume (SV) and TPR were derived from CO, HR, and ABP by a standard formula. ABP (mm Hg) was significantly higher in -/- (132+/-4) (P < 0.0001) than in +/+ mice (95+/-2). CO (ml min(-1)), HR(beats min(-1))and SV (microl beat(-1)) did not differ significantly between -/- and +/+ mice (CO -/- = 7.3+/-0.5, +/+ = 8.3+/-0.6; HR -/- = 407+/-22, +/+ = 462+/-21; SV -/- = 17.6+/-1.1, +/+ = 17.6+/-1.7). However, TPR (mm Hg ml(-1) min(-1)) was significantly elevated in -/- mice (18.4+/-0.7) compared to +/+ mice (12.3+/-1) (P = 0.0003). Autonomic ganglion blockade with a mixture of hexamethonium and pentolinium was followed by comparable percent reductions in CO (-/- = 28+/-4, +/+ = 29+/-3), HR (-/- = 9+/-4, +/+ = 16+/-4) and SV(-/- = 21+/-4, +/+ = 15+/-6) in both genotypes. However, the concomitant decrease in ABP (%) in -/- (41+/-2) was significantly greater than in +/+ (23+/-4) mice (P = 0.0009) and was accompanied by a significant reduction in TPR. We conclude that the hypertension associated with lack of endogenous ANP is due to elevated TPR, which is determined by an increase in cardiovascular autonomic tone.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Chronic Disease; Hemodynamics; Hypertension; Mice; Mice, Knockout; Vascular Resistance

Adrenomedullin (AM), a potent vasodilator and natriuretic peptide, is found in human blood. To investigate the pathophysiological role of AM in essential and malignant hypertension (EHT and MHT), we measured the plasma concentrations of AM in patients with EHT of WHO stage I or II (n = 42) and in those with MHT (n = 9) by a specific radioimmunoassay, and compared these concentrations with those in normotensive controls (n = 46). The plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) in these subjects were also measured by immunoradiometric assays, and their relations to plasma AM were examined. The plasma AM level in the EHT patients (7.15+/-0.21 pmol/l, mean+/-SEM) was significantly (p < 0.01) higher than that in the normotensive controls (6.14+/-0.25 pmol/l), and a further elevation was observed in the MHT patients (14.1+/-3.8 pmol/l). Similar elevations of plasma ANP and BNP were seen in the two patient groups. The plasma AM level significantly (p < 0.01) correlated with not only the systolic (r = 0.44) and diastolic (r = 0.46) blood pressures, but also with the plasma levels of ANP (r = 0.43) and BNP (r = 0.43). The elevated plasma concentration of AM in the MHT patients decreased significantly (p < 0.05) after antihypertensive treatment, and the plasma ANP and BNP levels similarly declined. These results suggest that AM may participate, along with ANP and BNP, in mechanisms counteracting a further elevation of blood pressure in patients with EHT and MHT.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Calcitonin Gene-Related Peptide; Creatinine; Female; Humans; Hypertension; Hypertension, Malignant; Male; Middle Aged; Natriuretic Peptide, Brain; Peptides; Radioimmunoassay; Renin

This was an association study of genetic polymorphisms to compare the distribution of the genotypes and alleles of the HpaII polymorphism of the atrial natriuretic peptide (ANP) gene in hypertensive patients and normotensive controls. The setting was an outpatient clinic run by a University Department handling referrals from primary care. The patient cohort was composed of 217 subjects, consisting of 109 healthy controls and 108 patients with newly diagnosed or documented hypertension. The genomic DNA was extracted from peripheral blood leukocytes, amplified by polymerase chain reaction, and digested with the restriction enzyme HpaII. H1 and H2 alleles were identified after electrophoresis. The main outcome measures were to identify the frequencies of ANP genotypes and alleles in hypertensive patients and normotensive controls. The H1H1, H1H2, and H2H2 genotypes occurred in 1%, 19%, and 80% of controls and 3%, 18%, and 80% of hypertensive patients, respectively. The frequencies of the H1 and H2 alleles were 0.11 and 0.89 in controls and 0.12 and 0.88 in hypertensive patients. The frequencies of the ANP genotypes and alleles did not differ significantly between controls and hypertensive patients. Our findings differed from previous reports and suggested that this polymorphism is not associated with hypertension in this population.

Topics: Adult; Aged; Alleles; Atrial Natriuretic Factor; Blood Pressure; Deoxyribonuclease HpaII; DNA; Electrophoresis, Polyacrylamide Gel; Female; Gene Frequency; Genetic Markers; Genotype; Humans; Hypertension; Male; Middle Aged; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic

We have previously established the existence of atrial natriuretic factor (ANF) gene expression within the renal parenchyma. Neither the role nor the regulation of this extracardiac source of ANF is clearly defined. To determine whether renal ANF gene expression, similar to cardiac expression, is linked to the activity of the renin-angiotensin system (RAS), we compared renal ANF gene expression in rats after suprarenal aortic banding, a hypertension model associated with activation of RAS, and in the deoxycorticosterone acetate (DOCA)-salt model, which is characterized by depression of RAS. Renal ANF mRNA was measured with a quantitative competitive reverse transcription polymerase chain reaction method. DOCA-salt hypertension significantly reduced the expression of renal ANF. In contrast, aortic banding significantly increased renal ANF expression. In both cases, ANF gene expression in the heart increased. Ramipril treatment at 10 micrograms/kg of aortic-banded rats, a treatment that specifically affects local RAS but maintains hypertension, normalized renal ANF mRNA levels. Altogether, these results suggest that renal ANF gene expression is modulated by local RAS and is independent of circulating RAS and hypertension per se. The marked decrease of renal ANF mRNA in DOCA-salt hypertension suggests a pathogenic role for renal ANF gene downregulation by decreasing the sodium excretory mechanism mediated by the local expression of ANF acting on receptors found in the inner medullary collecting ducts. In aortic banding, renal ANF gene expression upregulation suggests a local compensatory function consistent with the consensus role of natriuretic peptides in the modulation of RAS, thus ameliorating the sodium-retaining effects of renal underperfusion.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression Regulation; Hypertension; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium, Dietary; Transcription, Genetic

A 47-year-old man with hypertensive heart disease and left heart failure due to left ventricular diastolic dysfunction was admitted to our hospital because of emergent hypertension. Chest radiography on admission showed slight cardiomegaly and mild pulmonary congestion with right pleural effusion Echocardiography showed concentric hypertrophy and normal contraction of the left ventricular wall Pulsed Doppler left ventricular inflow velocity wave and pulmonary venous flow velocity wave disclosed restrictive filling patterns. After Ca antagonist, nitrate, and diuretics were administered, blood pressure was normalized, and left ventricular inflow velocity wave showed the relaxation abnormality pattern and pulmonary venous flow velocity wave showed the normal pattern. Radioiodinated iodine-123 metaiodobenzyl guanidine (123I-MIBG) imaging in the state of normalized blood pressure showed decreased heart to mediastinum ratio and increased washout rate. Left heart catheterization and angiography revealed normal end-diastolic pressure and coronary arteries, but coronary flow reserve evaluated with Doppler flow wire and intracoronary adenosine triphosphate administration was impaired: Plasma level of atrial and brain natriuretic peptides, which were markedly elevated on admission, decreased with the improvement of heart failure. Doppler flow velocity patterns, plasma levels of atrial natriuretic peptide and brain natriuretic peptide, cardiac sympathetic nerve activity, and coronary flow reserve might be useful for evaluating the severity of left ventricular diastolic dysfunction in patients with hypertensive heart disease.

Topics: Atrial Natriuretic Factor; Calcium Channel Blockers; Coronary Circulation; Diastole; Diuretics; Echocardiography; Echocardiography, Doppler, Pulsed; Heart Diseases; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nitrates; Radionuclide Imaging; Technetium Tc 99m Sestamibi; Ventricular Dysfunction, Left

It has been demonstrated previously that the atrial natriuretic factor prohormone fragment 31-67 (ProANF31-67) circulates in animals and possesses natriuretic and vasodilating actions. Although the plasma levels of the peptide are reportedly elevated in patients with high blood pressure, its role and actions in hypertension are unknown. In the present study, synthetic human ProANF31-67 was infused intravenously at doses of 0, 10, 30, and 100 ng/kg/min into respective groups of anesthetized normotensive and spontaneously hypertensive rats. Mean arterial pressure (MAP), urine flow rate (UV), and sodium excretion (UNaV) were measured during two consecutive 30-min periods. In both strains of rats, reductions in MAP with ProANF31-67 were similar in magnitude and dose-related. Sodium excretion responses to the peptide infusions also were remarkably similar in both normotensive and hypertensive rats, and the responses demonstrated 3- to 5-fold (P < 0.05) increments compared to control at the doses of 10 and 30 ng/kg/min. However, in the two strains of rats, attenuation of natriuresis occurred with the highest infusion dose of 100 ng/kg/min and was probably related to the large decreases in MAP of 17-23 mmHg at this dose of the peptide. The present results indicate the ProANF31-67 has important hemodynamic and renal effects in hypertension and may represent one compensatory mechanism involved in this disease.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Hemodynamics; Humans; Hypertension; Male; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Sodium

We have investigated the vasorelaxant effect of atrial natriuretic peptide (ANP) on isolated non-contracted aorta from coarctation hypertensive rats (HR) and the role of endothelium in this vasorelaxant action. After 7-14 days of surgery, mean blood pressure was higher (P < 0.01) in HR compared with sham operated rats (SR), used as the control. ANP (10(-6) mol/l) significantly lowered basal tone in previously unstimulated HR thoracic aortic rings; however, it had no effect in HR abdominal aorta or in SR abdominal and thoracic aorta. Endothelial destruction potentiated the vasorelaxant effect of ANP on basal tone in HR thoracic aorta. A similar potentiation of the ANP-response was observed by pre-treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) mol/l) or methylene blue (2 x 10(-5) mol/l) in unrubbed HR thoracic aorta. Treatment with calcium-free Krebs + EGTA (2 x 10(-3) mol/l) + sodium nitroprusside (10(-5) mol/l) or calcium-free Krebs significantly decreased basal tone and abolished ANP-response. These effects were observed only in HR thoracic aorta. Similarly, staurosporine (10(-7) mol/l) and calphostin C (10(-6) mol/l), inhibitors of protein kinase C (PKC), diminished basal tone and abolished the ANP-response in HR thoracic aorta. Acetylcholine (10(-6) mol/l) had a small but significant action on the basal tone of unrubbed HR thoracic aorta. These results demonstrate that ANP has a vasorelaxant effect on aortic basal tone when the vessel is exposed to high blood pressure. Inhibition of ANP effects on basal tone by calcium-free Krebs and PKC antagonists suggests that the HR aorta increases Ca2+-active tone, that modifies the response of vascular smooth muscle to the vasodilating hormone ANP.

Topics: Acetylcholine; Animals; Aorta, Abdominal; Aorta, Thoracic; Atrial Natriuretic Factor; Calcium; Endothelium, Vascular; Hypertension; Isometric Contraction; Male; Muscle Relaxation; Muscle Tonus; Muscle, Smooth, Vascular; Protein Kinase C; Rats; Rats, Sprague-Dawley

Normotensive primary hyperaldosteronism is exceedingly rare. We report two new cases of this syndrome in two middle-aged women, one of Asian origin. The presenting signs were tetany in one case and an adrenal mass in the other. Neither patient had hypertension, despite repeated measurements with a manual armlet. A typical biological profile of primary hyperaldosteronism was demonstrated in both patients, including hypokalemia with inappropriate kaliuresis, elevated resting plasma aldosterone, and undetectable plasma renin activity. The circadian rhythm of blood pressure was studied by ambulatory monitoring pre- and post-operatively. It confirmed the lack of hypertension, but the circadian rhythm of blood pressure was lost before surgery in one patient. Surgical removal of the histologically typical aldosterone-producing adenomas normalized the kalemia. The main finding in these two patients was spontaneously low blood pressure in the post-operative period. This suggests that excess aldosterone induced relative hypertension in these patients whose blood pressure was spontaneously very low. Genetic screening for dexamethasone-sensitive hyperaldosteronism was negative in both patients.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Blotting, Southern; Chromatography, High Pressure Liquid; Dexamethasone; Female; Gas Chromatography-Mass Spectrometry; Humans; Hyperaldosteronism; Hypertension; Potassium; Radioimmunoassay; Renin; Tetany; Tomography, X-Ray Computed

Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (-/-) develop salt-sensitive hypertension relative to their wild-type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt (HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the -/- mice is associated with failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP "knockout" mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in -/- and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT1 receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control -/- mice compared with control +/+ mice. Losartan did not affect ABP or HR in +/+ mice, but reduced ABP and HR in the -/- mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approximately ten-fold in control -/- mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in -/- mice and abrogated the difference in plasma catecholamine between -/- and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Hypertension; Losartan; Mice; Mice, Knockout; Sodium Chloride, Dietary

Pathophysiological implications of the vascular nitric oxide (NO)/cGMP pathway were investigated in various rat models of hypertension. The expression of brain and endothelial constitutive NO synthases (bNOS, ecNOS) was determined by Western blot analysis, and the biochemical activity of soluble and particulate guanylate cyclases (GC) was assessed by the amount of cGMP generated in the thoracic aortae of rats with deoxycorticosterone acetate (DOCA)-salt, two-kidney, one dip (2K1C), and spontaneous hypertension (SHR). Plasma nitrite/ nitrate levels were decreased in DOCA-salt and 2K1C hypertension, and increased in SHR. The vascular expression of bNOS as well as that of ecNOS was decreased along with tissue nitrite/nitrate contents in DOCA-salt and 2K1C hypertension. The expression of both bNOS and ecNOS was increased in SHR with concomitant changes of tissue nitrite/nitrate contents. The activity of soluble GC was decreased, and that of particulate GC was increased in DOCA-salt hypertension. The soluble GC activity was increased, while the particulate GC activity was not affected in 2K1C hypertension. The soluble GC activity was not significantly changed, but the particulate GC activity was decreased in SHR. These results indicate that the high blood pressure is associated with differentially-altered vascular NO/cGMP pathway in different models of hypertension.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blotting, Western; Desoxycorticosterone; Guanylate Cyclase; Hypertension; Isoenzymes; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Nitrites; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Solubility

The clearance receptor for natriuretic peptides (NPRC), a candidate gene for essential hypertension, is highly expressed in adipose tissue, where is nutritionally regulated. The objectives of the present study were to sequence the human 5'-flanking regulatory region of NPRC, to identify allelic variants and their frequencies, and to study the genotype/phenotype correlation in hypertensive patients.. Using polymerase chain reaction (PCR) and direct automated sequencing, a biallelic (A/C) polymorphism was detected at position -55 in a conserved promoter element named P1. The novel C(-55) variant makes the promoter sequence identical to the mouse gene and introduces a second Hgal site in the amplified DNA, allowing the genotyping of a large number of subjects. In a random sample of 232 white Caucasians the C(-55) allele was more commonly found (81.7% of all alleles) with 155 CC (66.8%), 69 AC (29.7%) and only eight AA (3.5%) genotypes. Atrial natriuretic peptide (ANP) levels were determined in 84 patients with essential hypertension. In the presence of obesity (body mass index (BMI) > or = 30 kg/m2) the homozygous CC hypertensives (n = 21) had significantly lower plasma ANP (33.6 +/- 11.1 pg/ml) compared with the AC patients (n = 11; 46.8 +/- 15.9 pg/ml; P = 0.01), whereas systolic blood pressure (SBP) and mean blood pressure (MBP) had the opposite association (SBP 163.9 +/- 18.7 versus 150.9 +/- 12.9 and MBP 123.3 +/- 12 versus 114.5 +/- 5.9 mmHg; P< 0.05). The difference in ANP levels were also present when overweight patients (BMI > or = 27 kg/m2) were considered.. A common 'ancestral' C(-55) variant of the NPRC P1 promoter is associated with lower ANP levels and higher SBP and MBP in obese hypertensives. The C(-55) variant, in the presence of increased adiposity, might reduce plasma ANP through increased NPRC-mediated ANP clearance, contributing to higher blood pressure.

Topics: Adult; Aged; Alleles; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Mass Index; Female; Gene Frequency; Genetic Testing; Genotype; Guanylate Cyclase; Humans; Hypertension; Male; Mice; Middle Aged; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic; Receptors, Atrial Natriuretic Factor; Regulatory Sequences, Nucleic Acid; Sequence Homology, Nucleic Acid

We investigated whether plasma brain and atrial natriuretic peptide (BNP and ANP, respectively) levels could reflect left ventricular (LV) geometry and function in patients with mild to moderate essential hypertension. A positive correlation was found between LV mass index (LVMI) and plasma ANP levels in 84 untreated, hypertensive patients, but not between LVMI and plasma BNP levels. As compared with other geometric patterns, plasma BNP levels were increased in concentric hypertrophy, in which LVMI was increased and LV diastolic function was decreased. These data suggest that production of BNP was increased in hypertensive patients with concentric hypertrophy via LV overload or depression of diastolic function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Echocardiography; Epinephrine; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Radioimmunoassay; Renin; Ventricular Remodeling

The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with high ANF. Plasma ANF levels were unrelated to systolic or diastolic blood pressure or heart rate. A negative correlation between plasma ANF and urinary DA was found only in the patients groups. In conclusion, plasma ANF was increased in pheochromocytoma and neuroblastoma patients. Our data suggest that the excessive catecholamine secretion is not responsible for the increased ANF secretion in these patients. The significance of the relationships among plasma ANF and urinary and plasma catecholamines requires further investigation.

Topics: Abdominal Neoplasms; Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Atrial Natriuretic Factor; Biomarkers, Tumor; Blood Pressure; Catecholamines; Child; Child, Preschool; Female; Humans; Hypertension; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasm Staging; Neuroblastoma; Pheochromocytoma; Urinary Bladder Neoplasms

In hypertension, the relationship between atrial natriuretic peptide (ANP) and vasopressin (AVP) is not yet clear, although their renal actions are effectively autoregulation. To examine the possible interaction further, the responses to ANP infusion (75 ng x min (-1), i.v.) have been investigated in both hypertensive and normotensive AVP-replete (HT and NT) and AVP-deficient (HTDI and NTDI) rats. This study aimed to assess the renal function and the plasma hormone concentrations of AVP, angiotensin II (AII), ANP, aldosterone, and corticosterone in the conscious, chronically catheterized, fluid-balanced rats, and to examine the cardiovascular, renal, and endocrine responses to a constant infusion of a low-dose ANP. Data gained from the present study showed, for the first time, the hormone profile, plasma electrolyte composition, and detailed renal function of the servo-controlled, fluid-balanced rats. The similarities of plasma electrolyte composition between servo-controlled and untreated rats indicated that the servo-controlled fluid replacement technique maintained the differences between the strains and maintained body fluid balance during the experimental periods. Following ANP administration, there were no changes in glomerular filtration rate (GFR) in all groups, but an enduring diuresis and natriuresis were observed in HT and NT, which were milder in HTDI rats. However, the hypotensive effect of ANP was of a similar magnitude in all rat strains. HTDI rats exhibited an inhibition of the renin-angiotensin system (RAS), which may have participated in the reduced mean arterial blood pressure (MAP) and natriuresis observed in these rats. The renal actions of ANP appear to rely upon renal tubular events, as indicated by increased fractional electrolyte excretions in the AVP-replete rats. This study highlights the importance of AVP to the profile of the renal actions of ANP in normal rats.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Hypertension; Kidney; Male; Rats; Water-Electrolyte Balance

Mice lacking the gene (Npr1) encoding the natriuretic peptide receptor A (NPRA) have hypertension with elevated blood pressure and cardiac hypertrophy. In particular, Npr1 gene-deficient male mice exhibit lethal vascular events similar to those seen in untreated human hypertensive patients. Serum testosterone levels tend to be lower in hypertensive male humans than in normal males without hypertension, but the genetic basis for this tendency remains unknown. To determine whether Npr1 gene function affects the testosterone level, we measured serum testosterone in male hypertensive mice lacking a functional Npr1 gene, wild-type animals with two copies, and the gene-duplicated littermates expressing four copies of the gene. In the Npr1 gene-knockout (zero-copy) mice, the serum testosterone level was 62% lower than that in the two-copy control mice (80+/-10 ts. 120+/-14 ng/ml, respectively; P < 0.005). Serum testosterone in the four-copy mice was 144% (P < 0.005) of that in the two-copy wild-type control mice. To investigate the role of NPRA in testicular steroidogenesis, we analyzed atrial natriuretic peptide (ANP)-dependent guanylyl cyclase activation, accumulation of intracellular cGMP, and testosterone production in purified primary Leydig cells from animals with zero, two, or four copies of the Npr1 gene. Leydig cells lacking the Npr1 gene did not show ANP-stimulated guanylyl cyclase activation or cGMP accumulation and had no ANP-dependent testosterone production. ANP stimulation of Leydig cells from the four-copy males elicited a 2-fold greater production of cGMP compared to that in the two-copy wild-type counterparts (260+/-12 vs. 126+/-7 pmol/l x 10(6) cells; P < 0.001). Similarly, ANP-dependent testosterone production in Leydig cells was nearly twice as high in four-copy mice as in two-copy wild-type controls (561+/-18 vs. 325+/-11 ng/l x 10(6) cells; P < 0.001). ANP-dependent guanylyl cyclase activation and production of cGMP in Leydig cells increased progressively with the number of Npr1 gene copies. Our results establish the existence of an alternate mechanism for testicular steroidogenesis that is stimulated by NPRA-dependent cGMP signaling, in addition to that mediated by gonadotropins, via a cAMP pathway. These findings demonstrate the role of Npr1 gene function in the maintenance of serum testosterone levels and testicular steroidogenesis and provide a genetic link between hypertension associated with decreased NPRA and low testosterone levels

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Enzyme Activation; Guanylate Cyclase; Hypertension; Leydig Cells; Luteinizing Hormone; Male; Mice; Mice, Knockout; Mice, Mutant Strains; Receptors, Atrial Natriuretic Factor; Testosterone

The present study was aimed at investigating the regulation of atrial natriuretic peptide (ANP) system in association with either enhanced or attenuated activity of the renin-angiotensin system (RAS). The cardiac tissue mRNA and peptide levels of ANP were measured in rats with two-kidney, one clip (2K1C) or deoxycorticosterone acetate (DOCA)-salt hypertension. Plasma renin concentration was increased in 2K1C hypertension along with increases of renin mRNA and protein contents in the clipped kidney. On the contrary, it was suppressed in DOCA-salt hypertension along with decreases of renin mRNA and protein contents in the remaining kidney. The plasma ANP concentration was similarly increased in both models of hypertension. The cardiac tissue ANP contents were not significantly changed, but the tissue ANP mRNA levels were upregulated in the hypertrophied heart in these two models of hypertension. It is suggested that the cardiac ANP system is transcriptionally enhanced by cardiac hypertrophy associated with hypertension, independent of the systemic RAS.

Topics: Animals; Atrial Natriuretic Factor; Desoxycorticosterone; Gene Expression Regulation; Hypertension; Male; Myocardium; Organ Size; Peptides; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger

In this report, reporter gene beta-galactosidase (LacZ) was chosen to compare two different intramuscular gene transfer methods, direct injection and gene suture. Evidence showed that gene suture can produce a higher foreign gene express efficiency in skeletal muscle compared with the direct injection method. The highly efficient eukaryotic expressing vectors of human atrial natriuretic factor (ANF) were constructed (pcD2/pAdVAntage/hANF and pcDNA3/hANF), and in vivo ANF gene delivery was performed by intramuscular gene suture. The effects of ANF gene transfer on blood pressure and renal sodium and water excretion were studied in three models of hypertensive animals. Results showed that a marked decrease of mean arterial pressure (MAP) and a significant increase of urine volume and urinary sodium excretion was produced in rats receiving the hANF construct due to the local expression of ANF and its secretion into plasma. Taken together, these results indicate that gene suture may represent a novel gene delivery modality in gene therapy.

Topics: Animals; Atrial Natriuretic Factor; beta-Galactosidase; Blood Pressure; DNA; Gene Expression; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Immunohistochemistry; Injections, Intramuscular; Lac Operon; Male; Muscle, Skeletal; Plasmids; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Sodium

The activation of B(2) receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure.. To test whether the absence of bradykinin B(2) receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B(2) receptor gene knockout (B(2)(-/-)), heterozygous (B(2)(+/-)), and wild-type (B(2)(+/+)) mice. The BP of B(2)(-/-) mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136+/-3 versus 109+/-1 mm Hg in B(2)(+/+), P<0.01). In B(2)(+/-) mice, BP elevation was delayed. At 40 days, the heart rate was higher (P<0.01) in B(2)(-/-) and B(2)(+/-) than in B(2)(+/+) mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B(2)(-/-) and B(2)(+/-) mice was accelerated, leading at 360 days to a LV weight-to-body weight ratio that was 9% and 17% higher, respectively, than that of B(2)(+/+) mice. In B(2)(-/-) mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B(2)(+/+) mice), an elevation in LV end-diastolic pressure (25+/-3 versus 5+/-1 mm Hg in B(2)(+/+) mice, P<0.01), and reparative fibrosis.. The disruption of the bradykinin B(2) receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Disease Models, Animal; Endothelin-1; Fibrosis; Gene Expression; Heart Rate; Heterozygote; Homozygote; Hypertension; Hypertrophy, Left Ventricular; Kallikrein-Kinin System; Male; Mice; Mice, Knockout; Myocardium; Phenotype; Receptor, Bradykinin B2; Receptors, Bradykinin; RNA, Messenger; Sarcomeres

Topics: Atrial Natriuretic Factor; Diet, Reducing; Humans; Hypertension; Obesity

To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression.. Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared.. Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments.. Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.

Topics: Adrenomedullin; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Enalapril; Gene Expression; Heart; Hypertension; Losartan; Male; Natriuretic Peptide, Brain; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Reference Values

To determine how the downregulation of atrial natriuretic peptide (ANP) gene expression, previously demonstrated to occur only in the brain of the stroke-prone spontaneously hypertensive rat (SHRsp), in contrast to the stroke-resistant SHR (SHRsr), co-segregates with stroke occurrence in SHRsp/SHRsr F2 descendants in order to study the 'protective' role towards stroke previously demonstrated in SHRsp for the quantitative trait locus STR2 that also carries the ANP gene.. Eight male SHRsp, eight male SHRsr and 16 male SHRsp/SHRsr F2-intercross animals (progeny of brother/sister mated F1 hybrids from an original cross between F0 SHRsp and SHRsr) were selected for this study. All rats were exposed to a stroke-permissive Japanese-style diet starting at the age of 6 weeks. Half of the F2 animals had early strokes; the remainder had late strokes. Blood pressure was measured before sacrifice. Analysis of brain ANP expression using an RNase protection assay was performed in all animals.. Downregulation of brain ANP in the stroke-prone phenotype was found to co-segregate with the occurrence of early strokes in the F2 rats independently of blood pressure levels.. The observed lower expression of ANP in the brains of stroke-prone rats appears to be the result of an inhibitory effect by another gene or genes. It seems unlikely that this specific trait represents a primary protective mechanism.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Genetic Predisposition to Disease; Hypertension; Male; Phenotype; Rats; Rats, Inbred SHR; RNA, Messenger; Stroke; Time Factors

We studied the role of angiotensin II in pressure overload-induced B-type natriuretic peptide (BNP) gene expression by using a double transgenic rat (dTGR) model, in which transgenic rats for the human angiotensinogen and renin genes are crossed. Pressure overload produced by [Arg8]-vasopressin (AVP) infusion (i.v., 0.05 microg/kg/min for 2 h) in conscious, chronically instrumented rats, resulted in a significantly greater increase in BNP mRNA levels in the left atrium of the dTGR rats than in Sprague-Dawley (SD) control rats (3.6- vs 1.6-fold, p < 0.05), while in the left ventricle there was no significant difference between the strains. In dTGR rats, the early activation of the BNP gene expression was associated with a decrease in immunoreactive BNP levels in the atrium (27.5%, p < 0.05), but not in the ventricle. In SD rats, ir-BNP levels did not change significantly in either atria or ventricles in response to AVP infusion. These results show that the pressure overload-induced activation of BNP gene expression differs between atrial and ventricular myocytes in the dTGR model of experimental hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Gene Expression; Heart Atria; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Ultrafiltration during haemodialysis (HD) may be the cause of blood pressure (BP) decline due to reduction of blood volume. In some patients, however, BP does not decrease or even rises during HD. The aim of the study was to answer the question: do uraemic hypertensive patients, showing a decline of mean blood pressure (MAP) during HD session (group A) differ from those showing a stable MAP during HD session (group B) with respect to hormonal profile of aldosterone (ALD), vasopressin (AVP), atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2), blood nitric oxide (NO) and plasma renin activity (PRA). A total of 39 haemodialysed, hypertensive patients (17 female, 22 men) were studied. 24 patients (group A) showed a MAP decline of 10 mm Hg or more, while 15 patients (group B) showed MAP changes of less than +/- 10 mm Hg during HD session. PRA, ALD, AVP, ANP, ET-1,2, NO concentration were assessed in blood samples withdrawn from the arterial blood line before HD and after 60, 120, 180 and 240 minutes of HD session. Plasma ET-1,2 and blood NO concentration were also assessed after 30 minutes of HD. BV was continuously monitored with a Crit-Line equipment, BP was measured before and every 30 minutes on HD. Before HD session both examined groups showed similar baseline plasma levels of ALD, AVP, ANP, ET-1,2, NO, PRA and MAP. A 4-hours HD induced a significant increase in plasma ALD and AVP concentrations and a significant decline in ANP level in both groups of patients. In group A, PRA and blood NO concentration increased significantly, while plasma ET-1,2, level did not change during HD. In group B, no significant changes in PRA and blood NO level were noticed, while plasma ET-1,2 rose markedly. In addition in group B, a significant positive correlation was found between MAP and plasma ET-1,2 level changes, but a significant negative correlation between MAP and blood NO level changes.. Patients with a decline of MAP over 10 mm Hg during HD differ from those with a stable MAP by a different response of plasma ET and blood NO to HD induced volume changes.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Volume; Female; Humans; Hypertension; Male; Nitric Oxide; Renal Dialysis; Severity of Illness Index; Uremia; Vasopressins

Treatment with a beta-adrenergic blocker (beta-blocker) in hypertension is associated with increased plasma atrial natriuretic peptide (ANP) levels despite a decrease in cardiac overload. The mechanism and pathophysiological significance of the phenomenon remain unclear. To clarify the role of the ANP system in the antihypertensive effects of the beta-blocker, we investigated the effects of carvedilol (30 mg/kg x day, orally, for 4 weeks) on the ANP system in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). Plasma ANP levels showed a significant increase despite a significant decrease in blood pressure and heart rate in the carvedilol group. Although ANP messenger RNA levels in the heart did not change, messenger RNA levels of the natriuretic peptide-C (NP-C) receptor as a clearance receptor showed a significant decrease in both the aorta and lung in the carvedilol group. NP-C receptor densities were also significantly decreased in the lung in this group. The biological half-life of exogenous ANP in circulating blood was prolonged in the carvedilol group compared with that in the control group. Administration of the ANP receptor antagonist, HS-142-1, resulted in a greater increase in systolic blood pressure in the carvedilol group than in the control group. In addition, both basal and ANP-stimulated cGMP contents in the aorta were significantly higher in the carvedilol group. These results suggest that carvedilol potentiates the hypotensive action of ANP by increasing plasma ANP levels and enhancing the vascular response to ANP. These effects were closely related to the down-regulation of the NP-C receptor. The newly found mechanism seems to account for a sizable portion of the antihypertensive effects of carvedilol and could be of potential importance in the treatment of cardiovascular disease with beta-blockers.

Topics: Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Carbazoles; Carvedilol; Cyclic GMP; Hypertension; Male; Propanolamines; Rats; Rats, Inbred SHR; Receptors, Atrial Natriuretic Factor; RNA, Messenger

The purpose of this study was to investigate whether the basal activity of the renin-angiotensin-aldosterone system or the basal levels of the atrial natriuretic peptide (ANP) are related to distinct patterns of left ventricular (LV) geometry in patients with essential hypertension. The left ventricle of patients with arterial hypertension may be exposed to a variety of growth-regulating mechanisms, including pressure overload and humoral activation. The interaction of such growth stimuli may be involved in the modulation of LV geometry. LV geometry was determined echocardiographically in 104 patients with mild to moderate essential hypertension. The same number of age- and sex-matched normotensive subjects served as controls. Plasma renin activity (PRA) and serum concentrations of aldosterone and ANP were measured by radioimmunoassay. Correlation analyses revealed that PRA was significantly associated with septal wall thickness and LV mass index (r = 0.25; p < 0.005 each). In addition, as compared with normal subjects (1.0 +/- 0.7 ng/ml/hr), PRA was significantly increased in patients with concentric LV hypertrophy (LVH) (3.4 +/- 6.6 ng/ml/hr, p < 0.01). Aldosterone displayed a close correlation with septal, posterior, and relative wall thickness (r > 0.27, p < 0.005 each). Compared with normal subjects (74 +/- 27 pg/ml), patients with hypertension and pathologic patterns of LV geometry were characterized by elevations of aldosterone (LV remodeling 203 +/- 93 pg/ml, concentric LVH 123 +/- 67 pg/ml; eccentric LVH 199 +/- 89 pg/ml; p < 0.05 each). ANP was significantly associated with septal wall thickness, left ventricular dimension, and LV mass index (r > 0.22, p < 0.005 each). Furthermore, compared with normal subjects (50 +/- 17 pg/ml), ANP values were significantly increased in patients with hypertension and concentric LVH (80 +/- 44 pg/ml, p < 0.005) and eccentric LVH (88 +/- 24 pg/ml, p < 0.001). Multivariate analysis adjusting for systolic blood pressure, body mass index, and age revealed that renin and ANP were independently associated with LV mass index (p < 0.05 each). Interestingly, adjusted PRA levels were not related to any specific pattern of LV geometry. In contrast, adjusted ANP levels were associated with concentric and eccentric LVH, whereas adjusted aldosterone levels were significantly elevated in subjects with LV remodeling and eccentric LVH (p < 0.005). Thus elevated levels of renin and ANP may be found in patients with hypertension

Topics: Aldosterone; Atrial Natriuretic Factor; Case-Control Studies; Echocardiography, Doppler; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Multivariate Analysis; Renin; Renin-Angiotensin System

Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP +/- SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 +/- 3; LS, 110 +/- 5). However, on HS diet -/- mice had significantly higher ABP (135 +/- 3; P < 0.001) than both -/- (115 +/- 2) and +/+ (110 +/- 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I.ml-1.h-1) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 +/- 1.9; LS, 21 +/- 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 +/- 2.9; LS, 19 +/- 3.7). Independent of genotype, concentration of endothelin-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 micrograms protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 +/- 4.7 and +/+, 32 +/- 4.1; ecNOS -/-, 160 +/- 19 and +/+, 156 +/- 19) compared with mice fed on LS diet (ET-1 -/-, 19 +/- 1.9 and +/+, 21 +/- 1.8; ecNOS -/-, 109 +/- 13 and +/+, 112 +/- 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting the pressor effect of salt.

Topics: Analysis of Variance; Angiotensin I; Animals; Atrial Natriuretic Factor; Blood Pressure; Diet, Sodium-Restricted; Endothelin-1; Exons; Female; Heterozygote; Homozygote; Hypertension; Kidney; Male; Mice; Mice, Knockout; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Protein Precursors; Renin; Sodium, Dietary

The purpose of this study was to investigate whether atrial and brain natriuretic peptides (ANP and BNP, respectively) represent autocrine/paracrine factors and are accumulated in pericardial fluid.. ANP and BNP, systemic hormones produced by the heart, have elevated circulating levels in patients with heart failure. Recent evidence suggests that the heart itself is one of the target organs for these peptides.. With an immunoreactive radiometric assay, we measured the concentrations of these peptides in plasma and pericardial fluid simultaneously in 28 patients during coronary artery bypass graft surgery.. The pericardial levels of BNP were markedly elevated in patients with impaired left ventricular function. We investigated the correlation of ANP and BNP levels in plasma or pericardial fluid with left ventricular hemodynamic variables. None of the hemodynamic variables correlated with ANP levels in plasma or pericardial fluid. Both plasma and pericardial fluid levels of BNP were significantly related to left ventricular end-diastolic and systolic volume indexes (LVEDVI and LVESVI, respectively). In addition, BNP pericardial fluid levels had closer relations with LVEDVI (r = 0.679, p < 0.0001) and LVESVI (r = 0.686, p < 0.0001) than did BNP plasma levels (LVEDVI: r = 0.567, p = 0.0017; LVESVI: r = 0.607, p = 0.0010). BNP levels in pericardial fluid but not in plasma correlated with left ventricular end-diastolic pressure (r = 0.495, p = 0.0074).. BNP levels in pericardial fluid served as more sensitive and accurate indicators of left ventricular dysfunction than did BNP levels in plasma. Thus, BNP may be secreted from the heart into the pericardial space in response to left ventricular dysfunction, and it may have a pathophysiologic role in heart failure as an autocrine/paracrine factor.

Topics: Aged; Atrial Natriuretic Factor; Autocrine Communication; Biomarkers; Cardiac Output, Low; Cardiac Volume; Coronary Artery Bypass; Coronary Disease; Diastole; Female; Hemodynamics; Humans; Hypertension; Male; Mitral Valve Insufficiency; Myocardial Ischemia; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Paracrine Communication; Pericardial Effusion; Radioimmunoassay; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

Transgenic mice with a dysfunctional guanylyl cyclase A gene (GCA -/-) are unable to transduce the signals from atrial naturetic peptide and develop hypertension and cardiac hypertrophy. Magnetic resonance imaging (MRI) was performed to assess cardiac hypertrophy in these animals, using wild-type siblings as controls. Anesthetized mice were studied by gated multislice, multiphase cine MRI at 1.5 T. Simpson's rule was used to estimate left ventricle (LV) mass and volumes from short-axis images. Correlation between LV mass evaluated by MRI and at necropsy was excellent, with LVnecropsy = 1.04 x LVMRI + 4.69 mg (r2 = 0.95). By MRI, GCA -/- LV mass was significantly different when compared with isogenic controls [GCA -/-, 226 +/- 43 mg (n = 14) vs. controls, 156 +/- 14 mg (n = 10); P < 0.0001]. LV volumes and ejection fraction in the two groups were not significantly different. MRI provides an accurate means for the noninvasive assessment of murine cardiac phenotype and may be useful in following the effects of genetic modification.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Disease Models, Animal; Guanylate Cyclase; Heart Ventricles; Hypertension; Magnetic Resonance Imaging; Mice; Mice, Transgenic; Mutation; Signal Transduction

Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.

Topics: Adenylyl Cyclases; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; GTP-Binding Proteins; Heart; Hypertension; Myocardium; Neuropeptide Y; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Adrenergic, beta; Signal Transduction

We have previously shown that a locus on rat chromosome 5, termed STR 2, co-localizes with the genes encoding atrial natriuretic and brain natriuretic peptides, and is closely linked to the development of strokes in rats of a F2 hybrid cohort obtained by crossing stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats. We also demonstrated that there are significant differences in vascular functioning that are co-segregated with stroke latency of stroke-prone spontaneously hypertensive rats.. To investigate the vascular responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats.. In view of the important vasoactive properties of natriuretic peptides, we tested the vascular responses to 10(-11)-10(-9) mol/l atrial natriuretic peptide and to 10(-11)-10(-7) mol/l brain natriuretic peptide in isolated rings of aortas and internal carotid arteries obtained from stroke-prone and stroke-resistant spontaneously hypertensive rats. The 6-week-old rats were exposed for 4 weeks either to their regular diet (n = 15 of both strains) or to the stroke-permissive Japanese-style diet (n = 14 of both strains). A group of 14 normotensive, age-matched and sex-matched Wistar-Kyoto rats was also studied.. Systolic blood pressures in stroke-prone and stroke-resistant spontaneously hypertensive rats were similar, and were significantly higher than those in Wistar-Kyoto rats. Vascular responses to nitroglycerin, atrial natriuretic peptide, and brain natriuretic peptide in rats of the two hypertensive strains and in Wistar-Kyoto rats fed their regular diet were comparable. In contrast, the vasorelaxant responses to atrial natriuretic peptide in stroke-prone spontaneously hypertensive rats fed Japanese diet were lower both in aortas and in internal carotid arteries than were those in spontaneously hypertensive rats (both P < 0.05 by analysis of variance) and in Wistar-Kyoto rats (both P < 0.05). Similarly, vasorelaxant responses to brain natriuretic peptide were lower both in aortas and in internal carotid arteries of stroke-prone spontaneously hypertensive rats than they were in spontaneously hypertensive rats (both P < 0.05) and in Wistar-Kyoto rats (P < 0.05). The responses to nitroglycerin in the stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats fed Japanese-style diet were also similar.. The vasorelaxant effects of natriuretic peptides are impaired in stroke-prone spontaneously hypertensive rats. This abnormality could play a role in the pathogenesis of stroke incidence in this hypertensive model.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Carotid Artery, Internal; Cerebrovascular Disorders; Cyclic GMP; Hypertension; In Vitro Techniques; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Nitroglycerin; Phenotype; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation

It has been shown in animal experiments that angiotensin II and aldosterone have mitogenic effects on the cardiovascular system, whereas atrial natriuretic peptide has antimitogenic properties. The aim of the present study was to relate plasma renin activity, angiotensin II, aldosterone and atrial natriuretic peptide to left ventricular structure and function, assessed by use of imaging echocardiography and transmitral Doppler velocimetry in 73 patients with essential hypertension, World Health Organization stages I-II, aged 43 +/- 10 (s.d.) years. Left ventricular mass, wall thickness and internal diameter were not independently related to the biochemical variables, except for a weak and positive association of wall thickness with plasma aldosterone (P = 0.06). However, left ventricular early inflow peak velocity and deceleration were independently and inversely related to age (P < 0.001) and to plasma aldosterone (P < 0.01), and positively to plasma atrial natriuretic peptide (P < 0.05). Peak flow velocity during atrial contraction was positively related to plasma atrial natriuretic peptide both before (P < 0.001) and after (P < 0.05) controlling for significant covariates (age, sex and blood pressure). We conclude that circulating renin, angiotensin II, aldosterone and atrial natriuretic peptide are not independently related to left ventricular mass in essential hypertension. The inverse association of plasma aldosterone with indices of diastolic function is compatible with a stimulating effect of aldosterone on myocardial fibrosis, which is opposed by atrial natriuretic peptide. The apparently conflicting positive association of this peptide with atrial peak velocity is most likely due to stimulation of its secretion by atrial involvement.

Topics: Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Coronary Circulation; Diastole; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged; Ventricular Function, Left

Treatment of spontaneously hypertensive rats (SHR) with captopril (100 mg . kg-1 . day-1) throughout development and during the first 16 wk of life leads to a reduction in blood pressure and left ventricular hypertrophy. Blood pressures and hypertrophy are reduced in these animals (vs. untreated SHR) for up to 24 wk after discontinuation of the drug. We used conventional blot hybridization and Western analysis to examine hypertrophy-dependent gene expression during this period. Ventricular expression of the atrial natriuretic peptide gene was reduced by >90% at 16 wk of age in the captopril-treated SHR. Expression increased in the 24 wk after discontinuation of treatment, but remained well below that of the untreated SHR. A similar reduction in ventricular c-myc gene expression was seen with captopril treatment. Neither renal expression of the atrial natriuretic peptide gene nor ventricular expression of the c-fos gene was affected by captopril. This study demonstrates that captopril treatment during a critical period of development in the SHR leads to a sustained reduction in hypertrophy-dependent myocardial gene expression, which does not revert to levels seen in the untreated SHR after discontinuation of the drug.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Captopril; Cardiomegaly; Gene Expression; Genes, fos; Genes, myc; Heart; Hypertension; Kidney; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Ventricular Function

The nature of all of the peptides critical to the mechanism(s) of the antihypertensive action of neutral endopeptidase (NEP) inhibitors is still unclear, but bradykinin is thought to be one such peptide. This study was designed to assess the effectiveness of an NEP inhibitor in deoxycorticosterone acetate (DOCA)-salt treated kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. Oral administration of BP102 (10-100 mg/kg), an NEP inhibitor, increased urine volume and urinary sodium excretion in a dose-dependent manner in anesthetized Sprague-Dawley rats. DOCA-salt hypertension was induced in both BN-Ka and Brown Norway Kitasato (BN-Ki) rats after left nephrectomy. The development of DOCA-salt hypertension in normal BN-Ki rats was prevented, and that in BN-Ka rats was also significantly reduced, by an 8-day administration of BP102. When BP102 was administered for 5 weeks, the high blood pressure of DOCA-salt treated BN-Ka rats was markedly lowered, and their heart weights were reduced. These results suggest that kinins play no role in the antihypertensive effect of this inhibitor and that other factors may be involved in this effect.

Topics: Administration, Oral; Animals; Atrial Natriuretic Factor; Desoxycorticosterone; Drug Administration Schedule; Enzyme Inhibitors; Heart; Hypertension; Kidney; Kininogens; Kinins; Male; Neprilysin; Organ Size; Prodrugs; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Sodium Chloride; Thiorphan; Time Factors

Plasma renin concentrations are an important factor in cardiovascular risk profiling.. To investigate the effects of sex, medication, and anthropometric factors that may contribute to the interindividual variation in the plasma concentrations of renin and its precursor prorenin.. Prorenin and renin levels in 327 men and 383 women, aged 52-69 years, who participated in a 1994 reexamination of a previous population survey in Bavaria, were measured by immunoradiometric assay.. Prorenin and renin levels in men were significantly higher than those in women, those in women without estrogen replacement therapy were significantly higher than those in women with estrogen replacement therapy, and those in diabetics were significantly higher than those in nondiabetics. Prorenin level was correlated negatively to blood pressure and positively to age and the use of diuretics; it was normal in subjects using angiotensin converting enzyme inhibitors and beta-adrenergic antagonists (beta-blockers). Renin level was correlated negatively to atrial natriuretic peptide level and the use of beta-blockers, and it was elevated above normal levels in subjects using angiotensin converting enzyme inhibitors and diuretics as well as in subjects who had previously suffered myocardial infarction. After exclusion of data for women being administered estrogen replacement therapy, multivariate analysis revealed that sex (P<0.001), age (P<0.02), blood pressure (P<0.002), diabetes (P<0.05), and the use of angiotensin converting enzyme inhibitors (P<0.002), beta-blockers (P<0.001), and diuretics (P<0.05) were independent determinants of plasma prorenin. Plasma renin was independently related to atrial natriuretic peptide level (P<0.01) and the use of angiotensin converting enzyme inhibitors (P<0.001), beta-blockers (P<0.001), and diuretics (P<0.05).. These data demonstrate that there is a sexual dimorphism of prorenin levels in humans, suggesting that sex hormones affect the regulation of the renin gene. Data confirm previous reports of elevated prorenin levels in diabetics and older subjects, as well as of lower than normal prorenin levels in subjects with hypertension in smaller populations. Our findings may help to clarify the potential (patho)physiologic functions of prorenin and to identify the factors that influence the constitutive secretion and intracellular processing of this prohormone.

Topics: Age Factors; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cross-Sectional Studies; Diabetes Mellitus; Enzyme Precursors; Estrogen Replacement Therapy; Female; Follow-Up Studies; Germany; Humans; Hypertension; Immunoradiometric Assay; Male; Middle Aged; Myocardial Infarction; Postmenopause; Prevalence; Random Allocation; Renin; Renin-Angiotensin System; Retrospective Studies; Sex Characteristics

To investigate potential therapeutic effects of atrial natriuretic peptide (ANP) gene delivery on renal and cardiac disorders, adenovirus harboring the human ANP gene (Ad.RSV-cANP) was delivered into Dahl salt-sensitive (DSS) rats on a high-salt diet. A single intravenous injection of the ANP gene caused a significant delay of blood pressure increase 3 days post-injection and the effect lasted for more than 5 weeks. A maximal blood pressure reduction of 32.8 mmHg was observed after ANP gene delivery, as compared with that of control rats injected with Ad.CMV-LacZ. Immunoreactive human ANP can be detected in the heart, lung, and kidney of rats after gene delivery. ANP gene delivery caused significant increases in renal blood flow, glomerular filtration rate, sodium output, urine excretion, and urinary cGMP levels. These beneficial effects were reflected morphologically by a reduction in cardiomyocyte size, attenuation of the glomerular-sclerotic lesions, tubular injury and arterial thickening. This study demonstrated the usefulness of somatic gene transfer as a new tool for ANP gene delivery in studying salt-related hypertension and renal and cardiovascular diseases. In addition, the findings also suggest that ANP gene delivery may have potential in therapeutic applications.

Topics: Adenoviridae; Animals; Atrial Natriuretic Factor; Cardiomegaly; Genetic Therapy; Genetic Vectors; Glomerular Filtration Rate; Hypertension; Kidney; Male; Rats; Rats, Inbred Strains; Regional Blood Flow; Sodium, Dietary

Beta-adrenoceptor antagonists are known to increase plasma atrial natriuretic peptide (ANP) levels despite their hypotensive action. The aim of the present study was to examine the role of the ANP system in the antihypertensive effects of a beta-adrenoceptor antagonist. We investigated the effects of propranolol (75 mg kg(-1) day(-1), p.o., 4 weeks) on the ANP system in stroke-prone spontaneously hypertensive rats. Plasma ANP levels were significantly higher in the propranolol group than in the control group. Both receptor densities and mRNA levels of ANP(C) receptor were significantly decreased in the lung as the major site of ANP clearance from the circulation. In contrast, both central venous pressure and ANP mRNA levels in the heart were not significantly different between the two groups. Under both basal and ANP-stimulated conditions, the cGMP content in the aorta was significantly greater in the propranolol group than in the control group, whereas the basal and stimulated cGMP content of the kidney was similar in the two groups. Inhibition of endogenous ANP action by a specific ANP receptor antagonist, HS-142-1, produced a greater increase of blood pressure in the propranolol group than in the control group. These results suggest potentiation of natriuretic peptide activity as a new antihypertensive mechanism of the beta-adrenoceptor antagonist propranolol.

Topics: Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Hypertension; Kidney; Lung; Male; Polysaccharides; Propranolol; Rats; Rats, Inbred SHR; Receptors, Atrial Natriuretic Factor; RNA, Messenger

This study has examined the association between circulating atrial natriuretic peptide (ANP), plasma cyclic GMP and urinary cyclic GMP in relation to hypertension and reduced renal function in 30 normotensives, in 30 patients with essential hypertension and in 22 patients with stable dialysis-independent chronic renal failure (CRF). Plasma ANP was significantly raised (about two-three-fold) in the CRF group compared with the hypertensive and normal groups; plasma cyclic GMP was also significantly raised in the CRF group (median group values: 4.6, 5.8 and 11.0 pmol/ml, respectively, for the normal, hypertensive and CRF groups). There were no significant differences in urinary cyclic GMP between the normotensives and hypertensives but urinary cyclic GMP was significantly reduced in the patients with CRF (median group values: 407.1, 450.9 and 247.8 pmol/min for the normal, hypertensive and CRF groups, respectively, P < 0.001). In the subjects with CRF, the clearance of cyclic GMP was reduced in proportion to the clearance of creatinine, but there was no significant difference in the fractional excretion of cyclic GMP (median group values: 78.1% in the normal group, 78.9% in the hypertensive group and 70.2% in the CRF group). In all groups, there was no association between circulating ANP and urinary cyclic GMP: By contrast, there was a positive association between plasma ANP and plasma cyclic GMP (r = 0.39 P < 0.001) that was independent of blood pressure or renal function. These results demonstrate that while a substantial amount of urinary cyclic GMP originates from the glomerular filtrate, to some extent, raised plasma ANP also contributes to the circulating levels of cyclic GMP. However, plasma cyclic GMP cannot be taken as a direct substitute for plasma ANP.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged

The increase in natriuretic peptides (NP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP) production and release by cardiocytes that occurs in hypertension has been considered to be a compensatory mechanism against ventricular overload. Studies on NP production in the spontaneously hypertensive rat (SHR), an experimental model of human hypertension, have produced controversial results and were carried out when hypertension was already established (> 17 weeks). At this time, age-related physiologic and molecular changes in cardiac muscle are difficult to separate from those related to hypertension, ie, increased ANF production and plasma levels. In addition, most of the studies used male rats because the rate of increase in arterial blood pressure--as well as the level to which it rises--is greater in males than in females. Studies of a similar nature using female SHR are not available. The aim of this work was to determine 1) whether ANF and BNP production and secretion increase with the development of hypertension in genetically hypertensive rats; 2) whether a sexual dimorphism in ANF and BNP production and secretion is present in the genetically hypertensive rat during the development of hypertension; and 3) whether the demand for ANF and BNP is the same from each chamber of the heart under these experimental conditions. Age-matched male and female SHR, Wistar-Kyoto (WKY), and Sprague Dawley (SD) rats at 2, 4, and 8 weeks of age were used. The normotensive SD were included to provide a wider basis for baseline findings, as WKY rats are not always a suitable control for SHR due to genetic variations. Natriuretic peptide plasma levels and tissue content were measured by radioimmunoassay. ANF, BNP, as well as alpha- and beta-myosin heavy chain (MHC) mRNA were estimated by Northern blot analysis. Blood pressure (BP) of more than 150 mm Hg was found only in 8-week-old male SHR. Plasma immunoreactive (ir)ANF and irBNP increased significantly at puberty (8 weeks) in both male and female SHR. The earliest molecular change encountered during the development of hypertension was a significant increase in BNP mRNA in the right and left atria from both male and female 8-week-old SHR. In the ventricles from both male and female SHR, there was no increase in the ratio of left ventricular wet weight/body weight, no increase in ventricular ANF mRNA transcripts, and no myosin heavy chain isoform switch (a protein marker of hypertrophy). irBNP ventri

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Gene Expression; Heart Ventricles; Hypertension; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Sex Factors

In previous studies we demonstrated that in normotensive rats, but not in spontaneously hypertensive rats (SHR), atrial natriuretic peptide (ANP) enhances bradycardic reflexes through an action on cardiac vagal afferent pathways. The present study aimed to determine whether cardiac hypertrophy, hypertension, or a nonreversible genetic factor accounted for the insensitivity of SHR to ANP action on cardiac reflex pathways. SHR were treated with the angiotensin-converting enzyme (ACE) inhibitor perindopril (3 mg/kg per day) for 6 weeks from 4 to 9 weeks of age (SHR-S, n=10) or for 9 weeks from 4 to 12 weeks of age (SHR-L, n=10) or were untreated (SHR, n=10) to produce differential effects on blood pressure and left ventricle/body weight ratio (LV/BW). Untreated normotensive Wistar-Kyoto rats (WKY, n=10) were also studied. At 13 weeks of age, all rats were instrumented with aortic and jugular catheters, and at 14 weeks we measured heart rate reflexes to rapid intravenous infusions of methoxamine (100 microg/kg, cardiac baroreflex) and serotonin (5 to 60 microg/kg, von Bezold-Jarisch cardiac chemosensitive reflex), with either alpha-rat ANP (150 ng/kg per minute IV) or saline vehicle (270 microL/h IV) infusion. Perindopril treatment for 6-week (SHR-S) and 9-week (SHR-L) durations maintained blood pressure at normotensive levels in both groups. SHR-S exhibited a small degree of cardiac hypertrophy (LV/BW was 8% higher than in WKY but 11% less than in untreated SHR), but LV/BW was normalized in SHR-L (to within 1% of WKY LV/BW). In WKY, ANP significantly (P<0.05) enhanced bradycardic responses to both the cardiac baroreflex (by 42+/-10%) and von Bezold-Jarisch chemosensitive reflex (by 17+/-5%) activation but had no effect in SHR. The cardiac reflex action of ANP was restored in SHR-L (ANP enhanced reflex bradycardia by 28+/-12% and 36+/-8%, baroreflex and von Bezold-Jarisch reflex, respectively; P<0.05), but SHR-S, which developed some cardiac hypertrophy, remained unresponsive to ANP. Our results suggest that the inability of ANP to sensitize cardiac vagal (nonarterial) afferents in SHR was not due to an inherited irreversible component, or the hypertension per se, but was associated with the presence of cardiac hypertrophy. A functional consequence of hypertension-induced cardiac hypertrophy may be the inhibition of the cardioprotective action of ANP through cardiac vagal reflexes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Bradycardia; Cardiomegaly; Heart Rate; Hypertension; Indoles; Male; Perindopril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Weight Gain

The aim of this study was to investigate the relationships between levels of natriuretic peptides and adrenomedullin and 24 h blood pressure levels in elderly hypertensives.. We performed both 24 h ambulatory blood pressure monitoring and measurement of plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and adrenomedullin in 118 asymptomatic hypertensive elderly (> 60 years old) patients. We classified the subjects into groups with isolated clinic hypertension (n = 40) and sustained hypertension (n = 78). We also measured the levels of these peptides in 37 elderly normotensive subjects.. Plasma ANP and BNP levels were slightly increased in patients with isolated clinic hypertension compared with elderly normotensives. Among the hypertensives, plasma ANP and BNP levels were more closely related to 24 h blood pressure levels than to office blood pressure levels. Sustained hypertensives showed significantly increased plasma levels of ANP and BNP compared with isolated clinic hypertensives, while adrenomedullin levels were similar in the two groups. Elderly hypertensives with left ventricular hypertrophy detected by electrocardiography had significantly higher levels of ANP and BNP, and higher BNP/ANP ratios than those without left ventricular hypertrophy, while there was no significant difference in adrenomedullin levels between the two groups.. Our results suggest that measurements of ANP and BNP may be useful in detecting left ventricular hypertrophy and in differentiating isolated clinic hypertension from sustained hypertension in elderly hypertensive patients.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Circadian Rhythm; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptides

Protein intake-induced natriuresis previously related to increased urinary dopamine excretion was reexamined in an extensive controlled study comparing healthy and hypertensive subjects. In healthy subjects, ingestion of 1 g/kg wt tuna induced natriuresis that was associated, between postprandial hours 1 and 2, with increased plasma tyrosine [191 +/- 13% (mean +/- SE); P < 0.01], 3, 4-dihydroxyphenylalanine (104 +/- 12%, P < 0.05 in plasma; 162 +/- 20%, P < 0.05 in urine), plasma free dopamine (156 +/- 32%; P < 0. 05), and dopamine sulfate (191 +/- 11%, P < 0.001 in plasma; 199 +/- 15%, P < 0.01 in urine) but affected urinary free dopamine excretion only at limits of significance. Hypertensive subjects had less (P < 0.02) natriuresis and, despite comparable plasma tyrosine and dopamine sulfate increases, no increase in plasma and urinary 3, 4-dihydroxyphenylalanine and plasma free dopamine. Their plasma and urinary free epinephrine responses were less (P < 0.05) than the borderline increases in control subjects. Compared with control subjects, they significantly increased plasma 3, 4-dihydroxyphenylalanine sulfate (P < 0.05), epinephrine sulfate (P < 0.05), and the dopamine sulfate-to-free dopamine ratio (P < 0.02). Postprotein natriuresis is thus associated with nutritional priming-induced plasma but not urinary free dopamine increase. Hypertensive subjects have attenuated natriuretic and plasma free dopamine responses and less free epinephrine increase. This may partly result from higher circulating 3,4-dihydroxyphenylalanine, dopamine, and epinephrine sulfoconjugates leaving fewer free amines for biological actions.

Topics: 3,4-Dihydroxyphenylacetic Acid; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Dietary Proteins; Dihydroxyphenylalanine; Dopamine; Epinephrine; Homovanillic Acid; Humans; Hypertension; Middle Aged; Norepinephrine; Postprandial Period; Pulse; Reference Values; Renin; Tyrosine

It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatmen

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Captopril; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Hypertension; Male; Methionine; Neprilysin; Propionates; Rats; Rats, Inbred SHR; Renal Circulation; Renin; Sulfhydryl Compounds

In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure.. Sprague-Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2, Gi alpha-3) and G beta proteins were determined by immunoblotting, whereas the levels of Gi alpha-2 and Gi alpha-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques.. The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Gi alpha-2, Gi alpha-3 and G beta proteins and Gi alpha-2 and Gi alpha-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF4-23 were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gs alpha were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5'-[gamma-thio]triphosphate (GTP gamma S), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DOCA-salt treatment but not in rats treated for 1 or 2 weeks.. These results indicate that the enhanced expression of Gi alpha-2 and Gi alpha-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Angiotensin II; Animals; Aorta; Atrial Natriuretic Factor; Autoradiography; Blotting, Northern; Colforsin; Desoxycorticosterone; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Hypertension; Immunoblotting; Isoproterenol; Peptide Fragments; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcolemma; Sodium Chloride; Time Factors

The aim of this study was to evaluate the long-term effects of the selective beta 1-blocker/beta 2-agonist celiprolol on atrial natriuretic peptide (ANP) levels in patients with moderate essential hypertension. The drug was given orally in a daily dose of 200 mg for 30 days. Plasma ANP levels increased by 187% despite the drop in blood pressure, while left atrial and ventricular diameters remained unchanged. These findings indicate that ANP secretion, which is mediated by beta 1-receptor blockade, is not affected by stimulation of the vasodilatory beta 2-receptors. There is strong evidence suggesting that beta-blockers exert part of their antihypertensive action by increasing ANP secretion.

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Celiprolol; Heart Rate; Humans; Hypertension; Male; Middle Aged

Orthostatic hypotension is a common phenomenon in the elderly. Hormonal changes during orthostatic stress have been described in elderly normotensive people and in those with essential hypertension. However, the hormonal response in elderly people who have systolic hypertension during orthostasis has not yet been quantified.. In this study we investigated 14 non-diabetic men, aged 60 to 75 years, with untreated systolic hypertension who were subjected to 45 degrees passive head-up incline on a tilt table for 15 min. Their hormonal profile and hemodynamic changes were analyzed before and after the stress.. In the supine position, plasma levels of norepinephrine, atrial natriuretic peptide and aldosterone were in the normal range, while the plasma renin activity was low. Immediately upon tilt the systolic blood pressure fell but it reverted to baseline values after 15 min of orthostasis. At that time the cardiac output decreased while the systemic vascular resistance and the plasma norepinephrine concentration rose. The atrial natriuretic peptide appeared to fall, and the renin-aldosterone level did not change.. The physiologic response to orthostatic stress in elderly people with systolic hypertension is comparable to that of elderly normotensive people and those with essential hypertension, i.e. a decrease in cardiac output and an increase in plasma norepinephrine levels. The atrial natriuretic peptide appeared to fall appropriately. The response of the renin-aldosterone system mimicked that in elderly patients with low renin essential isolated hypertension. These observations may have a bearing on the management of elderly people with systolic hypertension who also have orthostatic symptoms; they may not require a different approach from that needed for others of the same age group.

Topics: Aged; Aldosterone; Atrial Natriuretic Factor; Cardiac Output; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Renin-Angiotensin System; Tilt-Table Test; Vascular Resistance

Since the biochemical disturbance underlying hypertension may be an important determinant of patient outcome, we compared the effects of early treatment with different antihypertensive drugs on end-organ damage in the TGR(mREN2)27 transgenic rat (REN-2). In these REN-2 rats, hypertension is primarily caused by increased activity of the tissue renin-angiotensin system.. Seven-week-old REN-2 rats were either untreated or treated orally with an optimal daily dose of carvedilol (30 mg/kg), hydralazine (30 mg/kg), losartan (10 mg/kg) or quinapril (15 mg/kg). Nontransgenic littermates served as normotensive controls. After 11 weeks of treatment, we determined plasma norepinephrine concentrations, left ventricular atrial natriuretic factor messenger RNA and cardiac and vascular function and hypertrophy.. Chronic treatment with carvedilol and hydralazine significantly decreased blood pressure to a similar level but failed to normalize it, whereas both losartan and quinapril completely normalized blood pressure. Despite a blood pressure reduction in all treatment groups, only losartan, quinapril and hydralazine preserved endothelial function, while carvedilol did not. Furthermore, losartan and quinapril prevented cardiac and medial hypertrophy. The expression of atrial natriuretic factor messenger RNA paralleled the hemodynamic changes. Plasma norepinephrine levels were normalized by losartan or quinapril but remained increased after carvedilol and hydralazine treatment.. In REN-2 hypertensive rats, end-organ damage can be prevented by both inhibition of the angiotensin converting enzyme and blockade of the angiotensin II type 1 receptor, but not by merely lowering blood pressure. When blood pressure is not fully normalized, the effects on end-organs are clearly dissociated from the antihypertensive effects.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Carbazoles; Carvedilol; Heart Function Tests; Hydralazine; Hypertension; Isoquinolines; Losartan; Norepinephrine; Propanolamines; Quinapril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tetrahydroisoquinolines

We investigated the relation between atrial natriuretic factor (ANF) gene expression and the status of the renin-angiotensin system (RAS) in aortic tissue in rats made hypertensive by either aortic banding or by deoxycorticosterone acetate (DOCA)-salt administration. These experimental models of hypertension are known to have differences in terms of the status of RAS. ANF messenger RNA (mRNA) levels were measured in aortic tissue by using a newly developed quantitative competitive reverse transcription polymerase chain reaction (QC-RT-PCR) technique. Changes in the proportions of alpha1 and alpha2 isoforms of Na+K+-adenosine triphosphatase (ATPase) mRNA levels were used as indicators of aortic hypertrophy. Treatment with DOCA alone, salt alone, or DOCA-salt for 5 weeks increased aortic-weight/body-weight ratio and aortic angiotensinogen mRNA levels, but did not change alpha1 or alpha2 Na+K+-ATPase mRNA levels. Aortic ANF mRNA levels had a tendency to increase after treatment with DOCA, salt, or DOCA-salt, but this change did not reach statistical significance. Suprarenal aortic banding for 6 weeks or 12 weeks increased aortic-weight/body-weight ratio (12 weeks), decreased alpha2 Na+K+-ATPase and angiotensinogen mRNA levels, but did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Treatment with ramipril, an angiotensin-converting enzyme (ACE) inhibitor was carried out for 6 weeks just after aortic banding (prevention experiment) or after 6 weeks in rats that were banded for the previous 6 weeks (regression experiment). High-dose ramipril (1 mg/kg)--a treatment known to inhibit both tissue and circulating RAS--normalized aortic-weight/body-weight ratio, and also normalized alpha2 Na+K+-ATPase mRNA levels. Aortic angiotensinogen mRNA levels of banded rats treated with high-dose ramipril was higher than those of the normal control, sham operated, and banded rats. Treatment with high-dose ramipril did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Low-dose ramipril (10 microg/kg)--a treatment that selectively inhibits tissue RAS--normalized aortic-weight/body-weight ratio but did not normalize alpha2 Na+K+-ATPase mRNA levels (regression experiment) or angiotensinogen mRNA levels (prevention experiment) and did not change either alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. The results suggest that, in contrast to previous findings in heart and kidney, the regulation of ANF mRNA levels in aortic tissue is largely independent

Topics: Angiotensinogen; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression; Gene Expression Regulation; Hypertension; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium-Potassium-Exchanging ATPase

To investigate the relationship between circadian changes in urinary microalbumin excretion (UAE), blood pressure (BP) and physical activity in patients with essential hypertension.. The subjects were 45 patients with essential hypertension (EH group: 26 male and 19 female, age 56+/-12 years (mean +/- SD)) and 25 patients with diabetes mellitus (DM group: 14 male and 11 female, age 61+/-10 years). Their BP and physical activity (acceleration) were measured at 30-min intervals for 24 h by means of a multi-biomedical recorder (TM2425). Urine samples were collected during each of four 4-h daytime periods and one 8-h night-time period. From these samples, per-h UAE (UAE/h) was measured. Mean values for mean blood pressure (MBP) and acceleration were calculated for corresponding time periods. Plasma hormones were measured during an early morning rest period.. In the EH group, a significant positive correlation was observed between circadian variation of UAE/h and MBP in 35 (78%) subjects, and the mean coefficient of correlation (r) was 0.86+/-0.12. A significant positive correlation was observed between circadian variation of UAE/h and mean acceleration value (Gh) in 25 (56%) subjects, and the mean r value was 0.70+/-0.26. Multivariate linear regression analysis showed that MBP exerted a greater influence on UAE/h than Gh. Significant positive correlations were observed between UAE/day and plasma human atrial natriuretic peptide and plasma aldosterone concentration (r = 0.50, P < 0.01; r = 0.36, P< 0.05). None of these relations, however, was observed in the DM group.. In patients with essential hypertension, circadian changes in activity and variation of BP influence UAE/h, but no definite relationship of this kind was observed in patients with diabetes mellitus. Measurement of circadian changes in UAE or UAE/day may be useful in estimating the degree of daily stress in non-diabetic patients with essential hypertension.

Topics: Adult; Aged; Albuminuria; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Motor Activity

To investigate the involvement of endogenous opioids in acute increases in blood pressure and their functional relationship with atrial natriuretic factor and endothelin-1, we assessed plasma levels of beta-endorphin, met-enkephalin, dynorphin B, catecholamines, atrial natriuretic factor, and endothelin-1 before and after administration of the opioid antagonist naloxone hydrochloride (8 mg i.v.) in 28 hypertensive patients with a stress-induced acute increase in blood pressure. Ten patients with established mild or moderate essential hypertension and 10 normotensive subjects served as control groups. Opioids, atrial natriuretic factor, and endothelin-I were radioimmunoassayed after chromatographic preextraction; catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Patients with an acute increase in blood pressure (systolic, 203.2 +/- 2.2 mm Hg; diastolic, 108.4 +/- 1.3) had plasma opioid, catecholamine, and atrial natriuretic factor levels significantly (P < .01) higher than hypertensive control patients (systolic pressure, 176.4 +/- 1.0 mm Hg; diastolic, 100.0 +/- 1.4), who had a hormonal pattern similar to that of normotensive subjects (systolic pressure, 123.2 +/- 1.5 mm Hg; diastolic, 75.0 +/- 2.0). Endothelin-1 did not differ in any group. In patients with an acute increase in blood pressure, naloxone significantly (P < .01) reduced blood pressure, heart rate, opioids, catecholamines, and atrial natriuretic factor 10 minutes after administration. Naloxone effects on blood pressure, heart rate, opioids, and catecholamines wore off within 20 minutes. In control groups, naloxone failed to modify any of the considered parameters. Our findings suggest that pressor effects of opioid peptides mediated by the autonomic nervous system during stress-induced acute episodes of blood pressure increase in hypertensive patients.

Topics: Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Dynorphins; Endorphins; Endothelin-1; Enkephalin, Methionine; Female; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Opioid Peptides; Stress, Physiological; Stress, Psychological

Topics: Atrial Natriuretic Factor; Blood Volume; Calcium; Calcium, Dietary; Humans; Hypertension; Immersion; Natriuresis; Sodium, Dietary

Three atrial natriuretic peptide (ANP) receptors, ANP(A), ANP(B), and ANP(C), have been identified in the heart, suggesting that natriuretic peptides may have direct effects on cardiac function. To characterize the possible role of atrial natriuretic peptide (ANP) in the regulation of its own secretion, we studied here the effects of ANP (greater affinity for ANP(A) than for ANP(B) receptors) and C-type natriuretic peptide (CNP), a potent activator of ANP(B) receptors, on the release of atrial peptides under basal conditions and during acute volume expansion in conscious normotensive Sprague-Dawley rats. The effects of HS-142-1, a nonpeptide ANP(A) and ANP(B) receptor antagonist, on volume load-induced atrial peptide release in 1-yr-old conscious normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were also studied. As an index of secretion of atrial peptides from the heart, plasma levels of N-terminal fragment of pro-ANP (NT-ANP) were measured. In Sprague-Dawley rats, i.v. infusion of ANP for 30 min in doses of 0.3 and 1.0 microg/kg x min blocked the plasma immunoreactive NT-ANP (IR-NT-ANP) response to volume load (P < 0.001), whereas CNP had no significant effect. Neither ANP nor CNP infusion had any effect on plasma IR-NT-ANP levels under basal conditions. Bolus administration of HS-142-1 increased baseline plasma IR-ANP concentrations in both WKY and SHR strains (WKY: 3 mg/kg, 46 +/- 8 pmol/liter, P < 0.001; SHR: 1 mg/kg, 26 +/- 9 pmol/liter, P < 0.01; SHR: 3 mg/kg, 40 +/- 12 pmol/liter, P < 0.01). The corresponding increases in plasma IR-NT-ANP concentrations in the SHR in response to administration of HS-142-1 were 0.17 +/- 0.06 nmol/liter (P < 0.01) and 0.40 +/- 0.14 nmol/liter (P < 0.01). Moreover, HS-142-1 (3 mg/kg) augmented plasma IR-ANP and IR-NT-ANP responses to acute volume load in WKY rats. In contrast, HS-142-1 did not enhance the plasma IR-ANP response to acute volume load in SHR and resulted in a smaller increase in the plasma IR-NT-ANP concentration in SHR than in WKY rats. In conclusion, the findings that ANP, but not CNP, inhibited volume expansion-stimulated NT-ANP release and that HS-142-1, an antagonist of guanylate cyclase-linked natriuretic peptide receptors, increased plasma ANP and NT-ANP concentrations show that endogenous ANP directly modulates its own release via ANP(A) receptors in vivo. Furthermore, this modulation of acute volume expansion-induced atrial peptide release appears to be altered in

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Hemodynamics; Hypertension; Male; Natriuretic Peptide, C-Type; Peptide Fragments; Polysaccharides; Proteins; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

We compared the abundance and sensitivity of atrial natriuretic peptides (ANP) receptors in the brains of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats and examined the effect of blood pressure on the abundance of brain ANP receptors in several other experimental rat models. Brain slices from SHR generated more guanosine 3',5'-cyclic monophosphate in response to ANP than brain slices from WKY rats. No differences were found in brain particulate guanylate cyclase activity in both strains of rats. In rat brain homogenates, we observed that ANP bound in a specific and saturable fashion to samples from WKY rats, but not in samples from SHR. In vitro receptor autoradiography revealed that ANP binding was reduced in the subfornical organ, the choroid plexus, and the paraventricular nucleus of SHR compared with WKY rat brains. Correction of hypertension in SHR or induction of hypertension in other strains did not affect ANP binding in any of these brain regions. Altogether, our data suggest that the increased sensitivity of SHR brains to the action of ANP may be a consequence of factors other than the abundance of receptors and that it is not secondary to the elevation of blood pressure.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Atrial Natriuretic Factor; Brain; Cyclic GMP; Guanylate Cyclase; Hypertension; Hypothalamus; In Vitro Techniques; Kinetics; Male; Natriuretic Peptide, C-Type; Organ Specificity; Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Reference Values; Regression Analysis

Atrial natriuretic peptide (ANP) which alters sodium balance, blood volume and vascular tone represents an important candidate for investigating the genetic basis of essential hypertension (EH). Accordingly, we have studied Bgl1 and Xho1 restriction fragment length polymorphisms (RFLPs) of the ANP gene in 147 hypertensive, 141 normotensive and 67 population-based control subjects from a homogenous population of West African origin from St Vincent and the Grenadines. We found no association of either Bgl1 and Xho1 RFLPs with EH. This study suggests that the ANP locus may not exert a major gene effect on EH amongst the black people of St Vincent and the Grenadines.

Topics: Adult; Aged; Atrial Natriuretic Factor; Black People; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Saint Vincent and the Grenadines

Baroreflex control of heart rate in spontaneously hypertensive rats (SHR) is defective, largely because of a poor vagal contribution to the reflex. We have demonstrated previously that atrial natriuretic peptide (ANP) enhances reflex bradycardia in normotensive rats through an action on nonarterial vagal afferent pathways. In the present study, we investigated whether ANP could reverse the baroreflex abnormality in SHR. Heart rate reflexes were activated by three different methods in conscious, instrumented SHR and Wistar-Kyoto rats (WKY) in the presence of intravenous infusions of vehicle (saline) or rat ANP (150 ng/kg per minute). Heart rate responses were measured by (1) the steady-state changes in blood pressure after alternating slow infusions (over approximately 15 to 30 seconds) of a pressor (methoxamine) and depressor (nitroprusside) drug (stimulating predominantly arterial baroreceptors), (2) the ramp method of rapid infusion of methoxamine (over < 10 seconds; stimulating arterial and cardiopulmonary baroreceptors), and (3) the von Bezold-Jarisch method of activating chemically sensitive cardiac receptors through serotonin injections. ANP enhanced the heart rate range of the arterial baroreflex (steady-state method) by 13 +/- 3% in WKY but had no significant effect on the sensitivity or any other parameter of the steady-state baroreflex. When a very rapid rise in blood pressure was elicited by the ramp method in WKY, ANP significantly enhanced baroreflex bradycardia (sensitivity increased by 29 +/- 9%, P < .05). ANP also enhanced the bradycardia of the von Bezold-Jarisch reflex (by 33 +/- 16%, P < .05) in WKY. By contrast, ANP did not influence baroreceptor or chemoreceptor heart rate reflex responses in SHR. We conclude that in normotensive rats, ANP facilitates cardiopulmonary bradycardic reflexes. The lack of effect of ANP in SHR may be related to an underlying structural or genetic alteration in their cardiac sensors, perhaps associated with cardiac hypertrophy, that prevents the ANP-induced activation of cardiac sensory afferents, resulting in cardioinhibition.

Topics: Animals; Atrial Natriuretic Factor; Baroreflex; Bradycardia; Female; Hypertension; Infusions, Intravenous; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reflex, Abnormal; Serotonin

In the present studies we have investigated if the increased expression of Gi alpha proteins reported earlier in heart and aorta from SHR (spontaneously hypertensive rats) is the cause or effect of hypertension. The SHRs at various ages of the development of blood pressure (3-5 days, 2 weeks, 4 weeks and 8 weeks) and their age-matched WKY were used for these studies. The expression of Gi alpha-2 and Gi alpha-3 (inhibitory guanine nucleotide regulatory protein and Gs alpha (stimulatory guanine nucleotide regulatory protein) at protein and mRNA level was determined by immunoblotting and Northern blotting technique using specific antibodies and cDNA probes. The SHR at early ages up to 2 weeks did not show any increase in blood pressure, however it started to go up from 4 weeks. The levels of Gi alpha 2 and Gi alpha 3 at protein and mRNA in heart from SHR were not different in 3-5 days old SHR as compared to WKY (Wistar-Kyoto rats), however, the expression of Gi alpha-2 and Gi alpha-3 protein and mRNA was significantly increased in 2 weeks and older SHR. The mRNA level of the catalytic subunit type V enzyme was significantly decreased in SHR 2 weeks and later ages as compared to their age-matched WKY. On the other hand, the expression of Gs alpha was not different in SHR as compared to WKY at all the ages studied. In addition, the oxotremorine and C-ANF4-23 (a ring deleted analog of atrial natriuretic factor) mediated inhibitions of adenylyl cyclase in hearts and aorta were also significantly enhanced in 2 weeks and older SHRs as compared to WKY rats, whereas, at younger age of SHR (3-5 days old), no change in the percent inhibition of adenylyl cyclase by C-ANF4-23 was observed and oxotremorine was unable to inhibit adenylyl cyclase activity. Furthermore, the basal enzyme activity and the stimulatory responses of isoproterenol, NECA (N-ethylcarboxamideadenosine), glucagon and forskolin on adenylyl cyclase were significantly decreased at all ages of SHR as compared to WKY. These results suggest that the increased expression of genes for Gi alpha-2 and Gi alpha-3, decreased expression of type V enzyme mRNA and decreased cAMP levels precedes the development of blood pressure and may participate in the pathogenesis of hypertension.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Age Factors; Animals; Animals, Newborn; Aorta; Atrial Natriuretic Factor; Blood Pressure; Colforsin; Enzyme Inhibitors; Gene Expression Regulation, Developmental; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Hormones; Hypertension; Muscarinic Agonists; Myocardium; Oxotremorine; Rats; Rats, Inbred SHR; RNA, Messenger

To ascertain whether atrial natriuretic peptides could be used as prospective and independent predictors of total mortality in an elderly population.. Atrial natriuretic peptides, ANP(1-98) and ANP(99-126), were measured in 541 subjects from the 85-year-old population of Gothenburg, Sweden. Before the study cardiovascular disorders such as congestive heart failure, ischaemic heart disease, hypertension and atrial fibrillation were defined. Total mortality was recorded during the prospective 60-month follow-up period.. Individuals aged 85 years from the population of Gothenburg, Sweden, were visited once at home and made one visit to Vasa Hospital.. Sixty-month mortality in relation to circulating concentrations of atrial natriuretic peptides.. Circulating concentrations of ANP(1-98) and ANP(99-126) were significantly correlated with 60-month mortality in the total study population (ANP(1-98), P < 0.001: ANP(99-126), P < 0.01). In subjects with cardiovascular disorders, 60-month mortality was significantly correlated with increased concentrations of ANP(1-98) (P < 0.01) and ANP(99-126) (P < 0.05). In subjects with no defined cardiovascular disorder, 60-month mortality was significantly correlated with increased ANP(1-98) concentrations (P < 0.01).. In the elderly population, atrial peptides predict mortality in subjects with defined cardiovascular disorders as well as in the total population and may predict future cardiovascular disorder.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Atrial Natriuretic Factor; Heart Diseases; Heart Failure; Humans; Hypertension; Myocardial Ischemia; Survival Rate

The levels of adrenomedullin (ADM), a newly discovered vasodilating and natriuretic peptide, are elevated in plasma and ventricular myocardium in human congestive heart failure suggesting that cardiac synthesis may contribute to the plasma concentrations of ADM. To examine the time course of induction and mechanisms regulating cardiac ADM gene expression, we determined the effect of acute and short-term cardiac overload on ventricular ADM mRNA and immunoreactive ADM (ir-ADM) levels in conscious rats. Acute pressure overload was produced by infusion of arginine8-vasopressin (AVP, 0.05 microg/kg/min, i.v.) for 2 h into 12-week-old hypertensive TGR(mREN-2)27 rats and normotensive Sprague-Dawley (SD) rats. Hypertension and marked left ventricular hypertrophy were associated with 2.2-times higher ir-ADM levels in the left ventricular epicardial layer (178 +/- 36 vs. 81 +/- 23 fmol/g, P<0.05) and 2.6-times higher ir-ADM levels in the left ventricular endocardial layer (213 +/- 23 vs. 83 +/- 22 fmol/g, P<0.01). The infusion of AVP for 2 h in normotensive rats produced rapid increases in the levels of left ventricular ADM mRNA (epicardial layer: 1.6-fold, P<0.05) and ir-ADM (endocardial layer: from 83 +/- 22 to 140 +/- 12 fmol/g, P<0.05), whereas ventricular ADM mRNA and ir-ADM levels did not change significantly in hypertensive rats. Short-term cardiac overload, induced by administration of angiotensin II (33.3 microg/kg/h, s.c., osmotic minipumps) for two weeks in normotensive SD rats resulted in left ventricular hypertrophy (3.05 +/- 0.17 vs. 2.75 +/- 0.3 mg/g, P<0.05) and a 1.5-fold increase (P<0.05) in ventricular ADM mRNA levels. In conclusion, the present results show that pressure overload acutely stimulated ventricular ADM gene expression in conscious normotensive rats suggesting a potential beneficial role for endogenous ADM production in the heart against cardiac overload. Since pressure overload-induced increase in ADM synthesis was attenuated in hypertensive rats, alterations in the ADM system may contribute to the pathogenesis of hypertension in the TGR(mREN-2)27 rat.

Topics: Adrenomedullin; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Heart; Heart Failure; Heart Ventricles; Humans; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Peptide Biosynthesis; Peptides; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Transcription, Genetic

To determine whether increased concentrations of the N-terminal peptide of proatrial natriuretic peptide and of atrial natriuretic peptide are related to the severity of preeclampsia and gestational hypertension.. Blood samples were collected from 70 healthy pregnant women, 48 women with preeclampsia, and 19 women with gestational hypertension in the third trimester. We used a specific radioimmunoassay (RIA) method suitable for the determination of the plasma N-terminal peptide of proatrial natriuretic peptide in unextracted plasma. The atrial natriuretic peptide was measured by RIA from Sep-Pak C18-extracted plasma.. The N-terminal peptide of proatrial natriuretic peptide levels were significantly higher in preeclamptic women than in healthy pregnant controls (median 571 [range 189-2000] versus 266 pmol/L [80-634], P < .001) and also significantly higher in women with severe preeclampsia than in women with mild preeclampsia (766 [431-2000] versus 492 pmol/L [189-1283], P = .01). The N-terminal peptide of proatrial natriuretic peptide values were significantly elevated in the subgroup of hypertensive pregnancies with abnormal Doppler velocimetry. At entry into the study the values for the N-terminal peptide of proatrial natriuretic peptide were higher in the subgroup of women who developed severe preeclampsia and/or gave birth to a small for gestational age (SGA) infant compared to the values in the subgroup of women in whom the hypertensive condition remained stable (710 [271-1475] versus 407 pmol/L [189-1067], P = .006). Similar comparisons of atrial natriuretic peptide values did not reach significant differences.. The levels of N-terminal peptide of proatrial natriuretic peptide were higher in women with preeclampsia than in those with gestational hypertension and higher in women with gestational hypertension than in those with normal pregnancies. A marked elevation in N-terminal peptide of proatrial natriuretic peptide may predict development of severe preeclampsia and/or an SGA infant.

Topics: Adult; Atrial Natriuretic Factor; Case-Control Studies; Female; Gestational Age; Humans; Hypertension; Infant, Newborn; Infant, Small for Gestational Age; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Protein Precursors; Severity of Illness Index; Ultrasonography

The aim of this study was to investigate the effects of moxibustion at the meridian points BL-15 (Xin-shu) and BL-27 (Xiao-chang-shu) on renal function, systolic blood pressure, plasma levels of renin activity, aldosterone and atrial natriuretic peptide in spontaneously hypertensive rats. The results showed that urine volume increased significantly after moxibustion at the meridian points BL-15, but decreased at BL-27. Urinary excretion of Na+ decreased after moxibustion at the meridian points BL-15 and BL-27. Systolic blood pressure decreased after moxibustion at the meridian point BL-15. No effect was observed at BL-27. Plasma levels of aldosterone and renin activity increased significantly, but the levels of atrial natriuretic peptide decreased significantly after moxibustion at BL-15. Plasma levels of aldosterone and atrial natriuretic peptide increased significantly after moxibustion at the meridian points BL-27. These results suggest that the meridian points BL-15 and BL-27 are related to the regulation of renal function and the secretion of hormone with body fluid metabolism.

Topics: Acupuncture Points; Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Chlorides; Creatinine; Disease Models, Animal; Electrolytes; Hypertension; Kidney; Male; Moxibustion; Potassium; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Sodium

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Enzyme Inhibitors; Heart Failure; Hypertension; Macaca fascicularis; Neprilysin; Pyridines; Rats; Renin; Sodium; Thiazepines

Regular administration of recombinant erythropoietin (EPO) in patients with chronic renal failure (CRF) is frequently complicated by a rise in arterial blood pressure. Clinical studies intended to discern the possible role of endothelin (ET) in the pathogenesis of EPO-induced hypertension have produced contradictory results. Given the limitations of the clinical studies, this placebo-controlled study was carried out in CRF (5/6 nephrectomized) rats treated with either EPO, 150 U/kg intraperitoneally, or the vehicle alone twice weekly for 6 wk. Plasma ET was measured at baseline, and weeks 2, 4, and 6. In addition, plasma arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) were determined at the conclusion of the study period. As expected, blood pressure rose markedly after 1 wk of EPO therapy as compared with the placebo therapy. However, there was no significant difference in plasma ET levels between the EPO- and placebo-treated groups during the study period. Likewise, EPO therapy had no effect on plasma ANP level but depressed plasma AVP concentration. Thus, this placebo-controlled animal study revealed that EPO therapy markedly raised arterial blood pressure but had no effect on plasma ET in the CRF rats. This observation suggests that EPO-induced hypertension in this model is not mediated by an increased circulating ET level. However, the possible effect, if any, of EPO on local vascular tissue ET level is uncertain and awaits further investigation.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelins; Erythropoietin; Hypertension; Longitudinal Studies; Male; Rats; Rats, Sprague-Dawley; Vasopressins

Topics: Animals; Atrial Natriuretic Factor; Blood Circulation; Brain; Hormones; Humans; Hypertension; Kidney; Molecular Conformation; Natriuretic Agents

The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Bradykinin; Disease Models, Animal; Heart; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Kallikrein-Kinin System; Kallikreins; Kininogens; Male; Myocardium; Organ Size; Protein Synthesis Inhibitors; Puromycin; Radioimmunoassay; Ramipril; Rats; Rats, Wistar

Chronic pressure overload is known to increase cardiac mass and expression levels of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs. Although mechanical stretching of cardiac myocytes could cause these changes, humoral factor(s) secondary to pressure overload may also be involved. To dissociate humoral effects from the effects of mechanical loading on cardiac hypertrophic responses, we examined expression of ANP and BNP at both mRNA and protein levels and proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded under conditions with or without hypertension by aortic coarctation. Seven days after transplantation, cardiac atrophy that usually occurs in transplanted hearts without hypertension by coarctation was prevented in the transplanted hearts with hypertension by coarctation. The levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts with relative to those without hypertension by coarctation. The plasma level of angiotensin II was higher in rats with than without hypertension by coarctation. Plasma endothelin-1 levels were not significantly different between the two groups. In addition, levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts without hypertension relative to those in the in situ hearts. The proportion of the V3 myosin isoform was also increased in the transplanted hearts without hypertension relative to the in situ hearts. These results indicate that humoral factor(s) secondary to the pressure overload produced by aortic coarctation enhanced the cardiac hypertrophic response and elevated the levels of mRNAs encoding these embryonic markers. Moreover, our findings regarding ANP and BNP expression in the transplanted hearts provide additional evidence that the fetal genes are reexpressed during the process of cardiac atrophy as well as in cardiac hypertrophy.

Topics: Angiotensin II; Animals; Aortic Coarctation; Atrial Natriuretic Factor; Atrophy; Blood Pressure; Body Weight; Cardiomegaly; Endothelin-1; Heart Rate; Heart Transplantation; Hypertension; Male; Myosins; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred Lew; RNA, Messenger; Transcription, Genetic; Transplantation, Heterotopic; Transplantation, Isogeneic

Plasma renin activity (PRA) increases during heart failure; however, PRA is altered by drug therapy, and it is difficult to study the natural progression of elevated PRA in humans and the possible factors that contribute to its rise. This study evaluated PRA in a drug-naive hypertensive rat model (SHHF/Mcc-facp) that has a genetic program resulting in heart failure (HF). Mean arterial blood pressure and PRA were determined and correlated to heart weight index in conscious normotensive, spontaneously hypertensive rats and HF rats of various ages. PRA, atrial natriuretic peptide, and aldosterone levels progressively increase with age in male HF rats. PRA and blood pressure are independently correlated to cardiac hypertrophy in male HF rats. Atrial natriuretic peptide was elevated in spontaneously hypertensive compared with normotensive rats. Female HF rats have elevated PRA, but the increase is temporally delayed compared with that in male HF rats. Hypertension, PRA, and male gender are independent factors contributing to cardiac hypertrophy and heart failure in the HF model. The HF rat model may prove useful in determining the contribution of these factors in the progression from cardiac hypertrophy to heart failure.

Topics: Aging; Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Disease Susceptibility; Female; Heart Failure; Hypertension; Male; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WF; Rats, Sprague-Dawley; Regression Analysis; Renin; Species Specificity

The natriuretic peptide system is suggested to be involved in the pathogenesis of salt-sensitive hypertension; a recent report indicated that disruption of the atrial natriuretic peptide precursor gene caused salt-sensitive hypertension. However, natriuretic peptide receptor (NPR)-A knockout mice did not show enhanced salt sensitivity of blood pressure. The aim of the present study was to investigate the role of NPR-C, the other receptor for atrial natriuretic peptide, in increased salt sensitivity of blood pressure. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were placed on a 0.3% or 8% NaCl diet for 4 weeks. Blood pressure was elevated by salt loading only in DS rats. RNase protection assay demonstrated that NPR-C transcript level in the kidney was reduced by chronic salt loading in both DR and DS rats, whereas expression of NPR-A and NPR-B was not altered. The reduction of NPR-C mRNA in response to salt loading was enhanced in DS compared with DR rats. In situ hybridization indicated that the salt-induced NPR-C change was attributed mainly to suppressed expression of NPR-C in the podocytes. NPR-C gene expression was regulated by salt loading in a tissue-specific manner; the marked decrease in NPR-C mRNA by salt loading was seen only in the kidney. These data suggest that the exaggerated salt-induced reduction of NPR-C in the kidney of DS rats may play an important role in the pathogenesis of salt hypertension in this animal, possibly related to impaired renal sodium excretion.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Body Weight; Gene Expression; Hypertension; Isomerism; Kidney; Male; Natriuretic Agents; Rats; Rats, Inbred Strains; Receptors, Cell Surface; RNA, Messenger; Sodium Chloride; Tissue Distribution

Endothelial dysfunction may be related to cardiovascular risk factors, such as aging, hypertension, and atherosclerosis. We investigated whether aging and hypertension independently alter endothelial function in the renal circulation in humans in the absence of abnormalities in lipid and glucose metabolism. L-Arginine (500 mg/kg over 30 minutes) was intravenously administered to 33 patients with essential hypertension and 35 normotensive subjects. The L-arginine-induced increases in renal plasma flow (10.1+/-0.8% versus 15.8+/-0.9%, P<.05) and plasma cGMP (53+/-4% versus 82+/-5%, P<.05) were significantly smaller in patients with essential hypertension than in the normotensive subjects. Multivariate stepwise regression analysis showed that age (P<.0002) and the mean blood pressure (P<.0001) were independently and negatively correlated with the renal plasma flow response to L-arginine. Age (P<.002), mean blood pressure (P<.0001), and male sex (P<.05) were independently correlated with the L-arginine-induced increase in plasma cGMP. The peak change in plasma cGMP was significantly correlated with the L-arginine-induced increase in renal plasma flow (r=.63, P<.001). These findings suggest that aging and hypertension may independently impair endothelium-dependent renovascular dilation and that this effect may be caused at least in part by a decrease in nitric oxide production.

Topics: Adult; Aged; Aging; Arginine; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Endothelium, Vascular; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Osmolar Concentration; Renal Circulation; Vasodilation

To investigate the activation of particulate guanylate cyclase in pregnant women with pregnancy-induced hypertension (PIH), plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and guanosine 3',5'-cyclic phosphate (cGMP) were measured by radioimmunoassays specific to each substance. Ten normal nonpregnant women, and 30 normal pregnant women, 17 pregnant women with mild PIH and 11 pregnant women with severe PIH in the third trimester were included in this retrospective observational study. The diagnosis and classification of hypertension were carried out according to the technical bulletin (No. 91) of the American College of Obstetricians and Gynecologists. In the pregnant women with mild PIH, plasma cGMP levels as well as ANP and BNP levels were significantly (P < 0.05) higher than those in gestational age-matched normal pregnant or nonpregnant women. But in the pregnant women with severe PIH, plasma cGMP levels were significantly lower than those in pregnant women with mild PIH (P < 0.05), although plasma ANP and BNP levels were higher than those in pregnant women with mild PIH.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Female; Gestational Age; Humans; Hypertension; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pregnancy; Pregnancy Complications, Cardiovascular; Radioimmunoassay; Retrospective Studies

The objective of the study was to assess the evolution of renin, angiotensin II, atrial natriuretic factor (ANF) and blood pressure (BP) in the first trimester following renal transplantation in man Thirty-two recipients were investigated for 3 months post-transplantation. Twenty had a history of hypertension with moderate cardiac hypertrophy. Thirty-one retained their native kidneys. Five kidney donors had a history of mild hypertension. The recipients were perioperatively volume-expanded with 0.9% saline and diuresis was maintained for 48 h with furosemide and dopamine. The sodium intake was 25 mEq/24 hours. Prophylactic immunosuppressive therapy was antilymphocyteglobulins (25 cases), or anti-LFA1 (7 cases) and maintenance therapy was cyclosporine-prednisone (8 cases), or cyclosporine-prednisone-azathioprine (24 cases). Mean BP, serum creatinine, urinary sodium excretion (UNA) and hormonal (renin, angiotensin II and ANF) parameters were collected every other day for the first week after transplantation and then twice monthly. Twenty (62.5%) patients developed hypertension and hypertension was more frequent in patients with a delayed graft function, than in patients with immediate good graft function (10/20 vs. 4/12, p < 0.05%). Both hypertensive (group HBP) and normotensive (group NBP) patients had similar very low renin and angiotensin II plasma levels, after an initial early peak. Analysis of covariance with multiple regression analysis showed that in the HBP patients, BP was negatively correlated with UNA (p = 0.02) and positively with plasma ANF (p < 0.01). The normal BP patients also showed a correlation between BP and UNA, although it was limit of statistical significance (p = 0.05); there was no correlation between ANF and BP. We conclude that the RAS is rapidly depressed after renal transplantation and does not interfere with BP regulation. The hypertension in the early stage of post-transplantation varies inversely with the urinary sodium excretion. The defective sodium excretion, which dominates the effect of the low sodium diet, results in volume overload, increased ANF and volume-dependent hypertension.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Radioimmunoassay; Regression Analysis; Renin; Sodium

A genetic model of salt-resistant hypertension has been developed recently through disruption of the guanylyl cyclase-A (GC-A) natriuretic peptide receptor gene (Lopez, M. J., Wong, S. K., Kishimoto, I., Dubois, S., Mach, V., Friesen, J., Garbers, D. L., and Beuve, A. (1995) Nature 378, 65-68). These genetically altered mice were used to determine which of the natural peptides with natriuretic peptide-like structures regulate blood pressure through the GC-A receptor. Atrial natriuretic peptide (ANP) or B-type natriuretic peptide (BNP) half-maximally relaxed precontracted aortic rings in wild-type mice at about 24 nM, but failed to relax such aortas in GC-A null mice, even at micromolar concentrations. C-type natriuretic peptide (CNP), in contrast, caused half-maximal relaxation at concentrations of 335 and 146 nM in aortas from either wild-type or null mice, respectively, suggesting that this peptide acted through a receptor other than GC-A. Since the in vitro results with aortic smooth muscle do not necessarily reflect the physiology of the smaller blood vessels important in blood pressure regulation, the blood pressures of conscious mice infused with the various peptides were determined. ANP caused decreases in blood pressure when infused at rates of 500 ng/kg/min, a rate which resulted in a plasma concentration of 0.8 nM. In the null mice, in contrast, ANP failed to lower blood pressure even at infusion rates of 50 microg/kg/min. Much higher infusion rates for CNP (50 microg/kg/min), which yielded final plasma concentrations of 18.3 nM, were required to lower blood pressure in wild-type mice, but the effects of CNP were not altered in GC-A null mice. Thus, two natriuretic peptides (ANP, BNP) act through GC-A whereas another (CNP) acts through another receptor to regulate blood pressure.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Guanylate Cyclase; Hypertension; In Vitro Techniques; Mice; Mice, Mutant Strains; Muscle Relaxation; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Proteins; Receptors, Atrial Natriuretic Factor; Signal Transduction

Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.. To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.. Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.. In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Calcium-Transporting ATPases; Captopril; Cardiomyopathy, Hypertrophic; Diastole; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Mice; Mice, Transgenic; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Tetrazoles

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Cyclic GMP; Dihydropyridines; Hemodynamics; Hormones; Hypertension; Kidney; Rats; Rats, Inbred SHR; Renin; Tetrazoles

In our previous studies, we found that the atrial natriuretic peptide (ANP) binding and guanylyl cyclase activity of A-type natriuretic peptide receptors (NPR-A) were upregulated in renal papillae but downregulated in vascular tissues and glomeruli of rats with deoxycorticosterone acetate (DOCA)-salt hypertension [E. Nuglozeh, G. Gauquelin, R. Garcia, J. Tremblay, and E. L. Schiffrin. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F130-F137, 1990]. To further understand the molecular significance of these regulations, we measured the relative abundance of the transcripts of NPR-A and NPR-B by Northern blot in the aorta, mesenteric arteries, adrenal cortex, renal papillae, and lungs in DOCA-salt hypertensive and control rats. In renal papillae we also examined the translation and transcription of NPR-A by ribosome loading and run-on assay. Compared with controls, the steady-state levels of mRNA for NPR-A were increased in the aorta and mesenteric arteries but were decreased in the adrenal cortex and renal papillae in DOCA-salt-treated rats. NPR-B mRNA was decreased in the aorta, mesenteric arteries, and adrenal cortex in hypertensive rats. In lungs the mRNA for both receptors was unchanged. Translation of NPR-A mRNA, as assessed by ribosome loading, was reduced in renal papillae. Transcriptional activity of its gene was not detectable in these tissues. Guanosine 3',5'-cyclic monophosphate levels generated by NPR-A in renal papillae and by NPR-A and NPR-B in the adrenal cortex, aorta, and mesenteric arteries of DOCA-salt-treated rats remained increased in hypertension. The higher NPR-A activity in the presence of a lower level of its mRNA in renal papillae and the higher NPR-B activity in the presence of a lower level of its mRNA in the vasculature, adrenal cortex, and lungs can alternatively be explained by receptor stabilization or increased receptor recycling.

Topics: Adrenal Cortex; Animals; Aorta; Atrial Natriuretic Factor; Cyclic GMP; Desoxycorticosterone; Gene Expression Regulation; Hypertension; Kidney; Lung; Male; Mesenteric Arteries; Organ Specificity; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Ribosomes; RNA, Messenger; Sodium, Dietary; Transcription, Genetic

Atrial natriuretic factor (ANF) is expressed in several noncardiac tissues where it may have an autocrine or paracrine function. Such function may be expected of locally synthesized ANF in the renal parenchyma. Previous investigations of the existence of ANF mRNA in the renal parenchyma have yielded conflicting results. The investigations reported here were designed to detect and measure ANF mRNA in normal rats and in rats subjected to a deoxycorticosterone acetate (DOCA)-salt treatment schedule known to strongly activate cardiac ANF gene expression. The expression of the renal ANF gene was measured using a newly developed quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). This method uses an internal competitor that serves as an internal standard and makes the procedure independent of measurement relative to housekeeping genes. It was found that renal ANF mRNA levels were 10(7) times lower than those found in left or right atria, but immunoreactive (ir) renal ANF concentration by specific radioimmunoassay was 10(4) times lower than that of atrial irANF levels. Reverse-phase high-performance liquid chromatography analysis revealed that more than 99% of renal irANF is processed ANF(99-126). This finding suggests that most of the irANF measured in kidney extracts likely originates from atrial sources. Left atrial ANF mRNA levels after 1 week of DOCA-salt treatment was significantly higher than that of control rats ([21.06+/-2.99] x 10(-l5) mol/microg total RNAversus [8.59 +/-1.26] x 10(-5) mol/microg total RNA, P<.05). However, renal ANF mRNA levels in DOCA-salt rats were significantly decreased compared with those of control rats ([1.64+/-0.34] x 10(-22) mol/microg total RNA versus [3.96+/-0.61]x 10(-22) mol/microg total RNA, P<.05). These results indicate that (1) renal ANF mRNA can be consistently and specifically demonstrated after reverse transcription and PCR amplification; (2) renal and cardiac ANF synthesis are regulated in a tissue-specific, opposite manner during DOCA-salt treatment; and (3) the finding that renal ANF mRNA is downregulated by DOCA-salt treatment together with previous findings suggest the need for further investigation into the role of renal ANF mRNA downregulation in the pathogenetic mechanism that leads to volume expansion and hypertension after chronic DOCA-salt treatment.

Topics: Animals; Atrial Natriuretic Factor; Desoxycorticosterone; Gene Expression Regulation; Hypertension; Kidney; Male; Myocardium; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic

The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.

Topics: Aging; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Captopril; Cardiomegaly; Gene Expression Regulation; Heart; Heart Failure; Hypertension; Male; Myosin Heavy Chains; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

Water immersion (WI) is followed by hypoxemia and hemodilution, and induces alterations in renal hemodynamics (increase in tubular sodium load). These facts justified the performance of studies which aimed to assess the influence of WI on erythropoietin (EPO) secretion. Serum EPO and atrial natriuretic peptide (ANP) concentrations as well as plasma renin activity (PRA) were estimated in 18 patients with essential hypertension (EH) and in 9 healthy subjects (HS): before, after 2 h of WI and 2 h after discontinued WI. WI was followed by a significant increase in plasma volume and decrease in PRA, which were of similar magnitude in both examined groups. Patients with EH showed significantly higher basal levels of serum EPO (66.7+/-11.4 mU/ml in EH vs. 20.0+/-3.4 mU/ml in HS) and ANP (110.6+/-15.4 pg/ml in EH vs. 75.6+/-8.2 pg/ml in HS). WI was followed by a significant increase in both EPO (by 34.0+/-8.9 mU/ml in EH and 17.0+/-5.4 mU/ml in HS) and ANP (by 106.9+/-19.2 pg/ml in EH and 149.4+/-16.9 pg/ml in HS). Only in EH, a significant correlation was found between serum EPO level and mean arterial pressure post WI and natriuresis during WI, respectively.. (1) water immersion induced increase in plasma EPO both in healthy subjects and patients with essential hypertension. (2) Patients with EH are characterized by elevated basal plasma levels of ANP and EPO. (3) Participation of the renin-angiotensin system and ANP in the regulation of EPO secretion could not be proven both in normotensive subjects and hypertensive patients.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Immersion; Male; Plasma Volume; Radioimmunoassay; Renin; Sodium; Water

Based on our studies at the Hypertension research unit, we have found that the renin-angiotensin aldosterone. System (RAAS) undergoes several changes being the following the most relevant: Low plasma renin concentration (LPRC), while the plasma Aldosterone concentration is high (HPAC). At the same time we found calcium metabolism alterations: High urine calcium excretion, low serum ionic calcium and high PTH level. This alterations are more evident if the elder patient become hypertensive. We have found this changes in several groups in our community: black, ancient, obese and diabetic patients; who more often suffer hypertension and they must be followed up closely. In this group there are the sodium dependent hypertensive and they are the one who can get beneficial effects from the low salt diet and high calcium intake. When we studied the low plasma renin hypertensive we found the calcium changes mentioned before in ancient patient, as well as, high urine Zinc excretion. When we gave and oral calcium supplement to these patients, we saw that the calcium and Zinc alterations mentioned before were corrected. The high plasma renin concentration hypertensive patients showed low serum magnesium concentration and high urine magnesium excretion. A brief comment on the possible role of oxidative stress on essential hypertension is made.

Topics: Adult; Aged; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Black People; Calcium; Comorbidity; Diabetes Mellitus; Disease Susceptibility; Endothelium, Vascular; Female; Humans; Hypertension; Lipoxygenase; Magnesium; Male; Middle Aged; Models, Biological; Obesity; Oxidative Stress; Parathyroid Hormone; Renin-Angiotensin System; Risk Factors; Sodium, Dietary; Venezuela; Zinc

Human and rat adipose tissue contain very high levels of natriuretic peptides clearance receptor messenger (m)RNA, and fasting inhibits its gene expression in adipose tissue. In this study we evaluated plasma atrial natriuretic peptide (ANP) and gene expression of biologically active type A natriuretic peptide receptor (NPr-A) and clearance natriuretic peptide receptor (NPr-C) in adipose tissue of obese hypertensive and obese normotensive patients.. We studied 27 untreated obese hypertensives, 26 obese normotensives (body mass index > or = 30 kg/m2), 24 non-obese essential hypertensives and 23 lean healthy subjects (body mass index < or = 25 kg/m2). Blood samples were withdrawn for ANP, plasma renin activity and aldosterone radioimmunoassays. Subcutaneous peri-umbilical adipose tissue samples were obtained, by needle aspiration, in 13 obese hypertensives and in 12 obese normotensives and used for RNA extraction. Then, complementary synthesis and semiquantitative polymerase chain reaction (PCR) with primers complementary to sequences of different exons of the genes encoding for NPr-A, NPr-C and beta-actin, were performed. 32P-labeled PCR products were separated by electrophoresis, blotted onto nylon membranes, and the exposed autoradiographic films were analysed by densitometry. NPr signals were normalized by the beta-actin expression level.. Plasma ANP was lower in obese hypertensives than in obese normotensives (37.5+/-7 versus 43.2+/-6 pg/ml, P< 0.05), but was higher in non-obese hypertensives than in non-obese normotensives. In contrast, plasma renin activity and aldosterone were higher in the obese hypertensives. Although NPr-A and NPr-C expression were not statistically different between the two obese groups, the NPr-A: NPr-C mRNA ratios were significantly lower in obese hypertensives (P < 0.03).. Our data suggest that in obese hypertensives compared to obese normotensives, the lower NPr-A: NPr-C ratio might determine decreased biological activity and/or an increased clearance of natriuretic peptide in adipose tissue, suggesting that the natriuretic peptide and its receptor system may be important in obesity-related hypertension where ANP levels are lower.

Topics: Actins; Adipose Tissue; Aldosterone; Atrial Natriuretic Factor; Biopsy, Needle; DNA Primers; Female; Gene Expression; Guanylate Cyclase; Humans; Hypertension; Male; Middle Aged; Obesity; Polymerase Chain Reaction; Receptors, Atrial Natriuretic Factor; Renin; RNA, Messenger

Atrial natriuretic peptide (ANP) is involved in the pathogenesis of sodium-sensitive hypertension. The loss of Sca I restriction site in the ANP precursor gene abolishes the regular stop codon. The aim of our study was the analysis of the Sca I gene polymorphism in 23 patients with sodium-sensitive hypertension, the molecular characteristic of the mutation and the comparison of the blood pressure values, plasma renin activity, plasma ANP and aldosterone concentration between patients with or without mutation. Applying the polymerase chain reaction (PCR), followed by digestion with Sca I, the heterozygous mutation has been found in 9 (39%) patients. The sequencing of PCR products indicated that the loss of Sca I restriction site is caused by T2238-->C transition leading to the translation of ANP with two additional arginines. The higher concentration of ANP in plasma has been found in T2238-->C transition patients on normal and high sodium diet as compared with patients without mutation. These preliminary results suggest that the heterogeneity of sodium-sensitive hypertension is associated with the T2238-->C mutation of the ANP precursor gene.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Base Sequence; DNA; Female; Genotype; Humans; Hypertension; Male; Nucleotide Mapping; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Renin; Sodium, Dietary

This study was designed to investigate disturbances in arterial blood pressure and body fluid homeostasis in stable heart transplant recipients.. Hypertension and fluid retention frequently complicate heart transplantation.. Blood pressure, renal and endocrine responses to acute volume expansion were compared in 10 heart transplant recipients (57 +/- 9 years old [mean +/- SD]) 20 +/- 5 months after transplantation, 6 liver transplant recipients receiving similar doses of cyclosporine (cyclosporine control group) and 7 normal volunteers (normal control subjects). After 3 days of a constant diet containing 87 mEq/24 h of sodium, 0.154 mol/liter saline was infused at 8 ml/kg per h for 4 h. Blood pressure and plasma vasopressin, angiotensin II, aldosterone, atrial natiuretic peptide and renin activity levels were determined before and at 30, 60, 120 and 240 min during the infusion. Urine was collected at 2 and 4 h. Blood pressure, fluid balance hormones and renal function were monitored for 48 h after the infusion.. Blood pressure did not change in the two control groups but increased in the heart transplant recipients (+15 +/- 8/8 +/- 5 mm Hg) and remained elevated for 48 h (p < or = 0.05). Urine flow and urinary sodium excretion increased abruptly in the control groups sufficient to account for elimination of 86 +/- 9% of the sodium load by 48 h; the increases were blunted (p < or = 0.05) and delayed in the heart transplant recipients, resulting in elimination of only 51 +/- 13% of the sodium load. Saline infusion suppressed vasopressin, renin activity, angiotensin II and aldosterone in the two control groups (p < or = 0.05) but not in the heart transplant recipients. Heart transplant recipients had elevated atrial natriuretic peptide levels at baseline (p < or = 0.05), but relative increases during the infusion were similar to those in both control groups.. Blood pressure in heart transplant recipients is salt sensitive. These patients have a blunted diuretic and natriuretic response to volume expansion that may be mediated by a failure to reflexly suppress fluid regulatory hormones. These defects in blood pressure and fluid homeostasis were not seen in liver transplant recipients receiving cyclosporine and therefore cannot be attributed to cyclosporine alone. Abnormal cardiorenal neuroendocrine reflexes, secondary to cardiac denervation, may contribute to salt-sensitive hypertension and fluid retention in heart transplant recipients.

Topics: Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Cyclosporine; Female; Heart; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Renin-Angiotensin System; Sodium Chloride; Sodium, Dietary; Ventricular Function, Left; Water-Electrolyte Balance; Water-Electrolyte Imbalance

One of the possible mechanisms responsible for pre-eclampsia is a loss of efficiency of the L-arginine-nitric oxide pathway with subsequent inactivation of the guanylyl cyclases of the vascular smooth muscle cells. As a result there should be a decrease in plasma cyclic 3'-5' guanosine monophosphate (cGMP) concentrations in pre-eclampsia. We assessed the behavior of this nucleotid in the plasma of pre-eclamptic women.. Sixteen pre-eclamptic women, 16 normotensive pregnant women matched for gestational age and six nonpregnant controls were investigated. Arterial blood pressure was recorded at inclusion time and then once-a-day until the fourth day after delivery concomitantly with the collection of blood samples for determining plasma cGMP, atrial natriuretic peptides (ANP), creatinine, uric acid and platelet counts. Also 24 h urines were simultaneously collected to calculate renal clearance of cGMP.. Before the initiation of antihypertensive treatment, plasma cGMP levels were significantly higher (p < 0.01) in pre-eclampsia women as compared both to pregnant normotensive controls and nonpregnant women (7.02 +/- 0.9 versus 4.8 +/- 0.76 versus 1.93 +/- 0.15 pmol.ml-1, p < 0.01). Under antihypertensive treatment, cGMP levels decreased significantly (p < 0.05) to 5.48 +/- 0.9 pmol.ml-1. The increase of plasma cGMP was associated with high ANP levels; the likelihood that a renal impairment could account for an increase in plasma cGMP was ruled out because the clearance of creatinine was not impaired. Similarly the possibility of a significant linear correlation between cGMP levels and blood pressure values or biological data was excluded in these women.. Plasma cGMP concentrations are increased in pre-eclampsia. They decrease to control values when blood pressure returns to normal values; they indicate enhanced guanylyl cyclase activation by ANP and additional factors, but cannot be considered as a direct index of the severity of pre-eclampsia.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Guanylate Cyclase; Humans; Hypertension; Nitric Oxide; Parity; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

We and other laboratories have reported that arterial baroreflex-mediated control of heart rate is blunted in spontaneously hypertensive rats (SHR) compared with normotensive controls. Recently, we reported that atrial natriuretic peptide (ANP) microinjected into the caudal nucleus tractus solitarii of SHR further blunts this defect. The present study tested the hypothesis that ANP modulates arterial baroreflex-mediated control of sympathetic nervous system activity. Nine-week-old, male SHR (n = 29) and normotensive Wistar-Kyoto control rats (n = 24) were instrumented for microinjection into the caudal nucleus tractus solitarii and for direct measurement of arterial blood pressure, heart rate, and lumbar sympathetic nervous system activity. After urethane- and alpha-chloralose-induced induced anesthesia, arterial baroreflex-mediated control of heart rate and lumbar sympathetic nerve activity was assessed during phenylephrine- (5 to 40 micrograms.kg-1.min-1) induced increases and sodium nitroprusside- (15 to 300 micrograms.kg-1.min-1) induced decreases in mean blood pressure before and after microinjection of ANP (50 ng) or monoclonal antibody to ANP (0.55 micrograms) into the caudal nucleus tractus solitarii. ANP reduced and the antibody enhanced the sensitivity of baroreflex-mediated control of both heart rate and lumbar sympathetic nerve activity in SHR but not in Wistar-Kyoto controls (P < .05). Arterial baroreflex sensitivity was unchanged with control microinjections of vehicle or mouse IgG in SHR. These data suggest that endogenous ANP in the caudal nucleus tractus solitarii may contribute to the development and/or maintenance of hypertension in SHR by blunting baroreflex-mediated control of sympathetic nervous system activity.

Topics: Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Femoral Artery; Heart Rate; Hypertension; Immunoglobulin G; Male; Mice; Microinjections; Muscle, Smooth, Vascular; Nitroprusside; Phenylephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regression Analysis; Solitary Nucleus; Species Specificity; Sympathetic Nervous System

Topics: Atrial Natriuretic Factor; Humans; Hypertension; Sodium, Dietary

Ouabain is claimed to be a hormone of adrenal origin, capable of raising arterial pressure in rats. We infused ouabain in conscious sheep under carefully controlled circumstances to determine its effects on blood pressure, urine electrolytes, and vasoactive hormones. Eight healthy ewes were studied while taking a constant intake of dietary sodium and potassium. Ouabain infusion at 0.25 mg daily over 22 days reduced heart rate and arterial pressure and had no effect on pressor responsiveness to incremental intravenous infusions of angiotensin II. Ouabain induced minor, but statistically significant, decrements in urine volume, urinary sodium excretion, plasma renin and angiotensin II concentrations, and a rise in plasma aldosterone and cortisol. Plasma ouabain levels averaged 1.37 +/- 0.28 nmol/l during ouabain infusion. In conclusion, high-dose chronic ouabain infusion in sheep did not elevate arterial pressure or alter pressor responsiveness to angiotensin II, was antidiuretic and antinatriuretic, and induced minor perturbations in circulating renin, angiotensin II, aldosterone, and cortisol.

Topics: Adrenocorticotropic Hormone; Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dose-Response Relationship, Drug; Female; Heart Rate; Hypertension; Infusions, Intravenous; Ouabain; Potassium; Pulse; Rats; Renin; Renin-Angiotensin System; Sheep; Sodium; Time Factors

In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix.. Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.. (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Base Sequence; Body Weight; Constriction; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance hyperinsulinaemia and a high frequency of hypertension. It has recently been shown that insulin exerts a sodium-retaining effect, which is preserved in NIDDM: We sought to determine whether insulin affected renal sodium handling differently in hypertensive and normotensive NIDDM patients.. After a baseline period of 2 h, eight normotensive (N-) NIDDM patients and eight NIDDM patients with hypertension (H-) underwent a euglycaemic clamp with infusion of two sequential doses of insulin (50 and 500 mU/kg/h) or vehicle (time control) during 2-h periods each. Fractional clearances of sodium and lithium were determined according to standard methods. Fractional lithium clearance was used to assess segmental tubular sodium handling.. Insulin induced similar decrements in fractional sodium excretion (N-NIDDM: 43+/-5.9 and 57+/-9.1%,H-N IDDM: 48+/-16.4 and 62+/-12.5%, low and high insulin dose respectively). Distal tubular sodium absorption increased simultaneously. A fall in fractional proximal sodium reabsorption was observed in N-NIDDM (4.4+/-2.7 and 29.8+/-5.1%, low and high insulin dose respectively), which was attenuated in H-NIDDM (-5.0+/-7.3 and -2.1+/-13.9% respectively). The latter appeared to be related to a defective atrial natriuretic factor (ANF) and renal cyclic GMP response. A modest decrease in blood pressure occurred during insulin infusion that was not related to changes in ANF or FeLi.. The findings suggest that insulin-induced sodium retention may contribute to hypertension in NIDDM if the homeostatic response to offset this effect fails.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiovascular System; Case-Control Studies; Cyclic GMP; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Insulin; Insulin Resistance; Kidney; Male; Middle Aged; Natriuresis; Renin

Previous studies have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in essential hypertension. However, whether left ventricular geometry affects plasma ANP and BNP levels remains unknown. To investigate the effect of left ventricular geometry on plasma ANP and BNP levels in essential hypertension, we measured plasma ANP and BNP levels in 90 patients with essential hypertension. All patients were hospitalized, and fasting blood samples were obtained in the early morning after 30 minutes of bed rest. Plasma ANP and BNP levels were measured by immunoradiometric assay. Hypertensive patients were classified into four groups according to echocardiographic findings that showed normal geometry, concentric remodeling, eccentric hypertrophy, or concentric hypertrophy. Mean plasma ANP and BNP levels in all essential hypertensive patients were higher than those in age-matched normotensive control subjects. Plasma ANP levels in hypertensive patients with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were higher than in normotensive control subjects, although there were no differences between normotensive subjects and hypertensive patients with normal geometry. Plasma BNP levels tended to be higher in hypertensive patients with normal geometry, concentric remodeling, and eccentric hypertrophy than in normotensive control subjects; however, the differences were not significant. Plasma BNP levels and BNP/ANP ratio were specifically higher in concentric hypertrophy. There were significant correlations between ANP and left ventricular mass index, relative wall thickness, interventricular septal thickness, posterior wall thickness, and mean arterial pressure. Plasma BNP levels significantly correlated with relative wall thickness, interventricular septal thickness, posterior wall thickness, and left ventricular mass index but not with mean arterial pressure. In addition, plasma BNP levels were well correlated with ANP levels, and the slope for the linear regression model was steeper in concentric hypertrophy than in the other four groups. These results show that plasma ANP and BNP levels are increased in essential hypertensive patients with left ventricular hypertrophy. Furthermore, BNP secretion is augmented to a greater extent in concentric hypertrophy. Thus, measurement of plasma ANP and BNP levels may be useful for the detection of concentric left ventricular hypertrophy in pati

Topics: Adult; Aged; Atrial Natriuretic Factor; Echocardiography; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Prognosis; Regression Analysis

In order to investigate the role of increased lipid peroxidation in the development of cadmium-induced hypertension, 30 male albino rats were exposed to drinking water containing 15 micrograms/ml cadmium for 30 days, and the results were compared with those of 30 controls. Water containing high cadmium concentrations caused a significant accumulation of the element in blood and kidneys, associated with an obvious elevation in blood pressure. The systolic and diastolic blood pressures rose from 102.8 +/- 7.0 and 81.2 +/- 3.8 mm Hg to 128.1 +/- 4.6 and 107.9 +/- 7.4 mm Hg, respectively, in cadmium-treated rats (p < 0.01). A decreased glomerular filtration rate and increased serum creatinine levels were accompanied by elevated levels of cortical and medullary thiobarbituric acid reactive substances in cadmium-induced hypertensive rats. The mean thiobarbituric acid reactive substance level rose from a control value of 211.5 +/- 64.1 to 303.3 +/- 46.3 nmol/g protein (p < 0.01) in the renal cortex due to the high intake of cadmium. Despite its obvious diuretic and natriuretic action in control animals, the bolus injection of 1.2 and 2.4 micrograms/kg atrial natriuretic peptide corrected neither elevated blood pressure nor the reduced glomerular filtration rate in rats exposed to cadmium. However, the tubular response to atrial natriuretic peptide remained unaltered. These data suggest that a lack of vascular response to atrial natriuretic peptide is one of the many putative causes of cadmium-induced hypertension, and cadmium-mediated increased lipid peroxidation may be involved in this unresponsiveness.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cadmium; Creatinine; Glomerular Filtration Rate; Hypertension; Kidney; Lipid Peroxidation; Male; Rats; Thiobarbituric Acid Reactive Substances

In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and by hemodynamic factors. The objective of the present study was, in essential hypertensives, to investigate the relationship between blood pressure (BP) level as well as circulating hormones on the one hand and cardiovascular structure on the other. Seventy-nine untreated essential hypertensives were examined by 24-h ambulatory BP monitoring, echocardiography, microscopy of subcutaneous resistance vessels and analyzes of plasma for angiotensin II (P-Ang II), aldosterone, atrial natriuretic factor and 24-h urinary excretion of catecholamines. Multiple regression analysis showed a statistically significant correlation between P-Ang II and the end diastolic interventricular septal diameter (IVSDd) (R = 0.32, P = .005) and a weak correlation between P-Ang II and the left ventricular posterior wall diameter (R = 0.22, P = .049). These correlations were closer in the subgroup of patients (N = 54) who had never received antihypertensive treatment (R = 0.42/0.32, respectively). A weak, though statistically significant, correlation was found between the catecholamine excretion and systolic BP (R = 0.26, P = .03). A statistically negative correlation existed between catecholamines and end-diastolic left ventricular internal diameter index (R = -0.36, P = .001). No significant relationship was found between hormonal levels and the tunica media structure of the resistance arteries. In conclusion, P-Ang II was in this study significantly correlated to IVSDd, but not to resistance artery structure. In essential hypertension a complex relationship exists between humoral and hemodynamic factors and cardiovascular remodeling.

Topics: Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Catecholamines; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Radioimmunoassay

Regular administration of recombinant erythropoietin (EPO) is frequently complicated by a rise in arterial blood pressure. We therefore asked if prolonged stimulation of endogenous EPO production has the same effect. To this end, male Sprague-Dawley rats were placed in a hypobaric chamber (390 mm Hg) for 24 days. The control (NL) group was placed in the chamber at normobaric condition. The animals were then removed from the chamber and monitored through day 108. Plasma EPO peaked within 24 hours and returned to baseline by day 7 and remained so thereafter. Hematocrit rose steadily during the hypoxic phase and declined steadily during the normobaric phase, reaching the baseline on day 45. This was accompanied by parallel changes in erythrocyte mass and blood volume. The rise in hematocrit during hypoxia was accompanied by a parallel rise in blood pressure which peaked on day 24. Despite the restoration of normal hematocrit, erythrocyte mass and blood volume following resumption of normoxia, blood pressure remained elevated throughout the observation period. To dissect the role of hypoxia from that of the associated rise in hematocrit, the experiments were repeated using a group of rats whose hematocrits were kept constant by repeated phlebotomies. These animals exhibited a sustained rise in blood pressure identical to that found in the original group. Thus, prolonged hypobaric hypoxia leads to a severe hematocrit-independent systemic hypertension (HTN) that persists long after the restoration of normoxia. Given the transient nature of the rise in its plasma concentration, endogenous EPO does not appear to play a role in the genesis of the observed systemic HTN. The authors believe that this animal model can be used for future studies of the mechanism, consequences and treatment of acquired HTN.

Topics: Air Pressure; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Disease Models, Animal; Erythropoietin; Hematocrit; Hypertension; Hypoxia; Male; Rats; Rats, Sprague-Dawley; Time Factors

Renal responses of anaesthetized Milan hypertensive (MHS) and Milan normotensive (MNS) rats to des-[Glu18-Ser19-Gly20-Leu21-Gly22]r atrial natriuretic peptide-4-23 (cANP4-23) a specific ligand for atrial natriuretic petide (ANP) clearance receptors were examined.. The peptide was administered intravenously as an initial bolus injection (10 micrograms/kg body weight) followed by constant infusion (1 microgram/min per kg body weight) for 30 min. Glomerular filtration rate, urine flow, sodium excretion and mean blood pressures were measured. Using the same protocol, plasma ANP levels were determined.. Plasma ANP levels were significantly increased in both Milan strains (from 9.5 +/- 1.8 to 23.7 +/- 3.2 fmol/ml in MHS rats and from 9.8 +/- 1.2 to 15.9 +/- 1 fmol/ml in MNS rats). This increase was significantly greater in the MHS than in the MNS rats. The cANP4-23 infusions were diuretic and natriuretic in both strains of rats but despite a greater rise in plasma ANP level, the renal response was attenuated in the MHS compared with that in the MNS rats. Furthermore, the time course differed in that the hypertensive rats had a diuresis of slower onset. During cANP4-23 infusion, the mean blood pressure decrease was greater in the MHS rats, consistent with the fact that phenylephrine-precontracted isolated MHS rat aortae were threefold more sensitive to ANP-induced relaxation than were MNS rat aortae. Displacements of [125l]-rANP by rANP and cANP4-23 in isolated renal glomeruli indicated that MHS rats have similar amounts of cANP receptors but with a higher affinity for cANP than have MNS rats.. cANP4-23 infusion increased plasma ANP more in MHS than in MNS rats. Renal responses were attenuated in the MHS rat compared with those in MNS rats. These differential actions cannot be explained in terms of glomerular ANP receptor densities, although aortic ring sensitivities differ between the two strains of rat.

Topics: Amino Acid Sequence; Animals; Aorta; Atrial Natriuretic Factor; Glomerular Filtration Rate; Hypertension; In Vitro Techniques; Male; Molecular Sequence Data; Rats; Receptors, Atrial Natriuretic Factor; Sodium

It has been observed that while most hypertensive hemodialysis patients normalize their blood pressure with volume removal, there is a population of hemodialysis patients whose hypertension is refractory to volume removal. Our hypothesis is that such patients are still volume overloaded posthemodialysis and are not at a "true" dry weight. This study used atrial natriuretic peptide (ANP) assays (as a marker of hydration status) to study this hypothesis. Three groups of patients were studied: normotensive hemodialysis patients (n = 12; group 1), hypertensive hemodialysis patients who consistently normalize their blood pressure with fluid removal (n = 12; group 2), and hypertensive hemodialysis patients whose hypertension is refractory to fluid removal (n = 9; group 3). Plasma ANP levels were measured before and after hemodialysis by radioimmunoassay after extraction on Sep-Pac (Penninsula Laboratories, Belmont). On the day of study the predialysis mean arterial pressures in the three groups were 94.9 +/- 1.9 mm Hg in the normotensive group, 119.5 +/- 2.7 mm Hg in the dialysis-sensitive hypertension group, and 134.4 +/- 3.8 mm Hg in the dialysis-refractory hypertension group (P < 0.05 for comparisons between all groups). Mean arterial pressure did not change predialysis and postdialysis in the normotensive group (94.9 +/- 1.9 mm Hg to 93.1 +/- 1.8 mm Hg, respectively; P = 0.24), decreased in the dialysis-sensitive hypertension group (119.5 +/- 2.7 mm Hg to 100.8 +/- 3.7 mm Hg, respectively; P < 0.0001), and did not change in the dialysis-refractory hypertension group (134.4 +/- 3.8 mm Hg to 133.8 +/- 2.9 mm Hg, respectively; P = 0.77). Predialysis and postdialysis serum ANP levels were, respectively, 235.8 +/- 27.7 pg/mL and 237.8 +/- 36.2 pg/mL (P = 0.92) in the normotensive group, 809.2 +/- 295.5 pg/mL and 161.1 +/- 48.6 pg/mL (P = 0.03) in the dialysis-sensitive hypertension group, and 1,728.3 +/- 309.9 pg/mL and 1,936.1 +/- 359.1 pg/mL (P = 0.22) in the dialysis-refractory hypertension group. Mean predialysis ANP levels were higher in the dialysis-refractory hypertension group than in the dialysis-sensitive hypertension group (1,728.3 +/- 309.9 pg/mL v 809 +/- 359.1 pg/mL; P = 0.048). Mean prehemodialysis ANP in all hypertensive patients (n = 21) was higher (1,203.1 +/- 232.9) than in the normotensive patients (235.8 +/- 27.7) (P = 0.004). In conclusion, our findings are consistent with a hypothesis that inadequate removal of excess volume during hemodia

Topics: Adult; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Blood Volume; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO2+NO3 in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P < .01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO2+NO3 levels were higher (P < .05) in salt-sensitive (189 +/- 7.9 mumol/L) and salt-resistant (195 +/- 13.5 mumol/L) black patients than in control subjects (108 +/- 9.7 mumol/L). During high salt intake, plasma NO2+NO3 decreased significantly (P < .01) in both salt-sensitive (150 +/- 7.0 mumol/L) and salt-resistant (142 +/- 9.0 mumol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

Topics: Adult; Atrial Natriuretic Factor; Black People; Diet, Sodium-Restricted; Drug Resistance; Female; Humans; Hypertension; Male; Nitric Oxide; Sodium Chloride, Dietary; White People

1. The aim of the study was to detect differences between salt-sensitive and salt-resistant hypertensive patients in the response of the renin-aldosterone axis, plasma noradrenaline and atrial natriuretic peptide to high salt intake. 2. Fifty essential hypertensive patients followed 2 weeks of a standard diet with 20 mmol of NaCl daily, supplemented by placebo tablets for the first 7 days and by NaCl tablets for the last 7 days, in a single-blind fashion. Salt sensitivity was defined as a significant rise (P < 0.05) in 24 h mean blood pressure obtained by ambulatory blood pressure monitoring from the low- to the high-salt period. Biochemical and hormonal measurements were performed on the last day of both periods. 3. Twenty-two (44%) patients fulfilled criteria of salt-sensitive hypertension, whereas the remaining 28 (56%) were considered salt-resistant. High salt intake promoted a significant decrease (P < 0.05) in plasma creatinine, potassium, glucose, cholesterol, low-density lipoprotein-cholesterol, triacylglycerols, uric acid and plasma renin activity, and a significant increase in plasma atrial natriuretic peptide and 24 h urinary calcium excretion. The direction of these changes did not differ between salt-sensitive and salt-resistant patients. Salt-resistant hypertensive patients exhibited a significant decrease in plasma aldosterone induced by high salt intake (from 446 +/- 35 to 226 +/- 35 pmol/l; P < 0.001), whereas this parameter was not significantly modified in salt-sensitive patients (from 485 +/- 76 to 364 +/- 83 pmol/l; P not significant). Salt-sensitive patients showed an increase in plasma noradrenaline after high salt intake (from 1.15 +/- 0.11 to 1.56 +/- 0.14 nmol/l; P < 0.05), whereas salt-resistant patients presented a decrease in this parameter (from 1.48 +/- 0.08 to 1.12 +/- 0.08 nmol/l; P < 0.05). The change in plasma noradrenaline was directly correlated with the change in mean blood pressure induced by high salt intake (r = 0.479; P = 0.003). 4. We conclude that the increase in blood pressure induced by high salt intake in salt-sensitive patients is associated with a stimulation of the sympathetic nervous system and a blunted decrease in plasma aldosterone. Conversely, changes in renal function, electrolyte excretion and plasma concentrations of atrial natriuretic peptide induced by high salt intake seem to be similar in both salt-sensitive and salt-resistant patients.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Glucose; Calcium; Cholesterol; Cholesterol, LDL; Creatinine; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Potassium; Renin-Angiotensin System; Sodium Chloride; Sodium Chloride, Dietary; Triglycerides; Uric Acid

The present study is aimed to investigate the 24-hour pattern of Atrial Natriuretic Peptide (ANP) plasma concentration in normotensive (N) and hypertensive (H) heart transplanted patients (HTP) in order to detect the pathophysiological role of blood pressure regimen for ANP increase in HTP.. Eight NHTP and five HHTP have been investigated, all being hemodynamically compensated, without histological evidence of rejection and treated by Cyclosporine, Azathioprine and Prednisone. The control group was constituted by 10 clinically healthy subjects (CHS). ANP was assayed six times over the 24 h span. The contrasts between groups were statistically analyzed by means of Student's t-test for the 24 h mean values.. The t-test found a statistically significant difference between the ANP 24 h mean levels either of CHS and HTP or NHTP and HHTP. The ANP 24 h mean plasma levels are increased of 190.4% in HHTP and of 44.3% in NHTP in comparison with CHS.. The findings suggest that the further elevation of ANP in HHTP is a compensatory mechanism to antagonize high blood pressure. Moreover, being the ANP percent increase in HHTP three times more.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Circadian Rhythm; Female; Heart Transplantation; Humans; Hypertension; Male; Middle Aged; Postoperative Complications

Topics: Atrial Natriuretic Factor; Black People; Case-Control Studies; Humans; Hypertension; Polymorphism, Genetic; White People

We undertook this study to investigate the regulatory mechanism of cardiac gene expression in spontaneously hypertensive rats (SHR) during development. We measured cardiac mRNAs by Northern blot analysis. In 9-week-old SHR at the very early stage of cardiac hypertrophy, the expression of various cardiac genes related to the regulation of cardiac contraction and relaxation was already significantly changed compared with control Wistar-Kyoto rats, indicating that cardiac molecular changes are responsible for cardiac remodeling or the modulation of cardiac performance in SHR. We gave various types of antihypertensive drugs, at oral doses causing a mild and comparable hypotensive effect, to 27-week-old SHR to examine the effects on the altered cardiac gene expression. Imidapril, an angiotensin-converting enzyme inhibitor, normalized the increased gene expression of atrial natriuretic polypeptide and collagen types I and III and the decreased expression of alpha-myosin heavy chain in SHR heart. Atenolol (a beta 1-blocker) combined with doxazosin did not affect cardiac ANP and alpha-myosin heavy chain expression of SHR but normalized the increased collagen expression. In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR. These results show that the cardiac renin-angiotensin system is involved in the altered cardiac gene expression in SHR. The beta 1- but not alpha 1-adrenergic receptor is also responsible for the increased cardiac collagen expression in SHR.

Topics: Actins; Aging; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Collagen; Gene Expression Regulation; Heart Rate; Hypertension; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic; Transforming Growth Factor beta

Orthotopic heart transplantation may interrupt key neural and humoral homeostatic mechanisms that normally adjust Na+ and fluid excretion to changes in intake. Such an interruption could lead to plasma volume expansion.. We measured plasma volume and fluid regulatory hormones under standardized conditions in 11 heart transplant recipients (58 +/- 7 years old; mean +/- standard deviation) 21 +/- 4 months after transplantation, in 6 liver transplant recipients (51 +/- 6 years old) 13 +/- 8 months after transplantation (cyclosporine control group), and in 7 normal healthy control subjects (61 +/- 9 years old). Administration of all diuretics and antihypertensive drugs was discontinued before the study. After 3 days during which subjects ate a constant diet containing 87 mEq of Na+ per 24 hours, plasma volume was measured by a modified Evans blue dye (T-1824) dilution technique. Renal creatinine clearance was measured and blood samples were drawn for determination of plasma levels of vasopressin, angiotensin II, aldosterone, atrial natriuretic peptide, and plasma renin activity.. Supine resting plasma renin activity, angiotensin II, and aldosterone (renin-angiotensin-aldosterone axis) and vasopressin levels were not different among the control, heart transplant, and liver transplant groups. However, there was a trend toward elevated angiotensin II (p < or = 0.08) and aldosterone (p < or = 0.08) levels in the heart transplant recipients. Atrial natriuretic peptide levels were significantly elevated two to threefold in the heart transplant recipients when compared with those in the two control groups. Blood volume, normalized for body weight (milliliters per kilogram), was significantly greater (14%) in the heart transplant recipients when compared with that in liver transplant recipients and normal healthy control subjects. Blood volume values did not differ (p > or = 0.05) between the two control groups.. Extracellular fluid volume expansion (+14%) occurs in clinically stable heart transplant recipients who become hypertensive. Although hyperactivity of the renin-angiotensin-aldosterone axis is not apparent during supine resting conditions, our data suggest that the renin-angiotensin-aldosterone system is not responsive to a hypervolemic stimulus and this is likely a consequence of chronic cardiac deafferentation. Thus, poor adaptation of the renin-angiotensin-aldosterone system to fluid retention may be partly responsible for the incidence and severity of posttransplantation hypertension in some heart transplant recipients.

Topics: Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Denervation; Electrolytes; Female; Heart; Heart Transplantation; Hemodynamics; Hormones; Humans; Hypertension; Liver Transplantation; Male; Middle Aged; Neurosecretory Systems; Plasma Volume; Vasopressins; Ventricular Function, Left

We examined whether plasma brain natriuretic peptide levels are abnormally elevated in hypertrophic obstructive cardiomyopathy compared with other cardiac diseases.. We previously reported that plasma brain and atrial natriuretic peptide levels were elevated in hypertrophic cardiomyopathy.. We compared plasma concentrations of brain and atrial natriuretic peptide and hemodynamic and echocardiographic data in 50 patients with hypertrophic obstructive cardiomyopathy (n = 15, mean [+/-SD] intraventricular pressure gradient 37 +/- 16 mm Hg), hypertrophic nonobstructive cardiomyopathy (n = 15), aortic stenosis (n = 10, mean pressure gradient 41 +/- 18 mm Hg) and hypertensive heart disease (n = 10, mean systolic/diastolic blood pressure 203 +/- 16/108 +/- 11 mm Hg, respectively) and 10 normal subjects.. Plasma brain natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group (397.1 +/- 167.8 pg/ml*) than in the hypertrophic nonobstructive cardiomyopathy (60.0 +/- 48.1 pg/ml*), hypertensive heart disease (53.9 +/- 31.4 pg/ml*), aortic stenosis (75.4 +/- 54.3 pg/ml*) and normal groups (9.8 +/- 6.4 pg/ml [*p < 0.05 vs. normal group, p < 0.05 vs. hypertrophic obstructive cardiomyopathy group]). Although plasma atrial natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group than the other patient groups, the brain/atrial natriuretic peptide ratio in the hypertrophic obstructive cardiomyopathy group was higher (4.5 +/- 2.3) than those in the other three patient groups (1.1 to 1.4) and the normal group (0.7 +/- 0.5). Left ventricular end-diastolic pressure and left ventricular end-diastolic volume index were similar among the four patient groups. The interventricular septal thickness and the ratio of interventricular septal thickness to left ventricular posterior wall thickness were similar between the hypertrophic obstructive and nonobstructive cardiomyopathy groups.. Abnormal elevations of plasma brain natriuretic peptide levels are difficult to explain on the basis of hemodynamic and echocardiographic data and are a special feature of hypertrophic obstructive cardiomyopathy.

Topics: Adult; Aged; Aortic Valve Stenosis; Atrial Natriuretic Factor; Brain-Derived Neurotrophic Factor; Cardiomyopathy, Hypertrophic; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Osmolar Concentration

Central nervous system feedback loops centered on hypothalamic neurons control atrial natriuretic peptide (ANP). We evaluated the ANP response to arterial hypotension, isotonic blood volume expansion, and increase in plasma osmolality in 14 patients with multiple system atrophy (MSA). Seven of the patients were characterized by a lack of vasopressin response to hypotension (MSA type B), suggesting chronic sinoaortic denervation, and seven by a preserved response (MSA type A). Orthostatic hypotension decreased ANP in controls and type A patients, whereas ANP in type B was not affected. Isotonic saline infusion increased ANP and diuresis in controls and type A patients, whereas it did not affect ANP in type B. Osmotic load increased plasma osmolality and vasopressin in controls and MSA patients and ANP in controls and type A but not in type B patients. In MSA patients with altered afferent control of vasopressin, ANP secretion is not stimulated by blood volume expansion, osmotic load, or blood pressure, suggesting that afferent excitatory control plays a role in the release of ANP.

Topics: Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Brain Diseases; Diuresis; Female; Humans; Hypertension; Isotonic Solutions; Male; Middle Aged; Nerve Degeneration; Osmolar Concentration; Posture; Saline Solution, Hypertonic; Sodium Chloride; Vasopressins

In spontaneously hypertensive rats (SHR), high NaCl diets increase arterial pressure and sympathetic nervous system activity by decreasing noradrenaline release in the anterior hypothalamic area (AHA), thereby reducing the activation of sympathoinhibitory neurons in AHA. Atrial natriuretic peptide (ANP) can inhibit the release of noradrenaline, and ANP concentration is elevated in the AHA of SHR. The present study tests the hypothesis that in SHR, local ANP inhibits noradrenaline release from nerve terminals in AHA. Male SHR fed a basal or high NaCl diet for 2 wk and normotensive Wistar Kyoto rats (WKY) fed a basal NaCl diet were studied. In SHR on the basal diet, microperfusion of exogenous ANP into the AHA elicited a dose-related decrease in the concentration of the major noradrenaline metabolite 3-methoxy-4-hydroxy-phenylglycol (MOPEG) in the AHA; this effect was attenuated in the other two groups. In a subsequent study, the ANP-C (clearance) receptor agonist c-ANP was microperfused into the AHA to increase extracellular concentration of endogenous ANP in AHA. c-ANP reduced AHA MOPEG concentration in SHR on the basal NaCl diet but not in the other two groups. These data support the hypothesis that local ANP inhibits noradrenaline release in the AHA and thereby contributes to NaCl-sensitive hypertension in SHR.

Topics: Animals; Atrial Natriuretic Factor; Hypertension; Hypothalamus, Anterior; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium, Dietary

Genetic factors may be involved in both essential hypertension and cardiac hypertrophy. To identify genes contributing to elevated for blood pressure and cardiac hypertrophy in the spontaneously hypertensive rat (SHR), we performed a cosegregation analysis between blood pressure and heart weight and microsatellite markers for the candidate gene ANF on chromosome 5 in F2 animals obtained by mating SHR with Wistar-Kyoto (WKY) rats. We found evidence for a quantitative trait locus (QTL) determining mean blood pressure on chromosome 5 between atrial natriuretic factor (ANF) and MITR-3893 loci. No evidence for a QTL influencing heart weight was found. We propose that in SHR, blood pressure and heart weight may be independently controlled by different genetic mechanisms and that a gene close to ANF locus on chromosome 5 contributes towards hypertension in these animals.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Pressure; Chromosome Mapping; DNA; Female; Heart; Hypertension; Male; Microsatellite Repeats; Organ Size; Rats; Rats, Inbred SHR

Cardiac ventricle is shown to be an important source of circulating brain natriuretic peptide (BNP) in hypertensive rats with left ventricular hypertrophy (LVH). This study examined the effect of short-term exercise with a bicycle ergometer on plasma BNP concentrations in 21 essential hypertension patients with LVH established by echocardiography. The results were compared with those from 24 age-matched hypertensives without LVH. Blood pressure, heart rate, plasma renin activity (PRA), and plasma norepinephrine level increased during exercise, but the mean increases of these parameters were not different in the two groups. Resting BNP levels were slightly but significantly higher in the LVH group than in the non-LVH group. This peptide increased during exercise in the two groups, but the exercise-induced increase (percent increase) in plasma BNP was significantly greater in the LVH group than in the non-LVH group (207% +/- 50% v 141% +/- 36%, P < .05). The exercise-induced increase in BNP was significantly correlated with the left ventricular (LV) mass index (N = 45, r = .60, P < .01). By contrast, the exercise-induced increase in BNP was not correlated with the exercise-induced increase in heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, PRA, or noradrenaline level. These results suggest that short-term exercise induces an accelerated increase of plasma BNP in hypertensive subjects with LVH. The LV mass appeared to be related to the observed increase of plasma BNP concentration, at least in our hypertensive patients with LVH.

Topics: Adult; Aged; Atrial Natriuretic Factor; Exercise; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Renin

Hypertension is commonly associated with diabetes mellitus. The aim of the present study was to explore the pathophysiological significance of the natriuretic peptide (NP) system in hypertension associated with genetically obese/hyperglycemic Wistar fatty rats. The messenger RNA (mRNA) levels of the two biologically active NP receptors, NP-A receptor [more specific for atrial natriuretic peptide (ANP)] and NP-B receptor [more specific for C-type natriuretic peptide (CNP)], and CNP mRNA levels were determined in the aorta and kidney by ribonuclease protection assay. Plasma ANP levels were determined by RIA. Both NP-A and NP-B receptor mRNA levels in the aortae of Wistar fatty rats were double those in Wistar lean rats. Plasma ANP levels and CNP mRNA levels in the aorta of Wistar fatty rats were also significantly higher than those in Wistar lean rats. In contrast, there was no significant difference in renal levels of the mRNA for both NP receptors and CNP between the two strains. Administration of a NP-A and -B receptor antagonist, HS-142-1, to Wistar fatty rats resulted in a significant increase in systolic blood pressure and a larger decrease in plasma cGMP level than that in Wistar lean rats, with no difference in the extents of decrease in urine volume and urinary sodium excretion between the two strains. These results suggest that both the ANP/NP-A system and the CNP/NP-B system in vessels are up-regulated at the level of gene expression and may, thus, play an important role in counteracting the hypertension associated with diabetes mellitus.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Vessels; Cyclic GMP; Diuresis; Guanylate Cyclase; Hyperglycemia; Hypertension; Kidney; Male; Natriuresis; Natriuretic Peptide, C-Type; Obesity; Polysaccharides; Proteins; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger

Alcohol acutely causes vasodilation and hypotension in Orientals. To study the mechanisms responsible for the alcohol-induced blood pressure (BP) reduction, we examined levels of various vasoactive hormones after a single intake of alcohol in twelve Japanese men with mild hypertension. On the alcohol intake day, they consumed 1 ml/kg of alcohol with an evening meal, while on the control day they took an isocaloric control drink. BP and vasoactive hormone levels were determined before and 2 h after intake of the alcohol or the control drink. BP after alcohol ingestion was significantly lower than that before drinking or on the control day. This alcohol-induced hypotension was associated with significant increases in heart rate, plasma catecholamines and plasma renin activity (PRA). The changes in heart rate and plasma noradrenaline were inversely related to the changes in BP. Plasma levels of vasopressin and insulin were lower in the alcohol period than in the control period, but these changes were not correlated with the changes in BP. Levels of aldosterone, cortisol, atrial natriuretic peptide, prostaglandin (PG) E2, 6-keto-PGF1 alpha, beta-endorphin, and cyclic GMP were not significantly different between the alcohol and the control periods. These results suggest that changes in pressor hormones may not contribute to the acute hypotensive effect of alcohol, and that the sympathetic nervous system is activated by the BP reduction. The levels of the depressor hormones measured also appear to play no role in alcohol-induced hypotension.

Topics: Adult; Aged; Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Ethanol; Hormones; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Potassium; Renin

There is a lot of discussion on the effects of ethanol (ETOH) on blood pressure (BP). It has been suggested that chronic moderate ETOH consumption prevents the development of age-dependent hypertension in humans and spontaneously hypertensive rats (SHR). However, the mechanism mediating this effect is unknown. In the present studies, we hypothesized the implication of atrial natriuretic peptide (ANP), a BP-lowering hormone, on the antihypertensive effect of moderate ETOH consumption. A 20% v/v solution of alcohol was given as drinking fluid to SHR and normotensive Wistar-Kyoto (WKY) rats for up to 32 weeks. This treatment prevented, at least in part, the age-dependent increase of BP in SHR and WKY rats. The lower BP was associated with significantly lower levels of circulating atrial natriuretic peptide in both groups. After chronic ETOH administration, total ANP content and concentration were higher in the left and right atria of SHR and WKY rats than in water-treated controls. Despite the ETOH-induced increase in atrial ANP content, there was no significant change in atrial ANP mRNA, suggesting decreased atrial release. Chronic ETOH treatment significantly reduced ANP mRNA in the ventricles of SHR but not of WKY rats. Correspondingly, ventricular ANP content and concentration were lowered by ETOH in SHR only. Chronic ETOH administration induced a significant increase of plasma arginine vasopressin and a significant decrease of plasma aldosterone in SHR but not in WKY rats. Thus, chronic ETOH treatment prevented the age-dependent elevation of BP in both SHR and WKY rats and altered the activity of heart ANP as well as of the aldosterone and plasma arginine vasopressin systems.

Topics: Aging; Alcohol Drinking; Aldosterone; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Ethanol; Heart Atria; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure.

Topics: Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Electrolytes; Hypertension; Mice; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neprilysin; Protease Inhibitors; Proteins; Rats; Rats, Sprague-Dawley; Renin; Sodium; Thiorphan

To evaluate the effect of 7-day angiotensin II antagonism with losartan, an AT1-receptor antagonist, on systolic blood pressure, renal sodium and water excretion and on the atrial natriuretic factor system in one-kidney, one clip hypertensive rats.. The one-kidney, one clip hypertensive rats were separated into four groups: untreated (group 1), low-sodium diet (group 2), losartan (20 mg/kg orally, group 3) and low-sodium diet with losartan (group 4). All of the rats were kept in metabolic cages with urinary volume, urinary sodium level and water intake being evaluated daily. Body weight and blood pressure were assessed before treatment and at the end of the observation period. Renal glomerular and papillary atrial natriuretic factor receptors were assessed by radioligand binding experiments.. No differences were observed either in body weight or in blood pressure between groups at the outset After 1 week, blood pressure was 184+/-4, 184+/-7, 170+/-5 and 78+/-8 mmHg, in groups 1, 2, 3 and 4, respectively. Group 3 rats failed to gain weight and had high urinary volume. In contrast, group 4 rats lost 15% of their original body weight. Both of the losartan-treated groups presented an apparently reduced cardiac hypertrophy but it was only clear in the low-sodium diet group. Both of the losartan-treated groups had high plasma renin activity. All of the three treated groups showed upregulation of glomerular and no changes in papillary atrial natriuretic factor receptors. Overall, mortality was 18, 27, 0 and 36% in groups 1, 2, 3 and 4, respectively.. Losartan administration reduces blood pressure in one-kidney, one clip rats only when combined with a low-sodium diet. Both low-sodium diet and angiotensin II antagonism upregulate renal glomerular but not papillary atrial natriuretic factor receptors, suggesting a divergent regulatory mechanism.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Water; Cardiomegaly; Cardiovascular Diseases; Disease Models, Animal; Drinking; Drug Antagonism; Heart; Hypertension; Kidney; Losartan; Male; Natriuresis; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Time Factors

Impairment of humoral and neural regulation of blood pressure may contribute to preoperative and postoperative hypertension in coarctation of the aorta and may also affect the release of vasopressin and atrial natriuretic factor. Because vasopressin and atrial natriuretic factor have potent vasoactive effects, we measured plasma vasopressin and atrial natriuretic factor levels by radioimmunoassay before operation and for 5 days after operation in 11 patients aged 9 months to 12 years undergoing coarctation repair and in 12 control patients undergoing other cardiovascular operations. Six patients in the coarctation group required minimal antihypertensive therapy (group I) and five required prolonged intravenous antihypertensive therapy (group II). Before operation, vasopressin levels correlated with systolic blood pressure for all patients in the coarctation group (r = 0.83, p < 0.01) whereas atrial natriuretic factor levels did not. Before operation, atrial natriuretic factor levels were lower (28 +/- 5 vs 41 +/- 7 and 50 +/- 8 pg/ml, p < 0.05) and vasopressin levels were higher (28 +/- 6 vs 5.4 +/- 0.9 and 7 +/- 3 pg/ml, p < 0.05) in group II than in group I or control patients. Vasopressin levels were higher (p < 0.05) on the day of operation and on postoperative days 2 through 5 in group II than in group I and in control patients. Atrial natriuretic factor levels were lower during the day of operation in group II than in group I or in control patients (26 +/- 7 vs 51 +/- 16 and 50 +/- 7 pg/ml, p < 0.05) and remained lower than control values on postoperative days 1 and 3 through 5. Elevated vasopressin and lowered atrial natriuretic factor levels may contribute to preoperative and postoperative hypertension in coarctation.

Topics: Adolescent; Aortic Coarctation; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Child; Child, Preschool; Humans; Hypertension; Infant; Nitroprusside; Postoperative Care; Radioimmunoassay

Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.

Topics: Adrenal Glands; Animals; Atrial Natriuretic Factor; Base Sequence; Cell Line; Diet; DNA Primers; Female; Gene Targeting; Guanylate Cyclase; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Molecular Sequence Data; Myocardium; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Sodium Chloride

Chronic infusion of atrial natriuretic peptide (ANP) has been shown to cause natriuresis, diuresis, and hypotension in rats and humans. We explored the effect of a continuous supply of ANP by somatic ANP delivery on genetically hypertensive rats. A DNA construct containing the human ANP gene fused to the Rous sarcoma virus 3'-long terminal repeat (RSV-LTR) was injected intravenously into spontaneously hypertensive rats (SHR) through the tail vein. Expression of human ANP in SHR was identified in the heart, lung, and kidney by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of naked ANP plasmid DNA (12.3 kb) caused a significant reduction of systemic blood pressure in young SHR (4 weeks old), and the effect continued for 7 weeks. The differences were significant at 1 to 2 weeks (n = 6, P < .05) and 3 to 6 weeks after injection (n = 6, P < .01) A maximal blood pressure reduction of 21 mm Hg in young SHR was observed 5 weeks after injection with ANP DNA (159.4 +/- 3.02 mm Hg, mean +/- SEM, n = 6) compared with SHR injected with vector DNA alone (180.2 +/- 3.02 mm Hg, mean +/- SEM; n = 6; P < .01). Somatic gene delivery of human ANP DNA had no effect on the blood pressure of adult SHR (12 weeks old). After ANP gene delivery, there were significant increases in urinary volume and urinary potassium output (n = 6, P < .05) but not in body weight, heart rate, water intake, urinary sodium output, urinary creatine, and urinary protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Avian Sarcoma Viruses; Blood Pressure; Blotting, Southern; Cell Line; Cloning, Molecular; Data Interpretation, Statistical; DNA; Enzyme-Linked Immunosorbent Assay; Genetic Therapy; Humans; Hypertension; Male; Polymerase Chain Reaction; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Repetitive Sequences, Nucleic Acid; RNA, Messenger; Time Factors; Transfection

We investigated the relationship between changes in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and changes in cardiac function during mild exercise in patients with mild hypertension. The handgrip test (HGT) was performed by 21 untreated, mildly hypertensive patients, mean age 45 +/- 5 years. M-mode and pulse Doppler echocardiograms were recorded before and during HGT. In 7 patients (Group A), diastolic function, which was determined by the peak early velocity and peak atrial velocity (E/A) ratio using Doppler echocardiography was attenuated during HGT (1.19 +/- 0.21 TO 1.04 +/- 0.16, p < 0.05). There was no change in diastolic function in the remaining 14 patients, left atrial diameter, cardiac index, ejection fraction, plasma renin activity, plasma norepinephrine, blood pressure, nor heart rate were different between the two groups. While ANP was increased in Group A during HGT (from 41.0 +/- 18.2 to 54.0 +/- 24.1 pg/ml, p < 0.05) it was unchanged in Group B (36.8 +/- 16.3 to 33.5 +/- 11.9 pg/ml). BNP did not change in either Group (Group A: 2.9 +/- 3.1 to 3.0 +/- 3.4 pg/ml, Group B: 2.6 +/- 1.6 to 3.6 +/- 4.8 pg/ml). The percent change in ANP during HGT did not correlate with the percent change in BNP. Thus, the impairment of cardiac functional reserve appeared to influence ANP excretion in patients with mild hypertension.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Echocardiography; Exercise; Female; Hand Strength; Heart; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins

We examined the relationship between cardiac hypertrophy, myosin heavy chain (MHC) isoform expression, and production of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) before and after the development of DOCA-salt hypertension. DOCA-salt rats exhibited significant left ventricular hypertrophy at the prehypertensive stage (1 week of treatment), without MHC isoform switch or change in natriuretic peptide gene expression. In the hypertensive stage (5 weeks of treatment), pronounced left ventricular hypertrophy was observed, and this was characterized by an increase in beta-MHC protein, resulting in a switch from 90% alpha-MHC to 51% alpha-MHC and 49% beta-MHC. ANF and BNP mRNA levels and peptide content were significantly increased at this stage. Unexpectedly, the MHC isoform switch was evident in the non-hypertrophied right ventricle to the same degree as in the left ventricle. Natriuretic peptide production was also increased in the right ventricle at 5 weeks of treatment, but to a lesser degree than in the left ventricle. In contrast, in the hypertrophied left atrium there was no MHC isoform switch, while ANF and BNP mRNA levels were augmented. Plasma ANF was significantly increased in the prehypertensive stage; this was accompanied by a partial depletion of atrial ANF stores. Plasma BNP was increased only in the hypertensive stage, reflecting an increase in ventricular BNP synthesis and secretion. These results suggest that 1) cardiac hypertrophy, MHC isoform expression, and stimulation of natriuretic peptide production are processes that may be dissociated from each other; 2) increases in plasma ANF without a concomitant increase in plasma BNP reflect atrial hemodynamic overload, while increases in both ANF and BNP in plasma are associated with ventricular hypertrophy; and 3) there exist differences in the storage, secretion, and processing patterns of ANF and BNP in the atria.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Body Weight; Cardiomegaly; Centrifugation, Density Gradient; Chromatography, High Pressure Liquid; Desoxycorticosterone; Hypertension; Isomerism; Male; Myocardium; Myosin Subfragments; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA; Sodium Chloride

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), are two mechanistically similar enzymes involved in the metabolism of several vasoactive peptides. Selective inhibitors of ACE are effective antihypertensive agents in high-renin, renovascular rats and normal-renin, spontaneously hypertensive rats (SHR), but are not effective in the low-renin, deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In contrast, NEP inhibitors are only effective in the low-renin model of hypertension. Treatment with a combination of selective inhibitors or with a dual inhibitor of both enzymes produces an antihypertensive response regardless of basal plasma renin activity. In this study, we compared the activities of MDL 100,173, a novel subnanomolar inhibitor of both ACE and NEP, with those of equimolar doses of captopril, a selective ACE inhibitor, following intravenous administration in these three rat models of hypertension. Treatment with MDL 100,173 significantly lowered blood pressure compared to vehicle treatment in all three models, whereas captopril treatment lowered blood pressure in the renovascular and SHR models only. Administration of MDL 100,173 also significantly elevated diuresis and natriuresis compared to either vehicle or captopril treatment in the SHR and DOCA-salt rats. Urinary excretion of atrial natriuretic peptide (ANP) was increased by MDL 100,173 treatment in all three models of hypertension. Treatment with captopril did not alter urine, sodium, or ANP excretion in any of the models. However, plasma-renin activity was elevated by both MDL 100,173 and captopril '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Blood Pressure; Captopril; Disease Models, Animal; Diuresis; Hypertension; Hypertension, Renal; Male; Neprilysin; Protease Inhibitors; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sodium

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To assess the relationship of plasma atrial natriuretic peptide (ANP) levels with blood pressure levels and the occurrence of hypertension in a large population-based sample.. We performed a cross-sectional study of the relationship between ANP levels and blood pressure levels, diagnosis of hypertension, and family history of hypertension in Caucasians from Rochester, Minnesota.. Plasma ANP and blood pressure levels were measured in 1,338 Caucasian subjects who were members of 301 three-generation families from the population of Rochester. Hypertension was defined as systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more. Each subject in the parental generation was categorized as having zero, one, or two parents with hypertension. Analyses were done separately for each generation and gender stratum.. Within gender and generation strata, we noted no consistent pattern of positive or negative correlation of plasma ANP levels with systolic blood pressure, diastolic blood pressure, or heart rate. Within the grandparental generation, mean plasma ANP levels did not differ between those with normal blood pressure and those with hypertension. In the parental generation, mean plasma ANP levels did not differ between subjects with zero, one, or two parents with hypertension.. In Caucasians, interindividual differences in plasma ANP levels are not associated with interindividual differences in blood pressure levels, the diagnosis of hypertension, or family history of hypertension.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Child; Cross-Sectional Studies; Family Characteristics; Female; Humans; Hypertension; Male; Middle Aged; Minnesota; White People

Atrial natriuretic peptide (ANP) has been extensively studied in cardiovascular disorders in recent years. Particular attention has been paid to the role of ANP in the pathogenesis of hypertension and congestive heart failure and in the neurohormonal response to myocardial infarction. However, no published data are available on the significance of ANP in hypertensive patients with acute myocardial infarction.. We studied the relationship between plasma ANP concentration and systolic blood pressure, diastolic blood pressure, left atrial dimension, left ventricular diastolic dimension and left ventricular mass index in patients with essential hypertension in the acute phase of myocardial infarction. Plasma ANP concentrations were determined at 0, 4, 8, 16, 24, 48 and 72 h after admission in 40 patients with a first myocardial infarction (18 hypertensive patients, group 1; 22 normotensive patients, group 2). Left atrial dimension and left ventricular diastolic dimension were assessed echocardiographically within the first 48 h of acute myocardial infarction.. Maximum and mean plasma ANP values at 0, 4, 8, 16, 24, 48, and 72 h as well as mean ANP concentrations within the 72 h period were higher in group 1 than in group 2 (P < 0.001). Plasma ANP concentration, left atrial dimension (r = 0.59) and left ventricular diastolic dimension (r = 0.56) were positively correlated in both groups.. Acute myocardial infarction is characterized by a more pronounced rise in plasma ANP concentration in hypertensive patients than in those without a history of hypertension. Plasma ANP concentration correlates with left heart chamber sizes.

Topics: Acebutolol; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Creatine Kinase; Creatinine; Echocardiography; Female; Furosemide; Heart Atria; Heart Ventricles; Humans; Hypertension; Isoenzymes; Male; Metoprolol; Middle Aged; Myocardial Infarction; Nifedipine; Potassium; Sodium

To assess the efficacy of neutral endopeptidase 24.11 inhibition in the setting of elevated plasma levels of angiotensin II (Ang II), we studied the hemodynamic, renal, and hormonal effects of bolus injections of the potent and specific neutral endopeptidase inhibitor SCH 39370 or vehicle (control) in 10 sheep with Ang II-induced hypertension. Ang II infusion (5 ng/kg per minute for 6 days) sufficient to increase plasma Ang II levels 50% to 100% induced a consistent rise in mean arterial pressure (mean increment, 15 mm Hg; P < .0001) and increased plasma atrial natriuretic peptide (P = .017) and its second messenger cGMP (P = .049). Compared with time-matched control observations after vehicle alone, SCH 39370 (2.5 mg/kg) further increased plasma atrial natriuretic peptide (P = .0006), cGMP (P = .006), and plasma Ang II (P = .054). Systolic and mean arterial pressures tended to fall after SCH 39370, but these changes were not significant compared with control. No significant changes were observed in urinary volume and sodium excretion. Viewed in relation to previous studies in normotensive sheep, the current findings indicate that the vasodepressor response to neutral endopeptidase inhibition is blunted in hyperangiotensinemic sheep, in which neutral endopeptidase inhibition further augments plasma Ang II levels.

Topics: Analysis of Variance; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Dipeptides; Female; Hemodynamics; Hypertension; Metalloendopeptidases; Neprilysin; Protease Inhibitors; Renin-Angiotensin System; Sheep; Time Factors

To measure blood pressure (BP), plasma endothelin-1 (ET-1), atrial natriuretic peptide (ANP), antidiuretic hormone (ADH) and aldosterone (ALDO) concentration, and plasma renin activity (PRA) in patients treated with a low-dose cyclosporin A (CyA).. An open study of patients with rheumatoid arthritis (RA) or palmoplantar pustulosis (PPP).. Out-patient clinics at the Central Hospital of Jyväskylä and Helsinki University Central Hospital.. CyA was given to 25 patients with RA and to 10 patients with PPP.. RA patients were given CyA at a dose of 2.5 +/- 0.13 mg kg-1 body weight (BW) to 3.47 +/- 0.79 mg kg-1 BW (mean values +/- SD) at the start of the study and after 6 months, respectively, and the CyA dose was 2.67 +/- 0.13 mg kg-1 BW decreasing to 2.07 +/- 0.96 mg kg-1 (P < 0.001) after 4 months in PPP subjects.. Systolic (sBP) and diastolic blood pressure (dBP) increased from 127.8 +/- 13.6/79.7 +/- 8.4 mmHg to 140.0 +/- 19.8/83.8 +/- 9.7 mmHg during the study (P < 0.03). Plasma ET-1, ANP, ALDO and ADH concentration and PRA did not change during 4 to 6 months of CyA treatment. The plasma ANP concentration was constantly higher in CyA-treated RA patients (112 +/- 87 ng 1-1 to 118 +/- 78 ng 1-1) than in PPP patients (37.3 +/- 26 ng 1-1 to 47.7 +/- 39.9 ng 1-1; P < 0.02). The serum creatinine concentration remained within the normal range, but increased from baseline (76.7 +/- 11.9 mumol 1-1), to 90 +/- 15.4 mumol 1-1 (p < 0.001). The serum magnesium concentration decreased significantly (P < 0.005) after 6 months of CyA treatment in RA patients. No correlation was found between serum creatinine and plasma ET-1 concentration.. Increased blood pressure during CyA treatment was independent of circulating ET-1 levels. A low dose of CyA did not induce increased ET-1 synthesis as judged from plasma samples. The high plasma ANP level observed in RA patients could be due to fluid retention caused by concomitant treatment with non-steroid anti-inflammatory drugs. Fluid retention and decreased magnesium levels could also be involved in the development of hypertension in CyA-treated subjects.

Topics: Adult; Aldosterone; Arthritis, Rheumatoid; Atrial Natriuretic Factor; Blood Pressure; Cyclosporine; Endothelins; Female; Humans; Hypertension; Male; Middle Aged; Psoriasis; Renin; Vasopressins

The decreased volume of maternal extracellular fluid in preeclamptics may result in a different rate of atrial natriuretic peptide secretion and thus affect its plasma levels. Our objectives were to determine whether there was a difference in plasma levels of atrial natriuretic peptide in the various hypertensive disorders of pregnancy. Forty-nine pregnant women in the third trimester of pregnancy were evaluated: 21 with preeclampsia, 17 with chronic hypertension during pregnancy and 11 normotensives. The atrial natriuretic peptide concentration was 13.9 +/- 5.9 pg/ml, 17.8 +/- 13.5 pg/ml and 16.7 +/- 7.4 pg/ml in the preeclamptics, chronic hypertensives and normotensives, respectively. The differences between the three groups were not statistically significant. Atrial natriuretic peptide plasma levels remained stable in the various hypertensive disorders of pregnancy.

Topics: Adult; Atrial Natriuretic Factor; Chronic Disease; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third

To study the association between postural hypotension and (i) electrolyte levels and (ii) neurohumoral factors in elderly hypertensive patients using diuretics.. Cross-sectional study of patients and controls.. The subjects were gathered from senior citizen clubs or they were referred to the study by general practitioners. The subjects were examined on a geriatric ward in Turku City Hospital.. Seven subjects with postural hypotension and 13 controls.. Plasma electrolyte levels and neurohumoral response to head-up tilt.. There were significantly more hypokalaemic subjects in the postural hypotension group (5/7) than in the control group (1/13) (P < 0.01). The plasma potassium level was negatively correlated to plasma aldosterone (r = -0.57; P < 0.01) and renin activity (r = -0.69; P < 0.001). Subjects with postural hypotension had higher levels of noradrenaline, both supine (P < 0.05) and during tilt (P < 0.05). There were no significant differences in supine or tilt levels of plasma adrenaline, vasopressin, atrial natriuretic peptide, aldosterone and renin activity between the groups.. The results suggest that potassium depletion is associated with postural hypotension in elderly hypertensive patients using diuretics. However, it is unclear whether there is a causative link between potassium depletion and postural hypotension or whether they are both caused by some other factor, e.g. volume contraction.

Topics: Aged; Aged, 80 and over; Aldosterone; Atrial Natriuretic Factor; Case-Control Studies; Cross-Sectional Studies; Diuretics; Electrolytes; Epinephrine; Female; Humans; Hypertension; Hypotension, Orthostatic; Male; Neurotransmitter Agents; Potassium; Renin; Tilt-Table Test; Vasopressins

Because the phosphatidylinositol pathway may be part of the signaling system associated with stretch-induced release of atrial natriuretic peptide (ANP), we tested the hypothesis that formation of the intermediate inositol-1,4,5-trisphosphate (IP3) is impaired when ANP release is decreased in response to atrial stretch in hearts from aging genetically hypertensive (GH) rats. Immunoreactive ANP release into the coronary effluent and IP3 levels were studied in cardiac tissues of isolated perfused hearts from normotensive control (WAG) or GH rats aged 4, 11, or 16 months. Left atria were repeatedly distended and released with a latex balloon. ANP was measured in coronary effluent, and IP3 was measured in cardiac tissues. In all age groups, stretch and relief of stretch evoked considerably less ANP release in spontaneously beating hearts from GH than from WAG rats. Hearts from GH rats aged 16 months released no ANP, but electrical pacing restored some stretch-induced ANP secretion. With repeated stretch and release of stretch of the left atrium for 2 min, IP3 levels increased in left atrial tissue in WAG but not in GH hearts of all age groups. IP3 levels in (unstretched) left ventricles were much lower than in left atria and were unaltered by atrial stretch. In aging GH rats, the capacity to release ANP on atrial stretch is largely lost, in association with complete suppression of stimulus-induced increase in IP3 levels. These data support a role for IP3 in stretch-mediated atrial ANP secretion and suggest a progressive uncoupling of this signaling pathway in aging hypertensive rats.

Topics: Aging; Analysis of Variance; Angioplasty, Balloon; Animals; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Pacing, Artificial; Compliance; Disease Models, Animal; Hypertension; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Male; Myocardium; Organ Size; Rats; Rats, Wistar

We investigated the relationships between vascular endothelium and parathyroid function. Blood pressure (BP), circulating endothelins (ETs) and atrial natriuretic peptide (ANP), and BP responses to parathyroid hormone (PTH) and NG-nitro-L-arginine methyl ester (L-NAME) were measured in parathyroidectomized (PTx), PTx and fed a Ca2+ enriched diet (PTx-HCa) and sham SHR.22 weeks after surgery, BP was significantly decreased in PTx and PTx-HCa, plasma ETs levels were increased, whereas ANP levels were decreased. In anesthetized rats, BP increase induced by L-NAME was greater in PTx-HCa than in sham group, indicating increased endogenous nitric oxide release in hypoparathyroid rats. The hypotensive response to PTH remained unchanged. These data demonstrate that endothelium is activated in long-term hypoparathyroid SHR, reflecting an adaptative response to decreased BP.

Topics: Animals; Arginine; Atrial Natriuretic Factor; Endothelins; Endothelium, Vascular; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide; Parathyroid Glands; Parathyroid Hormone; Rats; Rats, Inbred SHR

Angiotensin converting-enzyme inhibitors (alacepril and imidapril) or an AT1-receptor antagonist (SC-52458) was administered to 10-week-old spontaneously hypertensive rats (SHR) for 7 days, and cardiac mRNA levels for contractile proteins and atrial natriuretic polypeptide (ANP) were comprehensively measured. The expression of skeletal alpha-actin and ANP was selectively enhanced in the heart of vehicle-treated SHR compared with Wistar-Kyoto rats (WKY), thereby suggesting that the phenotypic modulation of myocytes occurred at the early stage of hypertension. The above-mentioned three drugs similarly suppressed these enhanced gene expressions, nearly to the control levels. In contrast, although the treatment with hydralazine lowered the blood pressure of SHR similarly, hydralazine did not suppress ANP expression at all and only partially suppressed skeletal alpha-actin. Moreover, alacepril did not affect these gene expressions in WKY. Thus, AT1 receptor may be crucial for phenotypic modulation in the heart of SHR.

Topics: Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Autoradiography; Blotting, Northern; Captopril; Gene Expression; Hypertension; Male; Pyridines; Rats; Rats, Inbred SHR; Receptors, Angiotensin; RNA, Messenger; Tetrazoles

Stress hormones, tissue-plasminogen activator (t-PA) antigen, left-ventricular diastolic function and mood immediately before and after listening to three different kinds of music (a waltz by J. Strauss, a piece of modern classic by H. W. Henze, and meditative music by R. Shankar) were measured in 20 healthy persons (10 women, 10 men; mean age 25 [20-33] years) and 20 hypertensives (8 women, 12 men; mean age 57.5 [25-72] years). To recognise haemodynamic effects, mitral flow by Doppler ultrasound was used as a measure of left-ventricular diastolic function. Atrial filling pressure (AFF) was calculated from the flow integral (VTI) of the early E and the late A waves. The Zerssen scale was used to estimate the immediate mood of the subjects. In hypertensives the levels of cortisol (74 vs 78 ng/ml; P < 0.05) and t-PA antigen (4.3 vs 4.5 ng/ml; P < 0.05) were lower after than before the Strauss waltz. The muscle by Henze lowered the concentrations of cortisol (70 vs 84 ng/ml; P < 0.05), noradrenaline (203 vs 224 ng/l; P < 0.05) and t-PA antigen (4.1 vs 4.6 ng/ml; P < 0.05). After listening to the piece by Shankar the concentrations of cortisol (71 vs 78 ng/ml; P < 0.05), adrenaline 14.5 vs 24.5 ng/ml; P < 0.05) and t-PA antigen (4.2 vs 4.3 ng/ml; P < 0.05) were lower. In healthy subjects AFF (29 vs 26%; P < 0.05) rose after the Strauss music, VTI-E fell (69 vs 73 mm; P < 0.05, while natriuretic peptide rose (63 vs 60 pg/ml; P < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Affect; Aged; Atrial Natriuretic Factor; Echocardiography, Doppler; Epinephrine; Female; Hemodynamics; Humans; Hydrocortisone; Hypertension; Linear Models; Male; Middle Aged; Music; Norepinephrine; Psychological Tests; Stress, Physiological; Time Factors; Tissue Plasminogen Activator

The effects of beta-blocker treatment on hemodynamics were studied in relation to plasma atrial natriuretic peptide (ANP) levels in 17 outpatients with essential hypertension. Administration of propranolol for twelve weeks to untreated subjects resulted in a significant (P < 0.001) rise in plasma ANP levels (from 37.9 +/- 21.2 to 66.7 +/- 46.2 pg/mL, mean +/- SD). Systolic and diastolic blood pressures were significantly decreased (P < 0.05 and P < 0.01, respectively). Heart rate was also significantly decreased (P < 0.001). On the other hand, a significant reduction of cardiac index was detected (from 4.12 +/- 1.34 to 2.96 +/- 0.75 L/min/m2, P < 0.01) with chronic administration of propranolol, suggesting a reflection of decreased cardiac function. A significant negative correlation was observed between %changes in systolic blood pressure and %changes in plasma ANP (r = -0.594, P < 0.05). These results suggest that the increased plasma ANP levels may contribute to the antihypertensive effect with propranolol.

Topics: Adrenergic beta-Antagonists; Aged; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renin; Time Factors

In the absence of the potentially confounding influence of vasopressin in hypertension, the effects of atrial natriuretic peptide (ANP) on arterial blood pressure and renal handling of water and sodium were assessed from comparison of responses to intravenous ANP infusion in anaesthetized vasopressin-deficient New Zealand genetically hypertensive (DI/H) rats and their normotensive substrain (DI/N). After 320 min of hypotonic saline infusion, plasma ANP concentration was significantly higher in DI/H compared with DI/N rats. ANP administration increased circulating ANP concentration in both groups. Plasma angiotensin II concentration was higher in DI/H than in DI/N rats; infusion of ANP raised circulating angiotensin II in both groups though this achieved statistical significance only in DI/N rats. Plasma aldosterone concentrations were initially similar in normotensive and hypertensive animals and, in both, were reduced markedly by I.V. ANP infusion. Administration of ANP produced sustained hypotension in both groups. However, the hypotensive effect of ANP was more pronounced in DI/H compared with DI/N rats. Heart rate was initially similar in the two groups, and infusion of ANP produced no detectable change. By comparison with animals maintained on hormone-free infusate, urine flow increased markedly over the 80 min period of ANP infusion in both groups, by 142% in DI/H rats and 127% in DI/N rats. ANP administration produced a natriuresis in both groups but the increase in Na+ excretion was much greater in DI/H (342%) than in DI/N (139%) rats. It appears from the current study that vasopressin-deficient hypertensive rats are more sensitive to ANP with regard to effects on blood pressure and renal excretion than their vasopressin-deficient normotensive substrain. These differences may, in part, reflect adjustments to long-term elevation in blood pressure and in plasma ANP concentration in hypertension and, in part, rely on the associated disturbances in related endocrine systems.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Endocrine Glands; Heart Rate; Hypertension; Kidney; Male; Rats; Rats, Inbred Strains; Sodium; Vasopressins; Water

To elucidate the pathophysiological significance and the regulation of natriuretic peptide receptors (NP-R) in hypertension, we investigated the changes of NP-R in the lung, renal cortex and medulla using radioreceptor assay. We also examined the concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the atria and ventricles and plasma ANP concentration by specific radioimmunoassays. Elevated plasma ANP level, decreased atrial ANP concentration and increased ventricular ANP and BNP contents were observed in the DOCA-salt group when compared with the control group (p < 0.01). The ratio of BNP/ANP in the ventricle of the DOCA-salt rats was 50% of the control rats. The elevated plasma ANP secreted from the heart seems to reflect a defensive compensatory mechanism to counteract hypertension, and that ANP is the major natriuretic peptide secreted from the cardiac ventricle in DOCA-salt hypertensive rats. Scatchard plot analysis revealed that the maximal binding capacities (Bmax) of NP-R of the lung and renal cortex in DOCA-salt rats were significantly decreased from 71.0 +/- 10.4 to 38.4 +/- 5.9 (p < 0.05) and from 32.7 +/- 1.8 to 21.7 +/- 0.4 (fmol/mg. protein) (p < 0.01) compared with those in the control rats. The values of Bmax of the renal medulla between the two groups were not different. There was no significant change in the apparent dissociation constant (Kd) in the lung, renal cortex and medulla between the two groups. A competitive binding study using 125I- alpha-rANP1-28 and C-ANF4-23, a biologically silent clearance receptor (C-receptor) specific ligand, revealed that C-receptors are abundantly present in the renal cortex, while a relatively small quantity of C-receptor was detected in the renal medulla. In the lung, a substantial amount of C-receptor was detected. In the DOCA-salt treated rats, C-receptors were decreased in the lung and renal cortex compared with the control rats. These results indicate that the down-regulation of NP-R, especially C-receptor, was induced in the lung and renal cortex when plasma ANP levels were elevated in DOCA-salt hypertensive rats. In conclusion, our results suggest that down-regulation of C-receptor in the lung and kidney contributes to maintaining higher plasma ANP levels and maybe responsible for the counter-regulatory role of endogenous ANP in DOCA-salt rats. Our results show that the down-regulation of NP-R in the lung was larger than that in the kidney, suggesting that t

Topics: Animals; Atrial Natriuretic Factor; Desoxycorticosterone; Disease Models, Animal; Down-Regulation; Hypertension; Kidney; Lung; Male; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Sodium Chloride

To determine if defects in the atrial natriuretic peptide (ANP) system can cause hypertension, mice were generated with a disruption of the proANP gene. Homozygous mutants had no circulating or atrial ANP, and their blood pressures were elevated by 8 to 23 millimeters of mercury when they were fed standard (0.5 percent sodium chloride) and intermediate (2 percent sodium chloride) salt diets. On standard salt diets, heterozygotes had normal amounts of circulating ANP and normal blood pressures. However, on high (8 percent sodium chloride) salt diets they were hypertensive, with blood pressures elevated by 27 millimeters of mercury. These results demonstrate that genetically reduced production of ANP can lead to salt-sensitive hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Crosses, Genetic; Female; Gene Targeting; Genotype; Heart Atria; Heterozygote; Homozygote; Hypertension; Male; Mice; Mice, Inbred C57BL; Protein Precursors; Sodium, Dietary

Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca(2+)-ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload.

Topics: Animals; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiomegaly; Echocardiography; Hemodynamics; Hypertension; Male; Myocardium; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Sarcoplasmic Reticulum; Survival Analysis

Pheochromocytoma is a unique type of hypertension caused by excessive production of catecholamines by the chromaffin tumor. Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. The incidence varies from 0.1 to 0.8% of hypertensive population. The author's experience is based on 138 patients treated in one institution from 1956 to 1995. Hormonal activity of pheochromocytoma varies considerably, influencing the pattern, of blood pressure and the clinical symptoms. It is emphasized that different other humoral mechanisms may play a role in the pathophysiology of this type of endocrine hypertension. Biochemical tests and non-invasive localizing methods are essential for the definite diagnosis of pheochromocytoma. A great progress has been made in this respect during the last three decades. Surgical removal of the tumor is the only definite therapy with low morbidity and mortality.

Topics: Atrial Natriuretic Factor; Catecholamines; Humans; Hypertension; Neuropeptide Y; Pheochromocytoma; Renin

Antihypertensive treatments were given to young and adult SHRs, to prevent and reverse hypertension, respectively. Cardiac hypertrophy and the steady state level of the "fetal" genes, ANP, alpha-skeletal actin (alpha-skA), and beta myosin heavy chain (beta-MHC) mRNAs were assessed. Our findings show that the reduction of blood pressure does not consistently result in a similar regression of the "fetal gene program".

Topics: Actins; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Gene Expression; Hypertension; Myosins; Rats; Rats, Inbred SHR

To explore the clinical utility of measuring atrial natriuretic peptide (ANP) in the second and early third trimesters of pregnancy in order to predict pregnancy induced hypertension (PIH).. The study was done in a University Teaching Hospital. A prospective study of 200 women in their first pregnancy was conducted. ANP was measured at 2 gestational windows, 20-26 weeks and 30-34 weeks. This was correlated with pregnancy outcomes, in particular PIH. Student's t-test was used to compare ANP levels between women who developed PIH and those who did not. The receiver operator curve (ROC) was used to determine its clinical utility.. ANP levels were lower at 20-26 weeks in women who subsequently developed PIH but there was no significant difference at 30-34 weeks between women who had normotensive pregnancies and those who later developed PIH. The character of the ROC would indicate that it is not useful for prediction.. ANP levels in the second and early third trimesters has limited clinical utility for the prediction of PIH.

Topics: Adult; Atrial Natriuretic Factor; Female; Humans; Hypertension; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prospective Studies; ROC Curve

The cardiovascular consequences of endothelin (ET) blockade with the ETA-receptor antagonist FR 139317 were evaluated by determining the long-term effects of the drug on hemodynamic, hormonal, renal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SP the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg intraperitoneally, twice daily) it increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. There was also an increase in heart weight. At the end of the experiment the plasma levels of atrial natriuretic peptide and brain natriuretic peptide were significantly lower in the group treated with FR 139317 than in the controls. The endothelin plasma levels were significantly higher and the plasma renin activity was lower in the group treated with the endothelin receptor antagonist. These data indicate that endothelin is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by SHR-SP.

Topics: Animals; Atrial Natriuretic Factor; Azepines; Cardiomegaly; Endothelin Receptor Antagonists; Endothelins; Hypertension; Indoles; Rats; Rats, Inbred SHR; Renin

ANP-receptors affinities (KD) and capacities (Bmax) were assayed in cryosections of glomeruli from 'malignant' hypertensive rats (2K-1C) and spontaneously hypertensive rats (PHR). Plasma ANP concentration was twofold higher in 2K-1C (P < 0.05) and PHR (P < 0.02) than in the respective controls, KD and Bmax for rANP99-126 and ANP103-123 did not differ. ANP mediated cGAMP release in 2K-1C rats was also unaffected. ANP-C glomerular receptors (i.e. displacement of tracer binding with ANP103-123) were not down-regulated and had unchanged peptide binding affinity in either kidney of rats with 'malignant' hypertension and in PHR. The difference between Bmax for rANP99-126 and Bmax for rANP103-123 (ANP-A receptor binding) indicates moderate up-regulation of ANP-A receptors in the clipped, and down-regulation in the contralateral kidney of 2K-1C (2K-1C, right vs. left, P < 0.05). Since [ANP]pl, and also Bmax and KD for ANP were similar in both hypertension models investigated, changes of the [ANP]pl/ANP-receptor system can not completely explain the marked natriuresis of rats with 'malignant' hypertension.

Topics: Animals; Atrial Natriuretic Factor; Down-Regulation; Guanylate Cyclase; Hypertension; Hypertension, Malignant; Hypertension, Renovascular; Kidney Glomerulus; Kinetics; Male; Natriuresis; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

To further elucidate the renal effects of NEP inhibition, we employed NEP inhibitor UK 73967 (UK), with or without a kinin receptor antagonist Hoe 140 (Hoe), in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In Sprague-Dawley rats: 1) injected UK significantly decreased NEP, and increased kinins, urine volume (UV) and urinary sodium excretion (UNaV), while none of the variables changed with vehicle treatment; 2) no difference was found in plasma ANP between the vehicle and UK groups; and 3) Hoe canceled the increases of UV and UNaV caused by UK. In DOCA-salt rats: 1) infused UK significantly decreased NEP, and increased UV and UNaV, while UV and UNaV were slightly decreased, and NEP did not change with vehicle treatment; 2) plasma ANP was significantly higher in UK group than in the vehicle group; and 3) Hoe could not abolish the increase of UV and UNaV induced by UK. These data indicate that the contributions of renal kinins and plasma ANP to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Bradykinin; Cyclohexanecarboxylic Acids; Desoxycorticosterone; Hypertension; Kidney; Kinins; Male; Neprilysin; Protease Inhibitors; Rats; Rats, Sprague-Dawley

To investigate polymorphisms in the atrial natriuretic peptide gene of African Americans at intron two (Hpall) and exon three (Scal).. The allele frequency of the Hpall mutation was 25% in the hypertensive group (n =60) compared with only 3.4% in normotensive individuals (n = 44, P < 0.0001). The genotype heterozygote for the present mutation was much more common among those with hypertension (50 versus 6.8%, P < 0.0001). The groups were no different for the Scal site alone, although the two mutations were present together more often in the hypertensive group. The Hpall mutation was associated with hypertension in this typically salt-sensitive population.

Topics: Adult; Aged; Atrial Natriuretic Factor; Black People; Exons; Female; Genotype; Humans; Hypertension; Introns; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic

The cardiovascular consequences of endothelin (ET) blockade with the ETA receptor antagonist FR 139317 were evaluated by determining long-term effects of the drug on hemodynamic, hormonal, and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SPs the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg, i.p., b.i.d.) blood pressure increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. The increase in heart weight was also delayed. At the end of the experiment, the plasma levels of ANP and BNP were significantly lower in the group treated with FR 139317 than in the controls. The plasma ET levels were significantly higher and the plasma renin activity was lower in the group treated with the ET receptor antagonist. These data indicate that ET is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by an SHR-SP rat model.

Topics: Animals; Atrial Natriuretic Factor; Azepines; Cardiomegaly; Endothelin Receptor Antagonists; Endothelins; Hypertension; Indoles; Rats; Rats, Inbred SHR; Receptor, Endothelin A

Angiotensin (Ang) II and atrial natriuretic peptide (ANP) have opposing effects on blood pressure, sympathetic activity, vasopressin and ACTH secretion, salt appetite, and drinking. We observed their interaction by infusing Ang II (7.2 nmol/h) into the peritoneum (i.p.) or into the lateral ventricle (i.c.v.) of rats with osmotic minipumps for seven days. At sacrifice, rats receiving Ang II-i.c.v. had a systolic blood pressure of 184 +/- 3 (SEM) mmHg, those receiving Ang II-i.p. had 159 +/- 5 mmHg (p < 0.05), while controls had 109 +/- 2 and 110 +/- 2 mmHg, respectively (p < 0.05). Drinking and urine volume increased similarly in rats receiving Ang II by either route, while Uosm decreased. Renin (PRA) values were lower (p < 0.05) in rats receiving Ang II-i.c.v. (0.7 +/- 0.2 ng Ang l/ml/h) or Ang II-i.p. (0.9 +/- 0.2) than in the respective controls (2.3 +/- 0.7 and 2.0 +/- 0.3). Plasma ANP values with Ang II-i.c.v. (18 +/- 1.6 pg/ml) or with Ang II-i.p. (49 +/- 6) were also lower (p < 0.05) than respective controls (89 +/- 12, 76 +/- 4). Vasopressin (AVP) concentrations in the plasma were not influenced by the regimens. In the brain, the ANP contents in areas of the so-called AV3V-region (organum vasculosum laminae terminalis, preoptic periventricular nucleus, medial preoptic nucleus) were similarly and significantly reduced by both Ang II-i.c.v. and Ang II-i.p.. ANP values were also reduced in the median eminence by both types of Ang II-treatment, while ANP concentrations in the supraoptic nucleus were increased. The data show that Ang II infusions producing a chronic rise in blood pressure exert similar effects on drinking behavior, PRA, and ANP concentrations in blood and brain. The AV3V area may be pivotal to both models.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Brain Chemistry; Hypertension; Injections, Intraperitoneal; Injections, Intraventricular; Male; Paraventricular Hypothalamic Nucleus; Preoptic Area; Rats; Rats, Wistar

To explore the mechanisms of the renal effects of neutral endopeptidase (NEP) inhibition, the effects of an NEP inhibitor, candoxatril (UK 79,300; UK), in Dahl salt-sensitive (SS) and salt-resistant (SR) rats were examined. UK dose-dependently decreased blood pressure (BP) in SS rats (20 mg/kg: 174 +/- 5 vs. 155 +/- 8 mm Hg, p < 0.01) but not in SR rats. Urinary sodium excretion (UNaV) of both rat strains receiving high-salt diets was increased to a greater extent than that of rats receiving low-salt diets. Basal plasma atrial natriuretic peptide (ANP) level in hypertensive SS rats was higher than in SR rats (192 +/- 18 vs. 118 +/- 24 pg/ml, p < 0.05). UK increased ANP levels in the plasma and urine two- and 11-fold, respectively. UK-induced increases in UNaV, urinary cyclic GMP, and plasma ANP concentrations were significantly augmented by coadministration of a clearance receptor agonist, C-ANF(4-23) or brain natriuretic peptide (BNP). Thus, the effects of NEP inhibition appear to be potentiated by the reduced receptor-mediated metabolism of ANP. This may explain the greater response to the NEP inhibitor in Dahl rats with hypertension or high-salt feeding.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Hypertension; Indans; Natriuresis; Natriuretic Peptide, Brain; Neprilysin; Nerve Tissue Proteins; Peptide Fragments; Propionates; Rats; Rats, Inbred Strains; Sodium, Dietary

We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were > 500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted < 60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 microgram/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 muEq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 muEq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; beta-Alanine; Blood Pressure; Desoxycorticosterone; Diuresis; Heart Rate; Hypertension; Kidney; Male; Molecular Sequence Data; Natriuresis; Neprilysin; Organophosphonates; Peptide Fragments; Rats; Rats, Sprague-Dawley; Thiorphan

Blockade of atrial natriuretic factor (ANF) degradation by specific neutral endopeptidase (NEP) inhibitors may be useful in treatment of hypertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 42495 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin-angiotensin system (RAS) in conscious unrestrained spontaneously hypertensive rats (SHR) and compared them with the effects induced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four groups of adult SHR were treated orally for 4 weeks with placebo, SCH 42495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spirapril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h urine was collected every week for measurement of urinary volume, sodium, potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin activity (PRA), and aldosterone (ALDO) were determined from blood collected when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo-treated SHR; plasma cyclic GMP was higher, however, in the treated rats than in controls and urinary cyclic GMP increased only with the higher dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natriuresis throughout the study were not different from controls. In contrast, spirapril decreased BP; this effect was associated with significant increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Analysis of Variance; Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Enalapril; Hemodynamics; Hypertension; Male; Methionine; Natriuresis; Neprilysin; Rats; Rats, Inbred SHR; Renin-Angiotensin System

Vascular remodelling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests the pivotal role of vasoactive substances occurring in the blood vessel, such as angiotensin II (AII), in the control of vascular growth. We recently discovered that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced by vascular endothelial cells and can act as an endothelium-derived relaxing peptide. We also demonstrated gene expression of CNP and the ANP-B receptor, which is one of the three subtypes of the natriuretic peptide receptor and is specific to CNP in blood vessels in vivo. Thus, we propose the existence of a "vascular natriuretic peptide system (NPS)" similar to the vascular renin-angiotensin system (RAS). The present study showed that CNP exerted a growth-inhibitory action and antagonised the growth-promoting action of AII, which was mediated through the AII subtype 1 receptor in cultured vascular smooth muscle cells. In neointimal lesions of rat carotid artery, CNP gene transcript was detectable 2 weeks after balloon injury, and ANP-B receptor gene expression was augmented. These findings suggest that the vascular NPS is activated in proliferative vascular lesions, suppressing further proliferation by antagonising the action of the vascular RAS.

Topics: Angiotensin II; Animals; Arteriosclerosis; Atrial Natriuretic Factor; Base Sequence; Cattle; Cell Division; Cells, Cultured; Endothelium, Vascular; Gene Expression Regulation; Guanylate Cyclase; Hypertension; Male; Molecular Sequence Data; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; RNA; Stimulation, Chemical

Endothelin-1 (ET-1) may play an important role in the development and maintenance of hypertensive states. In patients with essential hypertension, ET-1 plasma concentration increases or remains unchanged. The aim of the present study was to investigate ET-1 plasma concentration in patients with mild-to-moderate essential hypertension and its interrelationship with catecholamines, neuropeptide Y and atrial natriuretic peptide (ANP).. The study included 37 patients (mean age 38.2 +/- 1.6 years) with mild-to-moderate essential hypertension. The control group consisted of 21 healthy volunteers (mean age 35.6 +/- 1.4 years). ET-1, neuropeptide Y and ANP were determined by radioimmunoassay methods and catecholamine plasma concentration was determined radioenzymatically.. Our study shows that plasma ET-1 and neuropeptide Y levels are elevated in patients with essential hypertension compared with a control group. No correlation was found in either of the groups between plasma ET-1 level and plasma neuropeptide Y, catecholamine or ANP concentrations.. Our results suggest that ET-1 is relevant in the development and maintenance of elevated blood pressure.

Topics: Adult; Atrial Natriuretic Factor; Catecholamines; Endothelins; Female; Humans; Hypertension; Male; Neuropeptide Y

Plasma atrial natriuretic peptide (ANP), plasma and 24-h urine catecholamines, plasma renin activity (PRA), and serum aldosterone were studied in offspring of hypertensive and normotensive families [n = 82; age 37 +/- 7 years (mean +/- SD)]. Despite higher age, higher blood pressure, and higher urine excretion of catecholamines--all of which are factors associated with increased ANP levels--the mean basal plasma ANP concentration tended to be lower in offspring of hypertensive than normotensive families. The same pattern was found in all age-tertiles, and the between-group difference was statistically significant in subjects aged 34-39 years (p < 0.01). Also, the family history of hypertension was associated with low ANP levels after covariate adjustment (p < 0.05). The 24-h urine excretion of epinephrine and norepinephrine tended to be higher in offspring of hypertensive than normotensive families while the morning venous plasma levels were similar. The ratio between venous plasma ANP and norepinephrine was lower in offspring of hypertensive than normotensive families (p < 0.05). PRA, serum aldosterone level, and 24-h urine excretion of dopamine did not differ significantly between groups. Inappropriately low basal plasma ANP concentrations and low plasma ANP/norepinephrine ratios may be related to the development of essential hypertension in offspring of hypertensive families.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Catecholamines; Family; Female; Humans; Hypertension; Male; Middle Aged; Renin; Sodium

We have recently described that urines from salt-loaded rats contain a potent natriuretic factor acting at the Na-K-Cl cotransport system (CIF: "Cotransport Inhibitory Factor"). Here we investigated the kinetics of the urinary CIF excretion which follows an oral salt-load: (i) in normal rats, relative to that of the atrial natriuretic peptide (ANP) and (ii) in an experimental model of salt-dependent genetic hypertension (Dahl's rats). Thus, Wistar rats were orally loaded with 2% NaCl for 8 days. Urinary CIF excretion was measured by testing the inhibitory potency of urines on bumetanide-sensitive lithium efflux in lithium-loaded human erythrocytes. Plasmatic levels of ANP were measured by radioimmunoassay. Plasma ANP rapidly and transiently increased during the first 24 hs of salt-load, decreasing thereafter down to normal levels in 6-8 days. Conversely, CIF slowly increased after 24 hs up to maximal constant levels after 5 days of salt-loading. Dahl salt-sensitive rats exhibited highly significant increases in urinary CIF excretion with respect to salt-resistant rats. In the basal state (before salt-loading) urinary CIF excretion was 101 +/- 13 vs 17.6 +/- 4.5 units/day in salt-sensitive vs. salt-resistant rats (n = 7 for each group, p < 0.001). This difference was maintained after salt loading (3 380 +/- 990 vs. 456 +/- 159 units/day, p < 0.05 at day 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Hypertension; Loop of Henle; Male; Natriuresis; Rats; Rats, Wistar

The effects on mean arterial pressure (MAP) and heart rate (HR) of unilateral microinjections of atrial natriuretic factor (ANF) into discrete sites of the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHR) were compared with those observed in normotensive Wistar-Kyoto rats (WKY). NTS sites were identified to be involved in cardiovascular control on the basis of the bradycardia and hypotension elicited by microinjections of 20 nl of 0.1 M L-glutamate. Microinjection of 20 nl of 10(-7) M ANF into 38 NTS 'cardiovascular sites' in rats of the SHR strain decreased MAP (-8.7 +/- 1.8 mmHg) and HR (-7.8 +/- 1.9 bpm) in 9 sites (24%), but caused no changes in the remaining 29 sites (76%). In WKY rats 35 cardiovascular sites within the NTS were studied. In 18 sites (51%) ANF microinjections induced a decrease in MAP (-15.1 +/- 1.9 mmHg) and in HR (-18.1 +/- 3.9 bpm), whereas the remaining 17 sites (49%) were unaffected. The decreased responsiveness of the NTS to ANF in the SHR animals could play a role in the development and/or maintenance of the elevated arterial blood pressure in genetically hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular System; Glutamic Acid; Heart Rate; Hypertension; Male; Medulla Oblongata; Microinjections; Rats; Rats, Inbred SHR; Rats, Inbred WKY

In order to examine whether changes in circulating atrial natriuretic peptide (ANP) and sodium excretion during saline infusion in patients with essential hypertension (EH) could be modulated by the severity of resting arterial blood pressure (BP), 30 subjects with EH and nine normotensive subjects were given 2 L of isotonic saline infusion at a rate of 500 mL/hour. Plasma ANP concentrations in EH increased significantly from 64.9 +/- 5.1 (mean +/- SEM) to 92.5 +/- 12.8 pg/mL at the first hour and peaked at the second hour. In normotensives, the increase of plasma ANP was not significant until the fourth hour of infusion. Hypertensive subjects sustained a greater percentage increment of mean BP (MBP) than normotensives at the end of infusion. Those with pre-saline MBP exceeding 107 mmHg (group A) exhibited a faster and greater rise in plasma ANP after saline loading than those having less than or equal to 107 mmHg (group B). The post-saline four-hour natriuresis was appreciably higher in group A than group B, while the percentage increment of MBP at the fourth hour was significantly greater in the latter as compared to normal controls. These results indicate that patients with higher basal arterial pressure attain a faster and greater ANP response following saline infusion than those with lower BP. This phenomenon may be responsible for the maintenance of short-term fluid-volume and BP homeostasis during acute sodium loading in established EH.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Sodium; Sodium Chloride

Blood pressures were determined in Milan hypertensive (MHS) and Milan normotensive (MNS) rats at different ages. Mean blood pressure, plasma atrial natriuretic peptide (ANP) concentration and renal glomerular receptors numbers and affinities were determined in young (25-day-old), adult (60- to 80-day-old) and aged (300-day-old) rats.. Mean blood pressures, always higher in the MHS than in the MNS rats, increased with age in both strains. Plasma ANP concentrations were similar in the young and aged rats of both strains, but were higher in the adult MHS than in the adult MNS rats. There were no quantitative differences in the ANP receptors between young and old rats of the two strains, but an increase in the maximal binding capacity was observed, in both strains, when adult rats were compared with young rats. Moreover, saturation experiments with [125I]-rat ANP revealed a downregulation of the ANP receptors in the renal glomeruli isolated from the adult MHS rats. In isolated glomeruli the cyclic GMP stimulation by ANP was similar in adult rats of both strains.. Downregulation in glomeruli of MHS rats, probably involving the clearance receptors for ANP, is concluded to occur.

Topics: Aging; Animals; Atrial Natriuretic Factor; Binding Sites; Blood Pressure; Cyclic GMP; Disease Models, Animal; Down-Regulation; Hypertension; Kidney Glomerulus; Male; Radioimmunoassay; Rats; Receptors, Atrial Natriuretic Factor

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prazosin

1. The aim of this study was to determine plasma levels of N-terminal atrial natriuretic peptide and atrial natriuretic peptide in normal subjects and in patients with essential hypertension, cardiac transplant and chronic renal failure, using radioimmunoassays directed towards the mid-portion pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30) of the N-terminal atrial natriuretic peptide and atrial natriuretic peptide (99-126). The circulating form(s) of the immunoreactive N-terminal atrial natriuretic peptide in plasma extracts has been investigated using all three radioimmunoassays by means of gel filtration chromatography to further clarify the major immunoreactive molecular circulating form(s) of N-terminal atrial natriuretic peptide in man. 2. The plasma level (mean +/- SEM) of N-terminal pro-atrial natriuretic peptide (31-67) in the normal subjects was 547.2 +/- 32.7 pg/ml (n = 36) and was significantly elevated in patients with essential hypertension (730.2 +/- 72.3 pg/ml, P < 0.025, n = 39), in cardiac transplant recipients (3214.0 +/- 432.2 pg/ml, P < 0.001, n = 9) and in patients with chronic renal failure (3571.8 +/- 474.1 pg/ml, P < 0.001, n = 11). Plasma levels of N-terminal pro-atrial natriuretic peptide (1-30) and atrial natriuretic peptide were similarly elevated in the same patient groups when compared with the mean plasma values in the normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Chromatography, Gel; Female; Heart Transplantation; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peptide Fragments; Protein Precursors; Radioimmunoassay

Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.

Topics: Adrenomedullin; Adult; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Cyclic AMP; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peptides

We examined plasma renin activity (PRA), plasma aldosterone (PA), atrial natriuretic factor (ANF) and endogenous digitalis-like factor (DLF) in 15 healthy subjects and 15 patients with essential hypertension (EH) to obtain basal values and values after extracellular fluid volume (ECFV) expansion caused by infusion of isotonic saline solution over a period of 2 hours (20 mg/kg). A significant increase in diuresis and natriuresis accompanied by a decrease in PRA and PA and an increase in ANF was observed in both groups. No significant differences were observed in ANF levels between normotensive subjects and hypertensive patients. Hypertensive patients showed significantly higher basal values of DLF than normotensive subjects. However, an increase in plasma DLF following ECFV expansion was observed only in the group of healthy subjects. There was a positive correlation between ANF and natriuresis and a negative correlation between ANF and systolic and diastolic blood pressure (BP). Changes in DLF correlated positively with changes in diastolic BP in both groups, while in healthy subjects a negative correlation was recorded between PRA and DLF. We conclude that the increased diuresis and natriuresis in ECFV expansion is presumably accounted for not only by suppression of PRA and PA, but also by stimulated ANF secretion, while in healthy subjects stimulation of DLF may be involved as well. The insufficient DLF response to saline infusion may indicate an exhausted DLF reserve in hypertensive patients. As a vasoactive substance, DLF can participate in the regulation of blood pressure and play a role in the pathogenesis of arterial hypertension.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Male; Reference Values; Renin; Saponins; Sodium; Water-Electrolyte Balance

Nonmodulation seems to represent an inheritable trait characterized by abnormal angiotensin-mediated control of aldosterone release and renal blood supply and salt-sensitive hypertension. Recently, we demonstrated that atrial natriuretic peptide (ANP) response to angiotensin II also is altered in nonmodulators. Moreover, an abnormal ANP response to acute volume expansion has been shown by others in hypertensive patients displaying some features of nonmodulators. These data induced us to hypothesize that nonmodulators. These data induced us to hypothesize that nonmodulation could be characterized by an abnormal ANP response to saline load.. Forty-three essential hypertensive men were subdivided into low-renin patients (n = 12), nonmodulators (n = 15), and modulators (n = 16) according to their renin profile and ability to modulate aldosterone and p-aminohippurate clearance responses to a graded angiotensin II infusion (1.0 ng.kg-1.min-1 and 3.0 ng.kg-1.min-1 for 30 minutes each) on both a low- (10 mmol Na+ per day) and a high- (210 mmol Na+ per day) Na+ intake. The intravenous saline load (0.25 mL.kg-1.min-1 for 2 hours) performed on a low-Na+ diet increased plasma ANP levels in low-renin (from 14.30 +/- 4.68 to 23.30 +/- 7.52 fmol/mL at 120 minutes, P < .05) and modulating patients (from 10.95 +/- 3.55 to 18.21 +/- 5.42 fmol/mL at 120 minutes, P < .05), whereas it did not change the hormone levels in nonmodulators (from 10.77 +/- 3.25 to 13.83 +/- 5.70 fmol/mL at 120 minutes, P = NS). When patients switched from a low- to a high-NaCl diet, plasma ANP levels increased significantly in all groups. However, when the saline load was repeated on a high-NaCl intake, ANP levels increased in both low-renin and modulating patients (P < .05), whereas it failed to increase in nonmodulators.. Nonmodulating hypertensive patients showed a reduced ANP response to saline infusion in the presence of a normal increase of plasma ANP with dietary NaCl load. The impaired ANP response to saline infusion could be due to a different distribution of volume load and contribute to determining the reduced ability to excrete sodium that is commonly described in nonmodulators.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Diet, Sodium-Restricted; Drug Resistance; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Phenotype; Sodium Chloride

Atrial natriuretic peptide exhibits natriuretic, diuretic and vasodilatory properties. We compared plasma concentrations of atrial natriuretic peptide, cyclic guanosine-3',5'-monophosphate (cGMP), electrolytes and urinary excretion of cGMP and electrolytes in hypertensive pregnant women to those in normotensive pregnant and normotensive non-pregnant women. Plasma atrial natriuretic peptide concentrations in hypertensive pregnant and normotensive non-pregnant women were equal, whereas in normotensive pregnant women it was lower (P < 0.05), than in non-pregnant. Urinary cGMP excretion was higher in both normotensive and hypertensive pregnant than in non-pregnant women (P < 0.01), whereas plasma cGMP levels were similar. A five-day nifedipine treatment (10 mg t.i.d.) had no effects on any of the variables. In hypertensive pregnancy, a reduction of systolic blood pressure by nifedipine correlated with the initial plasma atrial natriuretic peptide (P < 0.05) and a decrease in diastolic blood pressure with the initial plasma cGMP concentration (P < 0.05). The results of this small material suggest that plasma atrial natriuretic peptide concentration predicts the response to nifedipine in hypertensive pregnancy. However, the atrial natriuretic peptide-cGMP system does not seem to mediate the antihypertensive effect of nifedipine, while plasma atrial natriuretic peptide remained unaltered. Increased urinary cGMP excretion in both pregnant groups but lowered plasma atrial natriuretic peptide in normotensive pregnancy suggest other factors than circulating atrial natriuretic peptide to promote renal cGMP excretion during pregnancy.

Topics: Administration, Oral; Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Humans; Hypertension; Nifedipine; Pregnancy; Pregnancy Complications, Cardiovascular; Water-Electrolyte Balance

There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pressure overload by transverse aortic constriction (TAC). For the next 7 days the groups received either the specific angiotensin II subtype 1 receptor (AT1) antagonist (losartan, 1.05 g/l; n = 17), an angiotensin enzyme inhibitor (captopril, 2 g/l; n = 17), or no treatment (n = 22) administered in the drinking water and compared with three similarly treated sham-operated groups (n = 7 each). TAC resulted in a significant increase in heart weight-to-body weight ratio (0.634 +/- 0.087 vs. 0.525 +/- 0.039, g/g x 100, P < 0.05), which was prevented by losartan (0.506 +/- 0.069, g/g x 100, P < 0.0001) despite similar hemodynamic load (proximal systolic pressure 146 +/- 31 vs. 136 +/- 32 mmHg, untreated vs. losartan, P = NS). Proximal systolic pressure was positively correlated with the development of ventricular hypertrophy. In the presence of AT1-receptor blockade, the increase in heart weight-to-body weight ratio at any given systolic pressure was significantly attenuated compared with untreated TAC mice. The increase in heart weight-to-body weight ratio was also significantly attenuated by captopril compared with untreated banded controls (0.542 +/- 0.091, g/g x 100, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Atrial Natriuretic Factor; Biphenyl Compounds; Captopril; Cardiomegaly; Constriction; Gene Expression; Heart Ventricles; Hemodynamics; Hypertension; Imidazoles; Losartan; Mice; Mice, Inbred C57BL; Tetrazoles

The changes in haemoglobin concentration, haematocrit, plasma renin activity (PRA) and atrial natriuretic peptide (ANP) were studied in 10 haemodialysis patients with erythropoietin-associated hypertension. All patients received intravenously 1500 IU of recombinant human erythropoietin (rHuEPO) thrice weekly for 24 weeks. Treatment with rHuEPO induced significant rises in haemoglobin concentration (p < 0.001) and haematocrit (p < 0.01). However, the difference between post- and pretreatment levels of haemoglobin (delta Hb) was not correlated with that between post- and pre-treatment mean blood pressure (delta MBP). No correlation was found between delta Ht (difference between post- and pre-treatment values of haematocrit) and delta MBP. These results indicate that elevation of the haematocrit and haemoglobin concentration of haemodialysis patients does not necessarily lead to an increase in blood pressure. In these patients, no significant differences were observed in PRA and ANP, comparing pre-treatment values with those measured 4, 8, 12 or 24 weeks after commencing rHuEPO. This suggests that neither PRA nor ANP play a central role in the pathogenesis of rHuEPO-induced hypertension.

Topics: Adult; Atrial Natriuretic Factor; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

To explore the mechanisms for augmented neutral endopeptidase inhibitor-induced natriuresis in deoxycorticosterone acetate (DOCA)-salt rats.. We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats.. Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups.. The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Base Sequence; Blood Pressure; Desoxycorticosterone; Hypertension; Indans; Male; Molecular Sequence Data; Neprilysin; Polysaccharides; Propionates; Rats; Rats, Wistar; Sodium Chloride; Thiorphan

To study the tubular site or sites of the natriuretic action of atrial natriuretic factor and the possible differences between healthy subjects and patients with essential hypertension.. Nine healthy volunteers and six patients with essential hypertension were studied on four test days under standard conditions, water loading and hydropenia with mannitol or saline loading. On each test day baseline, atrial natriuretic factor infusion (1 microgram/min) and recovery measurements were performed after equilibrium had been reached. The measurements included the atrial natriuretic factor (ANF) plasma levels, blood pressure, glomerular filtration rate (GFR), effective renal plasma flow, urinary osmolality and the (fractional) excretions of (free) water, sodium and potassium.. Fractional free-water excretion and free-water reabsorption (as a function of osmolar clearance) were calculated during water loading and hydropenia with mannitol or saline loading, respectively, using standard formulae. [125I]-iothalamate and [131I]-hippuran were infused continuously for the measurement of GFR and effective renal plasma flow, respectively.. The plasma ANF concentration rose five- to eightfold during the infusion of ANF, which induced an increase in urinary sodium excretion, a small increase in GFR and a decrease in the effective renal plasma flow. Moreover, ANF induced an increase in fractional free-water excretion and a decrease in fractional free-water reabsorption. These changes did not correlate with changes in GFR. The blood pressure and potassium excretion were not affected. The effects of ANF on the plasma ANF levels, natriuresis and renal haemodynamics did not differ between the normotensive and the essential hypertensives. However, the increase in fractional free-water excretion was significantly greater in the patients with essential hypertension and correlated significantly with blood pressure (r = 0.56, P < 0.05).. These results indicate that the infusion of ANF at a low dose induces a similar natriuretic response in normotensive subjects and in patients with essential hypertension. This natriuresis is probably the result of both a glomerular and a tubular effect of ANF. Proximal as well as distal tubular sites seem to be involved. In essential hypertension an enhanced proximal as well as an impaired distal tubular action of ANF can be hypothesized.

Topics: Absorption; Adult; Atrial Natriuretic Factor; Diuresis; Drinking; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Tubules; Male; Mannitol; Middle Aged; Natriuresis; Reference Values; Sodium Chloride; Water

Atrial natriuretic peptide (ANP) has natriuretic and vasodilator actions that lower arterial pressure and may be beneficial to hypertensive patients. To assess the effects of ANP on left ventricular function in patients with hypertension, we compared it with the pure vasodilator nitroprusside. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained at baseline, during nitroprusside infusion, during a second baseline period, and during ANP infusion in 10 patients with hypertension. Mean arterial pressure fell during ANP and nitroprusside. Heart rate and plasma norepinephrine levels increased by similar amounts during the two agents, whereas cardiac index and stroke volume index were unchanged during both. Peak positive left ventricular dP/dt fell similarly during ANP and nitroprusside, but left ventricular dP/dt at a developed pressure of 40 mm Hg, a less load-dependent index of contractility, was unchanged during both. The relation between end-systolic pressure and volume during ANP infusion was not shifted leftward or rightward from that during nitroprusside infusion, indicating no inotropic effect. Both ANP and nitroprusside shortened at time constant of isovolumic relaxation calculated by the logarithmic method but did not change the time constant calculated by the derivative method. Peak filling rate was unchanged from baseline during both agents. ANP did not shift the end-diastolic pressure-volume point away from the relation constructed from baseline and nitroprusside points. We conclude that ANP has no direct effect on myocardial contractile or diastolic function in patients with hypertension.

Topics: Adult; Atrial Natriuretic Factor; Diastole; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Myocardial Contraction; Nitroprusside; Norepinephrine; Ventricular Function, Left

We examined corticosteroid secretory patterns and their relation to altered salt and water metabolism in Milan hypertensive and normotensive rats. Hypertensive rats had significantly higher blood pressures, exchangeable sodium (hypertensive, 41.2 +/- 0.3 mmol.kg-1; normotensive, 38.4 +/- 0.03 mmol.kg-1, P < .001), plasma volume (hypertensive, 5.39 +/- 0.12 mL.100 g-1; normotensive, 4.84 +/- 0.10 mL.100 g-1, P < .001), and plasma concentrations of atrial natriuretic peptide (hypertensive, 38.8 +/- 4.0 pg.mL-1, normotensive, 22.4 +/- 3.1 pg.mL-1, P < .02). These features coincide with those of mineralocorticoid-induced hypertension. Adrenal venous secretory rates (picomoles per minute) of corticosterone (hypertensive, 1696 +/- 202; normotensive, 873 +/- 139), 18-hydroxycorticosterone (hypertensive, 49.7 +/- 8.3; normotensive, 25.7 +/- 3.3), and aldosterone (hypertensive, 1.16 +/- 0.17; normotensive, 0.52 +/- 0.08) were higher in the hypertensive than the normotensive strain, but that of 11-deoxycorticosterone (DOC) (hypertensive, 94.4 +/- 14.9; normotensive, 114.3 +/- 33.9) was similar in the two strains. The corticosterone-DOC, 18-hydroxycorticosterone-DOC, and aldosterone-DOC ratios were higher in the hypertensive than the normotensive strain (P < .02), but the 18-hydroxycorticosterone-corticosterone and aldosterone-18-hydroxycorticosterone ratios were not. These results indicate increased activity of the "late" aldosterone biosynthetic pathway in the hypertensive compared with the normotensive strain caused by an increased conversion rate of DOC to corticosterone. The comparison of corticosterone secretion between the two strains indicates that 11 beta-hydroxylase rather than aldosterone synthase activity is more active in the hypertensive than the normotensive rats.

Topics: 18-Hydroxycorticosterone; Adrenal Glands; Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Water; Corticosterone; Desoxycorticosterone; Hypertension; Male; Plasma Volume; Rats; Sodium; Species Specificity

A total of 78 Chinese patients with clinically uncomplicated non-insulin-dependent diabetes (NIDDM) who had plasma creatinine concentrations of < 150 mumol/l were studied. Antihypertensive treatment was discontinued for at least six weeks prior to measurements of routine biochemistry, proteinuria, plasma atrial natriuretic peptide (ANP) concentrations and components of the renin-angiotensin-aldosterone system (RAAS). BP was measured on three occasions during the six weeks period prior to these measurements. At the end of the six week period, a total of 33 patients had definite hypertension (supine BP > or = 160/95 mmHg). The hypertensive patients had significantly higher plasma sodium (mean +/- SD): 140.3 +/- 1.9 vs. 138.5 +/- 2.0 mmol/l, P < 0.001) and lower plasma potassium (3.8 +/- 0.5 vs. 4.2 +/- 0.5 mmol/l, P < 0.01) concentrations. These were associated with reduced plasma aldosterone (median (range): 297 (98-1145) vs. 448.5 (93-1330) pmol/l, P < 0.01) and renin concentrations (16.8 (7.4-71.8) vs. 23.5 (7.4-83.7) ng/l, P = 0.06). The hypertensive patients also had significantly higher plasma ANP concentrations (36.5 (20.5-125.1) vs. 23.2 (11.7-63.0) pg/ml, P < 0.001), serum angiotensin converting enzyme (ACE) activity (65 (26-140.9) vs. 47 (22-106) units/l, P < 0.001) and urinary albumin excretion (UAE) (35.4 (1.6-4800) vs. 7.8 (1.8-310.4) mg/day, P < 0.001). Glycaemic control and renal function were similar between the two groups. Mean arterial pressure (MAP) correlated positively with plasma ANP concentration (r = 0.53, P < 0.001) and serum ACE activity (r = 0.37, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Electrolytes; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System

To investigate the possible role of dopamine, a catecholamine with natriuretic properties, in modulating the escape from the sodium-retaining effects of mineralocorticoids, we submitted six aldosterone-producing adenoma (APA) patients and six low-renin essential hypertensive patients to acute volume expansion by head-out water immersion with or without dopaminergic blockade by metoclopramide. Water immersion alone induced a marked, comparable natriuresis (P < 0.001) in both hypertensive groups where a slight reduction of already suppressed renin-angiotensin system and a marked stimulation of atrial natriuretic peptide was also observed (P < 0.03 and P < 0.002, respectively). Water immersion plus dopaminergic blockade by metoclopramide did not significantly affect the natriuresis observed during water immersion alone in APA patients; conversely, there was a blunted natriuretic response in low-renin hypertensives during water immersion plus metoclopramide, in comparison with that obtained during water immersion alone (P < 0.006). Furthermore, metoclopramide did prevent the suppression of plasma aldosterone levels produced by central volume expansion alone in low-renin hypertensives, although it did not affect plasma aldosterone levels during water immersion in APA patients. Our data suggest that dopaminergic blockade does not counteract the natriuretic ability of the other hemodynamic and humoral mechanisms involved in the escape phenomenon of APA patients, thus casting serious doubt on the possible role of dopamine in mediating the escape from the sodium-retaining effects of mineralocorticoids.

Topics: Adenoma; Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Dopamine; Female; Hemodynamics; Humans; Hyperaldosteronism; Hypertension; Immersion; Isotonic Solutions; Kidney; Male; Metoclopramide; Middle Aged; Mineralocorticoids; Potassium; Renin; Renin-Angiotensin System; Sodium; Sodium Chloride; Urination

We have previously reported that C-type natriuretic peptide (CNP), the third member of natriuretic family, was produced in vascular endothelial cells and hypothesized that CNP might be a local regulator of vascular tone and/or growth from endothelial cells. In order to clarify the pathophysiological significance of CNP in humans, we examined the presence of CNP in human circulation and determined plasma levels of CNP in patients with various cardiovascular disorders. The plasma level of CNP in healthy persons was 1.4 +/- 0.6 fmol/ml (n = 13). The plasma level of CNP was markedly increased in patients with septic shock (13.2 +/- 10.1 fmol/ml, n = 11), while there was no alteration in patients with congestive heart failure or hypertension. There was two-fold increase of the plasma CNP level in patients with chronic renal failure. These results indicate that CNP, which can be considered as an endothelium-derived relaxing peptide, is detectable in human circulation and suggest the pathophysiological significance of endothelial CNP in humans.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Chromatography, Gel; Chromatography, High Pressure Liquid; Cross Reactions; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Reference Values; Shock, Septic

A novel 8-bp bi-allelic insertion/deletion polymorphism is described within a polyadenylate stretch in the second intron of the human atrial natriuretic peptide gene locus. This new marker is located in the candidate gene for familial susceptibility to hypertension.

Topics: Atrial Natriuretic Factor; Base Sequence; Chromosome Mapping; Chromosomes, Human, Pair 1; DNA; Gene Frequency; Genetic Markers; Humans; Hypertension; Molecular Sequence Data; Mutation; Poly A; Polymorphism, Genetic; Sequence Deletion

Insulin-stimulated peripheral glucose uptake and insulin-induced renal tubular sodium reabsorption were investigated in normotensive men with a family history of hypertension (relatives, n = 35) compared with age- and body mass index-matched normotensive men with no family history of hypertension (controls, n = 23). The effect of insulin on the renin-aldosterone system was also studied. The euglycemic hyperinsulinemic clamp technique was used to measure peripheral glucose uptake (insulin sensitivity index). Renal clearance of 51Cr-labeled EDTA, sodium, and lithium was used to calculate fractional excretion of sodium and fractional proximal and distal tubular reabsorption of sodium before and during insulin infusion. The insulin sensitivity index was lower in relatives than in controls. Fractional excretion of sodium was reduced, and fractional proximal and distal tubular reabsorption of sodium were increased to the same extent in both groups during insulin infusion. Fractional distal tubular reabsorption of sodium was positively correlated to the reduction of serum potassium in all individuals. Plasma renin activity increased to the same extent in both groups, whereas plasma aldosterone was reduced only in controls. In conclusion, the impaired insulin-stimulated glucose uptake in peripheral tissues in normotensive sons of hypertensive families was accompanied by retained insulin-induced tubular sodium reabsorption. The lack of suppression of aldosterone secretion in these individuals may enhance sodium retention.

Topics: Absorption; Adult; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Insulin; Insulin Resistance; Kidney; Male; Middle Aged; Renal Circulation; Renin; Sodium

To clarify the natriuretic action of endogenous atrial natriuretic peptide (ANP) in patients with essential hypertension (EHT), we examined the relationship between ANP release and urinary sodium excretion in response to hypertonic saline infusion. Plasma ANP levels increased from 13.3 +/- 2.0 pg/ml to 37.0 +/- 3.0 pg/ml in patients with EHT and from 9.2 +/- 1.5 pg/ml to 21.1 +/- 4.0 pg/ml in normal subjects after the infusion. The area under the curve (AUC) of plasma ANP response was significantly higher in patients with EHT than in normal subjects (P < 0.05). There was a significant positive correlation between AUC and urinary sodium excretion in both groups (P < 0.01). However, the ratio of urinary sodium excretion to AUC was significantly lower in patients with EHT than in normal subjects (P < 0.01). These results suggest that impaired natriuretic response to endogenous ANP is one of the factors responsible for the development of EHT and that enhanced secretion of ANP in response to hypertonic saline infusion is a compensatory mechanism to the impaired natriuretic action of ANP in patients with EHT.

Topics: Adult; Aged; Atrial Natriuretic Factor; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Saline Solution, Hypertonic

1. Diabetes mellitus is associated with high body sodium, but the pathogenetic mechanism is still unknown. The possibility that an abnormal renal handling of sodium, an abnormal responsiveness of sodium-modulating factors or a shift in the set point for sodium metabolism may contribute to or be associated with sodium retention was tested with an acute saline infusion. 2. A consecutive sample of 33 patients with stable non-azotaemic diabetes mellitus (24 insulin-dependent patients) and 30 normal control subjects was studied. Two litres of a 0.9% NaCl infusion were infused over 4 h. The urinary sodium excretion during the infusion and the next 18 h was analysed in relation to blood pressure, creatinine and lithium clearances, Na(+)-K+ co-transport, Na(+)-Li+ countertransport, plasma levels of renin, angiotensin II, aldosterone, noradrenaline, adrenaline, atrial natriuretic factor and digoxin-like factor. 3. Diabetic patients and control subjects did not differ in blood pressure, body mass index, clearances of creatinine, sodium or lithium, intracellular sodium Na(+)-K+ co-transport and Na(+)-Li+ countertransport, urinary and plasma levels of digoxin-like factor, plasma renin activity, angiotensin II, aldosterone, noradrenaline, adrenaline and atrial natriuretic factor. The intravenous saline infusion caused a similar natriuresis in diabetic patients and normal subjects; the renin-angiotensin-aldosterone system was suppressed to a higher degree in diabetic patients than in normal subjects, whereas atrial natriuretic factor was stimulated to a similar extent; plasma digoxin-like activity was unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Norepinephrine; Peptides; Renin; Renin-Angiotensin System; Sodium

Topics: Adrenocorticotropic Hormone; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Drug Resistance; Humans; Hydrocortisone; Hypertension; Italy; Phenotype; Renal Circulation; Renin-Angiotensin System; Sodium; Sodium, Dietary

To evaluate plasma atrial natriuretic factor (ANF) behavior in hypertensive patients with either insulin-dependent (type I) or non-insulin-dependent (type II) diabetes.. Plasma ANF levels were measured in euglycemic normotensive patients (n = 18) and hypertensive patients (n = 18), in diabetic normotensive patients (type I diabetes, n = 12; type II diabetes, n = 12), and in diabetic hypertensive patients (type I diabetes, n = 12; type II diabetes, n = 22). In all groups, plasma ANF levels were determined at the end of a normal NaCl diet period (120 mmol NaCl per day for 10 days) in both the supine and the upright positions.. Plasma ANF levels were significantly higher (P < 0.05) in hypertensive euglycemic patients (supine vs. upright: 13.4 +/- 6.7 vs. 8.5 +/- 4.3 fmol/ml) than in normotensive type I diabetic patients (supine vs. upright: 8.6 +/- 2.2 vs. 5.9 +/- 2.9 fmol/ml) but not in euglycemic normotensive subjects (supine vs. upright: 11.4 +/- 5.1 vs. 7.6 +/- 5.8 fmol/ml) and normotensive type II diabetic patients (supine vs. upright: 10.1 +/- 4.1 vs. 7.9 +/- 4.1 fmol/ml). Moreover, in the normotensive groups plasma ANF levels did not significantly differ among euglycemic type I and type II diabetic patients. However, the highest levels of plasma ANF were observed in hypertensive type II diabetic patients (supine vs. upright: 16.9 +/- 7.4 fmol/ml [P < 0.01 vs. euglycemic normotensive subjects, P < 0.0001 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients and normotensive type II diabetic patients] vs. 11.6 +/- 2.9 fmol/ml [P < 0.005 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients]). On the contrary, plasma ANF levels were higher (P < 0.05) in hypertensive type I diabetic patients (supine vs. upright: 10.8 +/- 1.9 vs. 6.4 +/- 2.2 fmol/ml) compared with normotensive type I diabetic patients, but not with any other patient group. A significant correlation between supine ANF and insulin levels was found in both type II diabetic (r = 0.457; P < 0.05) and nondiabetic hypertensive patients (r = 0.716; P < 0.0001).. These findings indicate that circulating ANF levels are markedly elevated in type II diabetic patients affected by essential hypertension. On the contrary, plasma ANF levels are in the range of normality in normotensive type I and type II diabetic patients.

Topics: Adult; Analysis of Variance; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Hexosamines; Humans; Hypertension; Insulin; Male; Middle Aged; Posture; Potassium; Reference Values; Sodium

The purpose of the present study was to compare influence of central arginine vasopressin (AVP) and of atrial natriuretic peptide (ANP) on control of arterial blood pressure (MAP) and heart rate (HR) in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Three series of experiments were performed on 30 WKY and 30 SHR, chronically instrumented with guide tubes in the lateral ventricle (LV) and arterial and venous catheters. MAP and HR were monitored before and after i.v. injections of either vehicle or 1, 10 and 50 ng of AVP and 25, 125 and 500 ng of ANP. Sensitivity of cardiac component of baroreflex (CCB), expressed as a slope of the regression line was determined from relationships between systolic arterial pressure (SAP) and HR period (HRp) during phenylephrine (Phe)-induced hypertension and sodium nitroprusside (SN)-induced hypotension. CCB was measured before and after administration of either vehicle, AVP, ANP, or both peptides together. Increases of MAP occurred after LV administration of 1, 10 and 50 ng of AVP in WKY and of 10 and 50 ng in SHR. ANP did not cause significant changes in MAP in both strains as compared to vehicle, but it abolished AVP-induced MAP increase in WKY and SHR. CCB was reduced in WKY and SHR after LV administration of AVP during SN-induced hypotension. In SHR but not in WKY administration of ANP, AVP and ANP + AVP decreased CCB during Phe-induced MAP elevation. The results indicate that centrally applied AVP and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Heart Rate; Hemodynamics; Hypertension; Injections, Intravenous; Injections, Intraventricular; Male; Nitroprusside; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The distribution of atrial natriuretic polypeptide (ANP) and atrial specific granules in the myocytes of the atria and ventricles of an experimental animal model, stroke-prone spontaneously hypertensive rats (SHRSP) and a control, Wistar Kyoto rats (WKY), was examined using immunocytochemical and electron microscopic techniques. In the atria of both SHRSP and WKY, ANP-immunoreactivity was recognized in the perinuclear regions of essentially all cardiac myocytes. In the ventricles of WKY, ANP-immunoreactivity was hardly seen except for the impulse-conducting system. However, in the ventricles of SHRSP, almost all cardiac myocytes possessed immunoreaction products which were scattered evenly throughout the cytoplasm; this distribution pattern differed from that of the atrial wall of this strain.

Topics: Animals; Atrial Natriuretic Factor; Cerebrovascular Disorders; Cytoplasmic Granules; Disease Models, Animal; Disease Susceptibility; Heart Atria; Heart Ventricles; Hypertension; Immunohistochemistry; Male; Microscopy, Electron; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Hyperinsulinemia and insulin resistance are implicated in the etiology of hypertension, but the mechanisms involved have not been established. The objectives of this study were to determine whether untreated essential hypertensive patients are more sensitive to the antinatriuretic action of insulin and more resistant to the counteracting natriuretic effect of atrial natriuretic peptide in contrast to age- and sex-matched normotensive control subjects. Urinary sodium excretion was measured at baseline, during hyperinsulinemic euglycemic clamp, and during coadministration of insulin and atrial natriuretic peptide. Baseline urinary sodium excretion was not significantly different in the normotensive subjects (415 +/- 47 mumol/min, n = 12) and hypertensive patients (381 +/- 18 mumol/min, n = 10); with the institution of insulin infusion, there was a similar and significant decline from baseline (P < .001) to 289 +/- 35 mumol/min in normotensive subjects and 235 +/- 17 mumol/min in hypertensive patients. Atrial natriuretic peptide was able to oppose the antinatriuretic action of insulin in normotensive subjects, increasing urinary sodium excretion significantly to a mean level of 352 +/- 31 mumol/min (P < .05), which did not differ significantly from baseline. In the hypertensive group, atrial natriuretic peptide infusion had no effect on urinary sodium excretion (238 +/- 18 mumol/min), and the difference from baseline remained highly significant (P < .001). The hypertensive patients were significantly less insulin sensitive than their normotensive counterparts, as reflected by a lower glucose utilization rate and higher mean baseline plasma insulin level (P < .05 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Glucose Clamp Technique; Hemodynamics; Humans; Hypertension; Insulin; Insulin Resistance; Kidney Tubules; Male; Middle Aged; Natriuresis; Renal Circulation; Sodium

The human heart secretes both atrial natriuretic peptide and brain natriuretic peptide. This study attempts to clarify the pathophysiological significance of the peptides in cardiovascular diseases. Using immunoradiometric assay, plasma brain natriuretic peptide and atrial natriuretic peptide levels in essential hypertension, various secondary hypertension, chronic renal failure, chronic heart failure during cardiac pacing, and acute myocardial infarction were determined. Mean plasma brain natriuretic peptide and atrial natriuretic peptide levels in healthy subjects were 3.7 +/- 0.3 and 5.7 +/- 0.3 pmol/L, respectively, and increased as a function of age. Plasma brain natriuretic peptide levels showed a larger increase than atrial natriuretic peptide levels in various cardiovascular diseases. In chronic renal failure, whereas plasma atrial natriuretic peptide levels decreased significantly after hemodialysis and were correlated with the changes in body weight, changes in plasma brain natriuretic peptide levels were less prominent and did not show such a correlation. In chronic heart failure, both basal plasma brain natriuretic peptide and atrial natriuretic peptide levels were also significantly elevated. However, in response to acute ventricular or atrial pacing, brain natriuretic peptide levels did not show any increase in contrast to the marked increase of atrial natriuretic peptide levels. In acute myocardial infarction, brain natriuretic peptide levels showed more prominent changes than atrial natriuretic peptide levels and were correlated with serum levels of creatine kinase and cardiac myosin light chain I in most patients. These results suggest that both brain and atrial natriuretic peptides play an important role in the regulation of cardiovascular homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Gland Neoplasms; Adult; Aged; Aging; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiovascular Diseases; Female; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pheochromocytoma; Reference Values; Regression Analysis; Renal Dialysis

To evaluate the additive effect of moderate chronic renal failure to the abnormal dopamine generation and action observed in stable hypertension, we investigated 22 age-matched patients with a comparable degree of hypertension with and without chronic renal failure. Both groups were compared with each other and with an age-matched control group after a single oral dose of dihydroxyphenylalanine (DOPA) while cardiorenal responses and DOPA, dopamine, and their metabolites were measured. The hypertensive patients with chronic renal failure shared with their hypertensive counterparts without chronic renal failure an impaired DOPA decarboxylation to dopamine. However, patients with chronic renal failure had decreased hemodynamic and normal natriuretic responses compared with the hypernatriuresis of hypertensive patients with normal renal function; patients with chronic renal failure had elevated basal plasma concentrations of DOPA and dopamine sulfates as well as increased plasma and urinary DOPA sulfate but blunted urinary dopamine sulfate increases after DOPA administration; they presented augmented plasma atrial natriuretic factor concentrations. Thus, hypertensive patients with moderate chronic renal failure exhibit a decreased hemodynamic responsiveness to DOPA administration-induced dopamine elevation but with the natriuretic effect of dopamine maintained (possibly because of its permissive interaction with increased atrial natriuretic factor levels). Hypertensive patients with chronic renal failure have a heightened DOPA and dopamine sulfoconjugating propensity. Dopamine sulfate attenuates the biologic action of free dopamine. This may contribute (possibly via glomerular hypertension and hyperfiltration due to decreased postglomerular vasodilation) to progressive hypertensive renal damage, particularly in groups predisposed to dopamine deficiency, such as diabetics, blacks, and the elderly.

Topics: 3,4-Dihydroxyphenylacetic Acid; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Diastole; Dihydroxyphenylalanine; Dopamine; Female; Homovanillic Acid; Humans; Hypertension; Kidney Failure, Chronic; Levodopa; Male; Middle Aged; Reference Values; Sodium

Increasing dietary sodium intake increases blood pressure in some subjects with essential hypertension. Atrial natriuretic factor (ANF) has a potential role in modifying these changes. The purpose of this study was to observe the blood pressure and plasma ANF responses to low and high sodium diets in subjects with essential hypertension to see if the plasma ANF and blood pressure responses were related.. An in-patient study of subjects taking their normal diet (day 1), a 12 mmol sodium diet for 6 days and a 250 mmol diet for 6 days.. Seven men with essential hypertension.. Continuous 24 hour urine collections were analysed for sodium excretion. Blood pressure was recorded at 0900, 1205 and 1700 h on days 1, 7 and 13. Blood was taken at 0900 h (fasting supine overnight) and at 1200 h (after 2 hours erect posture) on the above days for plasma ANF, plasma renin activity (PRA) and serum aldosterone.. Urinary sodium excretion was (mean +/- SEM) 11 +/- 1 mmol on day 5 of the low sodium diet, and 294 +/- 17 mmol during the fifth day of the high sodium diet. Plasma ANF (supine and erect) was significantly lower (2.8 +/- 0.6, 1.6 +/- 0.2 pmol/l) on the low sodium diet when compared to the high sodium diet (8.6 +/- 2.4, 5.0 +/- 1.6 pmol/l (P < 0.05)). Supine and erect PRA and serum aldosterone were significantly higher on the low compared to the high sodium diet. Blood pressure responses were heterogeneous rather than bimodal. Mean arterial blood pressure was 107 +/- 3 mmHg on the low sodium diet and 111 +/- 4 mmHg on the high sodium diet (P < 0.05). Changes of blood pressure did not correlate with the changes of plasma ANF.. Failure of plasma atrial natriuretic factor to rise with increasing dietary sodium did not therefore determine the blood pressure response to the change in dietary sodium. No link was established between plasma atrial natriuretic factor response and sodium sensitivity.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Sodium; Sodium, Dietary

Pharmacokinetic and pharmacodynamic data were compared between elderly and young patients with hypertension who received single intravenous doses of amlodipine, a dihydropyridine calcium antagonist, followed by oral administration of amlodipine up to 10 mg once daily for 12 weeks. After intravenous administration, elderly patients had prolonged elimination half-life values (58 +/- 11 vs 42 +/- 8 hr; p < 0.05) caused by decreased clearance (19 +/- 5 vs 7 liters/hr; p < 0.05). Systolic and diastolic blood pressures were significantly decreased from baseline throughout the 3-month treatment period in both groups. After long-term oral administration, elderly and young patients had comparable decreases in mean blood pressure at a given drug plasma concentration. The antihypertensive effect of amlodipine is well correlated with plasma concentration and, at a given concentration, is similar in both elderly and young patients.

Topics: Administration, Oral; Adult; Aged; Amlodipine; Atrial Natriuretic Factor; Biological Availability; Blood Pressure; Blood Pressure Monitors; Drug Administration Schedule; Half-Life; Humans; Hypertension; Male; Middle Aged; Renin

Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.

Topics: Affinity Labels; Animals; Atrial Natriuretic Factor; Base Sequence; Cyclic GMP; Dose-Response Relationship, Drug; Gene Expression Regulation; Guanylate Cyclase; Hypertension; Kidney Glomerulus; Male; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger

To appreciate the role of some neuropeptides in the antihypertensive mechanism of clonidine, 17 patients with essential hypertension were given po clonidine 150 micrograms tid for 3 d. Plasma atrial natriuretic factor (ANF), vasopressin (Vas), and dynorphin A (Dyn A) were measured by radioimmunoassay. After the treatment, mean blood pressure (MBP), heart rate and 24 h urine norepinephrine, epinephrine were decreased, but no change was found in plasma Dyn A. The magnitudes of increased ANF and decreased Vas were correlated with the decreased MBP (r = -0.57 and 0.53, respectively, P < 0.05). These results suggest that both ANF and Vas are involved in the antihypertensive mechanism of clonidine.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Clonidine; Dynorphins; Female; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Vasopressins

Atrial natriuretic peptide (ANP) response during acute saline loading and its relationship to changes in blood pressure (BP) and sodium excretion were studied in 21 patients with essential hypertension (EH) and nine normotensive volunteers. Following 2 liters of isotonic saline infusion at a rate of 500 mL/hour, plasma ANP concentrations in patients with EH increased significantly from 69.9 +/- 6.0 (mean +/- SEM) to 103.6 +/- 17.1 pg/mL (p < 0.05) in the first hour and peaked at the second hour. In normal subjects, the increase in plasma ANP was not significant until the third hour of infusion (64.6 +/- 6.2 to 82.0 +/- 7.5 pg/mL, p < 0.05). Mean BP (MBP) remained stable and the natriuretic responses were similar in the two groups. However, hypertensive patients with a prompt rise in ANP during the initial two hours of infusion (fast responders) maintained a BP balance more efficiently than those with a delayed rise in ANP (slow responders), as the latter displayed a significant increase in MBP two hours after saline loading (126 +/- 5 to 133 +/- 5 mmHg, p < 0.05). Fast responders also had a greater percent of suppression of plasma aldosterone (-49.7 +/- 9.2 vs 15.9 +/- 42.0%, p = 0.05) one hour after saline loading, and a higher increment of natriuresis (263.9 +/- 43.8 vs 97.5 +/- 27.4%, p < 0.025) in the second hour of infusion than slow responders. Our results indicate that during acute saline loading, patients with EH have a faster and greater rise in plasma ANP than normotensives.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Sodium Chloride

Plasma concentration of two main cardiovascular substances - atrial natriuretic factor (ANF) and endothelin - were studied in control subjects (n = 21) under basal conditions and 90 minutes after oral administration of glucose. In hypertensive patients (n = 21) these determinations were repeated after 12 weeks treatment with an angiotensin I-converting enzyme inhibitor lisinopril (Prinivil, Merck Sharp and Dohme). While basal and post-glucose ANF concentrations did not differ in controls and hypertensive patients, a tendency to the higher endothelin levels was found in our group of essential hypertension when compared to normotensive subjects. Glucose loading did not change significantly ANF concentrations in any studied group but significantly lowered plasma endothelin in both controls (from 13 +/- 0.95 to 9.50 +/- 0.95 fmol/ml) and hypertensive patients (from 15.05 +/- 1.23 to 12.15 +/- 1.03 fmol/min). Treatment of hypertensive patients with lisinopril paradoxically increased concentrations of ANF (from 6.43 +/- 2.53 to 11.47 +/- 4.90 fmol/ml) and lowered that of endothelin (from 15.05 +/- 1.23 to 12.17 +/- 1.58 fmol/ml). From our findings we may suggest that the relative predominance of the vasoconstrictor (endothelin) over the vasodilator (ANF) humoral substances might participate in pathogenesis of EH and that the reversal of this disadvantageous ratio after lisinopril (increase of ANF and decrease of endothelin) might contribute to the blood pressure reducing effect of ACEI. The drop in plasma endothelin after glucose remains so far unexplained consequence of glucose loading in both control and hypertensive subjects.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Endothelins; Female; Glucose Tolerance Test; Humans; Hypertension; Lisinopril; Male; Middle Aged

To investigate the effects of a salt diet and of salt-induced hypertension on hepatic atrial natriuretic peptide (ANP) receptors in Dahl salt-resistant (DR) and Dahl salt-sensitive (DS) rats.. DS and DR rats were maintained for 5 weeks on either normal- (0.8% w:w NaCl) or high- (8% w:w NaCl) salt diets. Blood pressures were recorded by a tail-cuff analyser and plasma ANP concentrations were determined by radioimmunoassay. ANP binding and guanylate cyclase activities in purified liver plasma membrane fractions were determined by conventional radioreceptor and enzymatic techniques.. DS rats exhibited higher blood pressure than DR rats on the equivalent diet and in both groups the high-salt diet significantly increased systolic blood pressures. The high-salt diet significantly reduced plasma ANP concentrations in DR rats but not DS rats. Membrane fractions from DS rats exhibited increased ANP receptor densities compared to membranes isolated from DR rats on the equivalent diet. The high-salt diet induced a significant increase in receptor density in the DS but not the DR group. The fractional displacement of [125I]-ANP binding by the truncated, ring-deleted analogue des[QSGLG]-4,23-ANP-NH2 was reduced in membrane fractions isolated from DS rats maintained on the high-salt diet. There was no change in ANP receptor affinity. Increases in receptor density in DS rats were accompanied by increases in both basal and ANP-stimulated guanylate cyclase activities.. These results indicate that plasma membrane isolated from the liver of DS rats exhibit increased expression of the guanylate cyclase-linked ANP-B (guanylate cyclase-A and/or guanylate cyclase-B) receptors over similar preparations isolated from DR rats. ANP B receptor density is further increased when DS rats are maintained on a high-salt diet.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Guanylate Cyclase; Hypertension; Liver; Male; Radioimmunoassay; Radioligand Assay; Rats; Rats, Inbred SHR; Receptors, Atrial Natriuretic Factor; Sodium, Dietary; Up-Regulation

1. Lungs can take up from the vasculature, circulating forms of atrial natriuretic peptide (Turrin and Gillis, 1986, 1987) and also to synthesize ANP. 2. The lung peptide directly delivered by lungs into the lung vasculature could play a role in the local water/electrolytic balance. 3. Using Spontaneously Hypertensive Rats (SHR), isogenic normotensive controls, the Wistar-Kyoto strain (WKY), and the regular Wistar strain as second control (W), and using a highly sensitive RIA, we measured the immunoreactive IR-ANP content of extracted plasma, lung homogenate and lung perfusate, since there are references of altered ANP levels in this kind of hypertension. 4. The IR-ANP measured in the lung vasculature effluent collected throughout 32 min of Krebs perfusion, was significantly different in all of the three analyzed strains (SHR > WKY > W). 5. The results support the idea of a local function for the peptide hormone directly delivered into the lung vasculature of SHR, which could represent a local adaptation to haemodynamics SHR characteristics besides a genetic characteristic distinguishing WKY from W strains.

Topics: Animals; Atrial Natriuretic Factor; Female; Hypertension; Lung; Perfusion; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar

1. The pathophysiologic role of atrial natriuretic factor (ANF) in genetic hypertension was investigated in 5- and 21-week-old genetically hypertensive (LH), normotensive (LN) and low blood pressure (LL) rats of the Lyon strain. 2. Plasma ANF was significantly higher in 5-week-old LH than in age-matched LN and LL animals. It tended to be lower in 21-week-old LH than in LN rats. 3. Left and right atrial ANF content was also significantly lower at 21 weeks in the LH group. 4. Glomerular ANF receptors showed a significant decrease in LH in comparison to LL and LN animals.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Hematocrit; Hypertension; Kidney Glomerulus; Male; Organ Size; Protein Binding; Rats

The authors have previously shown that atrial natriuretic peptide (ANP) mediates its cellular effects in part by changes in Ca2+ homeostasis in kidney cortex and that Ca2+ + Mg2+ ATPase is linked to ANP receptors, being reciprocally modulated by the guanylate cyclase system. The present study was designed to examine the status of this coupling in diabetes-induced congestive heart failure and the effect of its alterations on the functional integrity of the renal cell. Ca2+ + Mg2+ ATPase and guanylate cyclase were tested in hypertensive-diabetic rats (D + H), which develop congestive heart failure (CHF) at ten weeks following streptozotocin (65 mg/kg) injection and abdominal aortic constriction. The ATPase activity was measured by the release of 32P from [gamma-32P]ATP in the medium. While the guanylate cyclase activity was decreased very rapidly in the hypertensive-diabetic group, the sensitivity of the Ca2+ pump to ANP was increased at an early stage (three weeks) and decreased at a late stage (ten weeks) of CHF. The authors conclude that a defect in coupling between the Ca2+ pump and the ANP-receptor system as observed in the D + H group may contribute to the development of nephropathy and CHF.

Topics: Animals; Atrial Natriuretic Factor; Ca(2+) Mg(2+)-ATPase; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Guanylate Cyclase; Heart Failure; Hypertension; Kidney; Male; Rats; Rats, Sprague-Dawley

The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.

Topics: Animals; Arteries; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Electrophoresis, Polyacrylamide Gel; Endothelins; Endothelium, Vascular; Hypertension; Lead; Lead Poisoning; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Norepinephrine; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase

The mechanism of hypoxic moderation of systemic systolic blood pressure was investigated in spontaneously hypertensive rats (SHR). Male SHR rats were divided into hypoxic (H, 5000 m for 15 d) and normoxic (N) groups. The systemic blood pressure of SHR-H (24.9 +/- 1.2 kPa) was found to be 3 kPa lower than that in SHR-N (27.0 +/- 1.3 kPa) (P < 0.05). This protective effect may have been related to the adaptive changes in vascular reactivity which manifested as an increase in the relaxation response of the aorta to ACh (P < 0.01) and a drop in its contraction in response to 5-HT (P < 0.05) following hypoxic exposure. The hypoxic moderating effect against the development of systemic hypertension may have also been related to the increased plasma levels of ANP observed.

Topics: Altitude; Angiotensin II; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Hypertension; Hypoxia; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin

Topics: Atrial Natriuretic Factor; Blood Preservation; Cryopreservation; Heart Diseases; Humans; Hypertension; Kidney Diseases; Specimen Handling

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Calcium; Extracellular Space; Female; Humans; Hypertension; Male; Reference Values; Renin; Sodium; Sodium, Dietary

Topics: Administration, Oral; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Biological Availability; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Hypertension; Molecular Sequence Data; Neprilysin; Oligopeptides; Organophosphonates; Prodrugs; Rats; Substrate Specificity

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Captopril; Drug Resistance; Female; Humans; Hypertension; Male; Natriuresis; Renin-Angiotensin System; Sodium Chloride, Dietary

Endothelin (ET) exerts direct vasoconstrictory effects and stimulates release of vasoactive substances. It has been demonstrated that ET stimulates the release of atrial natriuretic peptide (ANP) both under in vitro and in vivo conditions. The present study aimed at elucidating whether the cardiovascular effects of endothelin-3 (ET-3) in normotensive (WKY) and spontaneously hypertensive (SHR) rats are modulated by ANP. The experiments were performed on 17 conscious WKY and 17 SHR rats. The effects of i.v. administration of 1 microgram of ET-3 on blood pressure (BP) and heart rate (HR) were investigated under control conditions and during ANP infusion (0.3 microgram/kg/min). In both strains ET-3 elicited a transient significant hypotensive effect followed by an increase in BP. BP fall was significantly greater and pressor effect significantly smaller in SHR than in WKY. In WKY, but not in SHR rats, both hypotensive and pressor phases were significantly attenuated during ANP administration. The results are evidence of differential involvement of endogenous blood pressure regulating factors in the cardiovascular effects of ET-3 in WKY and SHR rats during ANP infusion.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelins; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. To examine whether posture-induced changes in central volume affect brain natriuretic peptide secretion, plasma levels of human brain natriuretic peptide-32-like immunoreactivity (hBNP-32-li) were measured by radioimmunoassay in 11 healthy subjects and 20 patients with essential hypertension after 15 min supine, 15 min sitting and 15 min with the legs raised at 60 degrees, together with plasma atrial natriuretic peptide concentration, plasma renin activity and plasma aldosterone concentration. 2. In the supine position, the plasma hBNP-32-li level was 1.57 +/- 0.10 fmol/ml in healthy subjects and significantly higher in hypertensive patients (2.39 +/- 0.13 fmol/ml, P < 0.001). In both groups, plasma hBNP-32-li level significantly (P < 0.001) decreased when sitting (normotensive, 1.22 +/- 0.08 fmol/ml; hypertensive, 1.85 +/- 0.15 fmol/ml, P < 0.001 versus normotensive) and increased again after leg raising (normotensive, 2.13 +/- 0.12 fmol/ml; P < 0.002 versus resting; hypertensive, 2.84 +/- 0.16 fmol/min, P < 0.001 versus resting, P < 0.025 versus normotensive). 3. The plasma atrial natriuretic peptide concentration showed similar behaviour to the plasma hBNP-32-li, whereas plasma renin activity and plasma aldosterone concentration increased during sitting and decreased during leg raising in both healthy subjects and hypertensive patients, who had significantly higher plasma aldosterone levels when supine and sitting.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Posture; Renin

This study was designed to investigate the modification of plasma and cardiac tissue brain natriuretic peptide concentrations in spontaneously hypertensive rats and Wistar-Kyoto rats in relation to those of atrial natriuretic peptide during the development of hypertension.. Blood pressure, tissue weight, and plasma and cardiac tissue atrial natriuretic peptide and brain natriuretic peptide concentrations were measured in conscious 5, 10, and 18 week old, spontaneously hypertensive, and in corresponding normotensive rats. Pharmacokinetics of atrial natriuretic peptide and brain natriuretic peptide were also examined.. Plasma concentrations of both atrial natriuretic peptide and brain natriuretic peptide in hypertensive rats increased significantly with development of hypertension. The pattern was not in parallel, so that the brain natriuretic peptide/atrial natriuretic peptide ratio was high in spontaneously hypertensive rats. Concentrations of brain natriuretic peptide in the cardiac ventricle were already higher in hypertensive rats than in controls as early as 5 weeks of age, whereas atrial natriuretic peptide concentrations in the ventricle, predominantly in the left ventricles, and the highest brain natriuretic peptide/atrial natriuretic peptide ratio was in the left ventricles from 18 week old spontaneously hypertensive rats. Pharmacokinetics showed that the plasma half lives of atrial natriuretic peptide and brain natriuretic peptide were not different between the two strains.. Although raised blood pressure stimulates both atrial natriuretic peptide and brain natriuretic peptide, production of brain natriuretic peptide in the ventricles is already increased in the prehypertensive stage, and in older hypertensive rats, it is more responsive to progression of hypertension than atrial natriuretic peptide. It is suggested that regulation of production and secretion of the two natriuretic peptides is not temporally coordinated during development of hypertension in this model.

Topics: Animals; Atrial Natriuretic Factor; Half-Life; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY

A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Binding Sites; Biological Availability; Computer Simulation; Crystallography, X-Ray; Drug Design; Hydroxyproline; Hypertension; Models, Molecular; Molecular Sequence Data; Molecular Structure; Neprilysin; Peptides, Cyclic; Rats; Thermolysin

Topics: Animals; Atrial Natriuretic Factor; Electrolytes; Hemodynamics; Hypertension; Male; Rabbits

Arterial pressure, sodium excretion, urine output, and plasma atrial natriuretic peptide (ANP) concentrations were measured before, during, and after a 3-h i.v. infusion of arginine-vasopressin (vasopressin; 20 ng/kg/min) in conscious Doca-salt hypertensive rats. Arterial pressure was 166 +/- 8 mm Hg before the infusion of vasopressin; in comparison, pressure was only 130 +/- 4 mm Hg 5 h after stopping the infusion. The fall in pressure after withdrawal of an equipressor dose of phenylephrine in hypertensive animals was much less. In sham normotensive rats, pressure did not fall below control levels after stopping either the vasopressin or phenylephrine infusion. Sodium excretion rates were higher during infusions of vasopressin than during phenylephrine infusions. However, the elevations observed during vasopressin were similar in the hypertensive (25.3 +/- 4.9 mumol/kg/min) and normotensive (22.9 +/- 2.7 mumol/kg/min) groups. Urinary output increased to a greater extent in the hypertensive rats during the infusions of both vasopressin and phenylephrine, but the increases were similar for the 2 pressor agents. Plasma levels of ANP were elevated during the infusions of vasopressin in the normotensive rats, but not in hypertensive rats. The results indicate that the fall in pressure associated with cessation of a pressor dose of vasopressin appears specific to the hypertensive state, and relatively specific to vasopressin. This withdrawal-induced antihypertensive phenomenon (WAP) does not appear to be due solely to the preceding natriuresis and diuresis during the infusion of vasopressin. However, because the hypertensive animal may be more sensitive to a given degree of sodium loss, the possibility that the natriuresis could play a contributing or permissive role cannot be excluded.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Desoxycorticosterone; Hematocrit; Hypertension; Natriuresis; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Sodium; Vasopressins

It has been demonstrated that an exaggerated natriuretic response to central hypervolaemia is not necessarily associated with hypertension; many hypertensive subjects manifest either an appropriate or a blunted natriuresis in response to ECFV expansion attained by head-out water immersion. In this study, we tested the hypothesis that an underlying condition of salt-sensitivity may explain the heterogeneity of the natriuretic response of essential hypertension. Both salt-sensitivity tests and 2h water-immersion studies were randomly performed in 18 untreated essential hypertensives under a selected and controlled diet. Salt-sensitivity was defined as a significant drop in mean arterial pressure of 10% or greater, calculated as the difference between the average of the 25 readings under the high and the low salt period. Water immersion did result in a significant natriuretic and calciuretic response in the whole hypertensive group (n = 18, p < 0.001 and p < 0.05, respectively), while the examination of the individual excretion disclosed either exaggerated and appropriate or blunted urinary response. When the hypertensive group was classified in relation to salt-sensitivity, the greater fall in mean arterial pressure during low salt diet (salt-sensitivity) was associated with the more pronounced natriuretic response during water immersion (r = -0.66, p < 0.003). An identical correlation (r = -0.58, p < 0.01) was also found between changes in mean arterial pressure (low salt diet) and urinary calcium excretion (water immersion) in the same hypertensives. The water immersion-induced suppression of plasma aldosterone and the increase in plasma atrial natriuretic peptide did result from comparable magnitude in the salt-sensitive and in salt-resistant subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Calcium; Diet; Extracellular Space; Female; Humans; Hypertension; Immersion; Male; Middle Aged; Natriuresis; Potassium; Renin; Sodium Chloride

Plasma renin activity (PRA) and plasma concentrations of angiotensin II (AngII), atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) were determined in the abdominal aorta and the renal veins before and 1 h after peroral ingestion of captopril 25 mg in 29 patients with arterial hypertension and unilateral renal artery stenosis or occlusion, in order to study the effect of ACE inhibition on single-kidney extraction ratio (ER) of PRA, AngII, ANP, and AVP, and on renal vein renin ratio (RVRR). PRA was increased, AngII and ANP were reduced, and AVP unchanged after captopril. On the affected side the negative ER or PRA (-1.03) and AngII (-0.28) and the positive ER of ANP (0.25) and AVP (0.14) were not significantly changed by captopril. On the non-affected side ER of AngII and ER of ANP were significantly reduced (ER of AngII, 0.41-0.00, ER of ANP, 0.29-0.17), but ER of PRA and ER of AVP were unchanged. RVRR was not significantly changed by captopril. RVRR was greater than 1.5 in 79% of the patients before captopril, in 82% after captopril, and in 93% either before or after captopril. It is concluded that captopril reduces ER of AngII and ER of ANP on the non-affected side but not on the affected side in unilateral renal artery disease with hypertension, and that the use of RVRR both before and after captopril improves the predictive value of RVRR with regard to the diagnosis of unilateral renal artery disease.

Topics: Adult; Aged; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Captopril; Female; Hormones; Humans; Hypertension; Kidney; Male; Middle Aged; Peptides; Renal Artery Obstruction; Renal Circulation; Renin; Veins

Cyclosporin A has markedly improved graft survival in transplant patients but its side effects, such as renal toxicity and hypertension, pose management problems in transplant recipients. This toxicity has been attributed to prostaglandin inhibition. Concurrent administration of misoprostol (a prostaglandin E1 analog) prevents chronic cyclosporin A-induced nephrotoxicity but not hypertension in rats.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Electrolytes; Glomerular Filtration Rate; Heart Rate; Hypertension; Kidney Diseases; Misoprostol; Osmolar Concentration; Prostaglandins; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin

A genetic model of essential hypertension in the dog was studied to describe the phenotypic expression of the arterial pressure, as well as to determine the relationship between mean arterial blood pressure (MAP), hormone, and renal excretory responses to four different levels of sodium intake (5, 40, 120, 240 mEq/day) delivered intravenously and isotonically. This model was developed at the University of Pennsylvania (U/Penn) and termed Pennsylvania hypertensive dogs (PHD). The MAP was recorded beat-by-beat, 24 h/day, in 16 dogs. Water and sodium balances were determined daily for 4 days at each level of intake and blood samples were collected on the last day of each salt step for analysis of plasma renin activity (PRA), atrial natriuretic peptide (ANP), aldosterone (ALDO), and vasopressin (AVP). After the study, the dogs were designated as hypertensive (PHD-HT) when the 24-h average MAP was greater than 110 mm Hg and systolic pressure was greater than 160 mm Hg. Dogs that failed to meet both criteria were designated as normotensive genetic controls (PHD-NT). Although sodium was retained during the first day of each increase of salt intake in both groups, a return to balance was observed within the 4 days. There was no apparent change in the slope of the chronic renal function curve in either group of PHD studied, although the PHD-HT exhibit a curve shifted to a higher level of MAP. Plasma hormone levels in both groups of PHD studied responded in a manner similar to normal mongrel dogs with reductions of PRA, ALDO, elevations of ANP, and no change in AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Analysis of Variance; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Dogs; Female; Hemodynamics; Hypertension; Infusions, Intravenous; Male; Natriuresis; Renin; Sodium

We have recently shown that ANF-R2 receptors are coupled to the adenylyl cyclase/cAMP system through inhibitory guanine nucleotide regulatory protein (Gi). The present studies were undertaken to investigate the regulation of ANF-R2 receptor-mediated inhibition of adenylyl cyclase in spontaneously hypertensive rats (SHR) which have been reported to have high plasma ANF levels. ANF99-126 inhibited adenylyl cyclase activity in a concentration dependent manner in both aorta and heart sarcolemma from SHR and age-matched Wistar-Kyoto (WKY) rats, however, the extent of inhibition was greater in SHR as compared to WKY. On the other hand, ANF99-126 also inhibited the adenylyl cyclase activity in rat platelets from WKY rats in a concentration dependent manner, however, the inhibition in SHR was completely attenuated. In addition GTP gamma S stimulated adenylyl cyclase activity by about 600% in aorta from WKY rats and about 300% in SHR. On the other hand, the GTP gamma S-stimulated adenylyl cyclase activity was higher in platelets from SHR as compared to WKY. The observed difference may be attributed to the differential alterations in ANF-R2 receptor number or postreceptor events or both. Nonetheless, these results indicate that ANF-R2 receptors in platelets from SHR are differentially regulated than those in heart and aorta.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Aorta; Atrial Natriuretic Factor; Blood Platelets; Cardiovascular Physiological Phenomena; Cardiovascular System; Dose-Response Relationship, Drug; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hypertension; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Sarcolemma

We have developed a radioimmunoassay for the measurement of immunoreactive BNP (1-32) in human plasma. Simultaneous measurement of ANP have also been carried out to allow for direct comparison between circulating BNP and ANP. Plasma levels of immunoreactive BNP (means +/- SEM) were 1.1 +/- 0.1 pmol/l in 36 normal healthy subjects and were significantly elevated in 50 patients with essential hypertension (1.6 +/- 0.2 pmol/l, P < 0.02). Similarly, in patients with essential hypertension plasma levels of ANP were also significantly raised (5.5 +/- 0.6 pmol/l, P < 0.001) when compared with the group of normal healthy subjects (2.8 +/- 0.2 pmol/l). ANP was significantly higher than BNP in normal subjects and in patients with essential hypertension, with ANP/BNP ratios of 2.8 +/- 0.2 and 3.8 +/- 0.3, respectively, in these two groups. A major finding was a significant and positive association between plasma levels of both BNP and ANP within the healthy subjects (r = 0.49, P < 0.05, n = 36) and within the hypertensive subjects (r = 0.76, P < 0.001, n = 50). When all plasma values for BNP and ANP were taken together for both groups, there was an overall correlation coefficient of 0.65 (P < 0.001, n = 86). Both BNP and ANP had significant positive associations with age in hypertensive patients, with correlation coefficients of 0.53 (P < 0.001, n = 50) and of 0.53 (P < 0.001, n = 50) for BNP and ANP, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Radioimmunoassay

Wistar rats given a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME), for 4 weeks develop time- and dose-dependent hypertension without cardiac hypertrophy. This initial study of the relation between left ventricular weight and L-NAME-induced hypertension has now been extended by giving 50 mg/kg per day L-NAME to Wistar rats (n = 30) for 8 weeks and comparing results with those from control rats (n = 10) and two-kidney, one clip rats (n = 14). Although L-NAME rats and two-kidney, one clip rats had increased systolic blood pressures during the last 3 weeks of the experiment (202 +/- 24 and 224 +/- 16 mm Hg, respectively), the ratio of left ventricular weight to body weight of L-NAME rats (2.12 +/- 0.32 mg/g) was not statistically different from that of control rats (1.93 +/- 0.13 mg/g), whereas that of two-kidney, one clip rats was increased (2.85 +/- 0.20 mg/g). The plasma renin activity of L-NAME rats was not significantly different from that of control rats. Two L-NAME rat subgroups were defined according to the presence of left ventricular hypertrophy (ratio of left ventricular weight to body weight > 2.19 mg/g, control mean +2 SD) (6 of 25) or its absence (19 of 25). Systolic blood pressure, plasma renin activity, and cardiac angiotensin converting enzyme activity of L-NAME rats with left ventricular hypertrophy were significantly higher than those of the subgroup without.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensins; Animals; Arginine; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Myocardium; NG-Nitroarginine Methyl Ester; Organ Size; Rats; Rats, Wistar; Renin; Time Factors

Plasma concentration of ANF and expression of left ventricular ANF-gene in rats with cardiac hypertrophy induced by abdominal aortic partial ligation were analyzed by RIA and Northern blot respectively. Results showed that plasma concentration of ANF and level of left ventricular ANF-mRNA in cardiac hypertrophic rats increased markedly, indicating that the cardiac load may induce transcription and expression of left ventricular ANF-gene. This effect could be potentiated by intracellular calcium modulator taurine and inhibited by vasodilator hydralazine.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomegaly; Gene Expression; Hypertension; Male; Rats; Rats, Wistar; RNA, Messenger; Transcription, Genetic

To assess whether intrarenal dopamine synthesis could contribute to the renal response to ANP in essential hypertension, the effects of alpha-human ANP infusion (50 ng.min-1.kg-1 b.w. for 30 min) on the urinary excretion of dopamine and sodium, urine flow rate and arterial pressure were evaluated in 7 patients with mild-moderate essential hypertension before (control period) and during DOPA-decarboxylase inhibition with carbidopa (carbidopa period). In the control period, urinary dopamine excretion was 400 pg.min-1 in baseline conditions and 340 pg.min-1 during ANP infusion. Carbidopa significantly decreased urinary dopamine excretion both before (210 pg.min-1) and during ANP (99 pg.min-1). In contrast, carbidopa did not affect sodium excretion (control from 184 to 460 mu Eq.min-1; carbidopa period from 140 to 390 mu Eq.min-1) or urine flow rate (control from 5.35 to 11.21 ml.min-1; carbidopa period from 4.29 to 11.54 ml.min-1). Arterial pressure fell significantly during ANP infusion in both periods, and no significant difference was observed between the two study days, i.e. in the absence of and during carbidopa administration. We conclude that DOPA-decarboxylase inhibition does not influence the diuretic and natriuretic response to alpha-human ANP infusion in patients with essential hypertension.

Topics: Adult; Aged; Aromatic Amino Acid Decarboxylase Inhibitors; Atrial Natriuretic Factor; Carbidopa; Diuresis; Dopamine; Female; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Natriuresis

From our perspective, Priscilla Kincaid-Smith's major achievement in the field of hypertension relates to the pathogenesis of vascular lesions. Our own studies of the hypertension of renal parenchymal disease have suggested a role for impairment of the cortisol-cortisone shuttle and decreased activity of the enzyme complex 11-beta-hydroxy-steroid dehydrogenase. We have defined the renal functional consequences of steroid-induced hypertension and shown that the rise in blood pressure produced by steroids with predominant glucocorticoid activity is not dependent on volume shifts or sodium status, although the magnitude of the rise is modulated by dietary sodium content. We have shown that normal pregnant women adapt readily to extremes of sodium intake while women with pre-eclampsia retain sodium, and have shown enhanced capillary permeability. Recent studies have defined an abnormal aldosterone:renin ratio, dopaminergic inhibition of aldosterone, elevations of plasma atrial natriuretic peptide and reduced urinary prostacyclin:thromboxane ratios in women with pre-eclampsia.

Topics: Adrenal Cortex Hormones; Atrial Natriuretic Factor; Australia; Female; History, 20th Century; Humans; Hypertension; Hypertension, Renal; Kidney; Nephrology; Pre-Eclampsia; Pregnancy; Renin-Angiotensin System

Cardiac function and plasma levels of atrial natriuretic factor (ANF) were studied in a group of 38 patients with untreated essential hypertension and in a group of 31 well matched normotensive controls. ANF was slightly but significantly higher in hypertensives and was directly correlated with mean arterial pressure and inversely with plasma renin activity (PRA). Hypertensives showed normal systolic function and higher cardiac mass compared to controls. ANF was inversely correlated to echocardiographic indexes of left ventricular performance in the former group. At Doppler echocardiographic evaluation, hypertensives showed an impairment in diastolic function which was correlated to the increase in ANF levels. Stepwise multiple regression analysis performed with ANF as the dependent variable and several biohumoral and echocardiographic parameters as the independent variables showed that only cardiac diastolic function and PRA significantly affect ANF levels in hypertensives. In conclusion, an impairment in cardiac diastolic function may be responsible together with other factors for the increased ANF levels encountered in essential hypertension.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Diastole; Echocardiography, Doppler; Female; Humans; Hypertension; Male; Renin

To explore roles of endogenous atrial natriuretic peptide (ANP) in blood pressure and volume regulation, we examined the effects of a newly developed ANP antagonist, HS-142-1 (HS) in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.. We examined 1) the effects of HS on ANP- or brain natriuretic peptide (BNP)-induced reductions in renal vascular resistance (RVR) of rat isolated perfused kidneys, 2) the effects of HS on cyclic GMP (cGMP) production in rat cultured vascular smooth muscle cells pretreated with ANP or BNP, and 3) the renal and systemic effects of HS in DOCA-salt-treated rats and control rats. We found that 1) HS dose-dependently reversed ANP- or BNP-induced decreases in RVR; 2) ANP or BNP at 100 nM caused an eightfold increase in cGMP production. These increases in cGMP were inhibited by HS in a dose-dependent fashion, and 300 micrograms/ml HS decreased cGMP to the control level. HS alone did not influence RVR or cGMP production; and 3) DOCA-salt rats showed higher plasma concentrations of ANP (198 versus 75 pg/ml) and BNP (23.7 versus 2.7 pg/ml, each p < 0.01) than the control rats. Bolus administration of 8 mg/kg HS elevated blood pressure by 8% (p < 0.01). This rise in blood pressure was attributed to an increase in systemic vascular resistance (+14%, p < 0.05). Conversely, urinary excretion of sodium (-41%), glomerular filtration rate (-27%), and plasma (-77%) and urinary cGMP (-69%, each p < 0.01) were decreased by administration of 8 mg/kg HS. These effects were dose dependent in DOCA-salt rats but slight or negligible in the control rats.. These results suggest that endogenous ANP and BNP may be involved in the regulation of blood pressure and body fluid volume in DOCA-salt rats in which ANP and BNP secretion is augmented.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Desoxycorticosterone; Dose-Response Relationship, Drug; Hemodynamics; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Polysaccharides; Rats; Receptors, Atrial Natriuretic Factor; Renal Circulation; Sodium Chloride; Vascular Resistance; Vasodilator Agents

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardenolides; Cardiac Output; Digoxin; Dopamine; Exercise; Exercise Therapy; Female; Humans; Hypertension; Kallikrein-Kinin System; Male; Middle Aged; Norepinephrine; Plasma Volume; Renin; Saponins; Sodium-Potassium-Exchanging ATPase; Taurine; Vascular Resistance

The aim of the study was an evaluation of the effect of different dietary sodium intake on: blood pressure, plasma concentration of atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), aldosterone (ALDO) and plasma renin activity (PRA) in patients with primary sodium sensitive arterial hypertension class I acc. to WHO criteria. Thirteen patients, non treated, with sodium sensitive arterial hypertension aged 30 +/- 8 years participated in the study. Blood samples were taken three times: in 5th day of normal sodium intake (100-120 mmol Na per 24 h); in 5th day of low sodium diet (10-20 mmol Na per 24 h); in 5th day of high sodium diet (200-220 mmol Na per 24 h). During 24 hours before each blood sampling the urine was collected and sodium and potassium excretions were evaluated. Concentrations of ANP, cGMP, ALDO in plasma and PRA were determined by radioimmunoassays and serum sodium and potassium concentration by flame photometry. Significant (p < 0.05) diminution of blood pressure, plasma ANP and cGMP concentrations and the increase of plasma ALDO and PRA after sodium restriction when compared to normal sodium diet were found. High sodium diet resulted in significant increase of blood pressure, plasma ANP and cGMP concentrations to the values comparable with these on normal sodium diet. On the contrary PRA and plasma ALDO concentration decreased (p < 0.001) below the values during normal sodium diet. Urinary sodium excretion corresponded to dietary sodium intake during all diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Hypertension; Male; Renin; Sodium, Dietary

The aim of this work was an evaluation of the effect of the acute hypervolemia induced by 90 min intravenous infusion of 1500 ml 0.9% NaCl (16.7 ml/min) on blood pressure, plasma concentration of the atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), aldosterone (ALDO), plasma renin activity (PRA) in patients with essential hypertension on the normal, low and high sodium intake. Twelve patients with noncomplicated essential sodium-sensitive arterial hypertension participated in the study. Sodium chloride infusions were performed three times: first--on the fifth day of normal daily sodium u intake (110-120 mmol/day), second--on the fifth day of low sodium intake (10-20 mmol/day), third--on the fifth day of high sodium intake (200-220 mmol/day). Acute intravenous sodium chloride load induced a significant increase of the mean arterial pressure (MBP) only when the patients were on the high sodium diet. This increase of the MBP was associated with a significantly lower increment of plasma ANP, cGMP, lower decrement of ALDO and PRA when compared to normal- or low- sodium intake. The results suggest an impairment of the adaptive homeostatic mechanisms induced by an acute intravenous sodium load in patients with noncomplicated salt-sensitive essential hypertension ingesting high-sodium diet.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Hypertension; Infusions, Intravenous; Male; Renin; Sodium Chloride; Sodium, Dietary

The relationship between atrial natriuretic peptide (ANP) and peripheral sympathetic nervous system function was studied in diabetic and hypertensive rats. Animals were studied in diabetic and hypertensive rats. Animals were divided into four groups: control, diabetic, hypertensive and diabetic plus hypertensive. Diabetes was induced by streptozotocin (65 mg/kg) injection and hypertension by abdominal aortic constriction. Studies were performed at 1 and 6 weeks. Plasma ANP was increased at 1 week in all groups except controls. Noradrenaline turnover, an index of sympathetic activity in kidney, was attenuated in all pathological groups unlike controls. These changes were associated with increased activity of Ca2++Mg2+ ATPase, which is known to serve as a Ca2+ pump in kidney cortex basolateral membrane. In contrast, at 6 weeks, Ca2++Mg2+ ATPase was significantly decreased only in the diabetic plus hypertensive group which also showed signs of congestive heart failure, increased sympathetic activity and decreased plasma ANP levels. Intracerebral microdialysis of the extracellular space around the paraventricular nucleus (PVN) of the hypothalamus showed a decreased concentration of ANP in the diabetic plus hypertensive group. Infusion of ANP and pentolinium, a ganglionic blocker in diabetic plus hypertensive Ca2+ restored pump activity towards control values; ANP alone had no effect. Our results indicate decreased plasma ANP levels, increased sympathetic drive and a depressed kidney Ca2+ pump in diabetic plus hypertensive rats with heart failure. The relationships between these factors, and the potential modulating role of ANP is discussed.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Glucose; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Diabetes Mellitus, Experimental; Hypertension; Isoproterenol; Kidney; Kidney Cortex; Male; Membranes; Norepinephrine; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

Hypercholesterolemia and hypertension are frequently associated risk factors for cardiovascular diseases. The interactions between hypercholesterolemia and the regulatory mechanisms of blood pressure are poorly understood. In this study we investigated the effects of hypercholesterolemia on salt metabolism and its hormonal control mechanisms in spontaneously hypertensive rats (SHR). Six-week-old SHR were randomly assigned to either a high (1%) cholesterol diet or a matched regular diet for 6 weeks, followed by a 2-week dietary washout. A group of normotensive Wistar-Kyoto rats received the high cholesterol diet and was used as a control. Plasma cholesterol increased significantly (P < 0.001) in both cholesterol-fed SHR and Wistar-Kyoto rats. Blood pressure was unaffected by 6 weeks of a high cholesterol diet. Hypercholesterolemia caused a significant increase in aldosterone (by analysis of variance: F = 8.40; P < 0.01) associated with a significant decrease in corticosterone (F = 4.64; P < 0.05) in the SHR, but not in the normotensive rats. In addition, in the cholesterol-fed SHR, urinary sodium excretion was reduced (P < 0.01), and the urinary potassium/sodium ratio was increased (P < 0.01) compared to those in the remaining groups of rats. The hormonal and urinary differences between the hypertensive subgroups were not detectable after withdrawal of cholesterol. These results demonstrate that diet-induced hypercholesterolemia specifically promotes reversible mineralocorticoid accumulation and sodium retention in SHR.

Topics: Adrenal Cortex Hormones; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cholesterol, Dietary; Corticosterone; Hypercholesterolemia; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Water-Electrolyte Balance

The effects of an intravenous infusion of physiological saline on plasma atrial natriuretic peptide (ANP), guanosine 3' 5' monophosphate (cGMP) concentrations, and on urinary cGMP and sodium excretion were studied in 13 patients with essential hypertension, class I according to WHO criteria, and in 10 healthy subjects. It was found that the groups did not differ as to basal and infusion-induced plasma ANP and cGMP and basal urinary cGMP and sodium excretion, but the sodium chloride infusion resulted in a significantly greater urinary cGMP and sodium excretion and creatinine clearance in hypertensive than in control subjects. The results of this study demonstrate that patients with essential hypertension respond to an intravenous sodium chloride load not only with exaggerated natriuresis, but also with augmented urinary cGMP excretion. The latter finding may in part be due to a greater glomerular filtration of cGMP, but increased renal contribution cannot be excluded. Apart from the possible stronger intrarenal effect of ANP on cGMP production in patients with hypertension, independent direct effect of volume expansion on cGMP excretion and modified activity of other cGMP generating systems may all be responsible for the higher urinary cGMP excretion in essential hypertension.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Hypertension; Infusions, Intravenous; Male; Natriuresis; Renin; Sodium Chloride

In this study, the effects of a six week treatment with the calcium channel blocking agent nitrendipine were assessed in 20 hypertensive type I diabetic patients who received a single oral dose of 20 mg daily. Plasma concentrations of atrial natriuretic peptide (ANP), plasma renin activity (PRA) and active renin, aldosterone, glycosylated hemoglobin (HbA1) and fructosamines were determined at the beginning and the end of the study. Interactions of these endocrine parameters with blood pressure behaviour were analyzed by a correlation matrix. In response to the drug treatment, the blood pressure was significantly lowered from 158.0/97.2 to 145.7/88.2 mmHg. The plasma concentrations of ANP were also significantly reduced from 106.8 to 89.7 pg/ml. There were no changes in serum aldosterone, while PRA and active renin exhibited a significant increase following the six week treatment. HbA1 and fructosamines remained unaltered. There were no significant correlations for ANP and blood pressure values, as well as for ANP and PRA or aldosterone. We did find, however, a significant correlation of the ANP values with the difference of the systolic blood pressure levels pre- and post-treatment. These data fully confirm the blood pressure lowering properties of this calcium channel blocker and its possible interference with steroidogenesis, since the effects of increased PRA on aldosterone secretion were clearly blunted. The lowering of plasma ANP levels may represent a decreased ANP secretion due to calcium channel blockade or might also be due to the natriuretic effects of nitrendipine, thus allowing ANP levels to decline as a function of lessened sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Hypertension; Middle Aged; Nitrendipine; Renin; Renin-Angiotensin System

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Edema; Glycopeptides; Humans; Hypertension; Natriuresis; Neprilysin; Substrate Specificity; Tissue Distribution

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Endothelins; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Time Factors

To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108 +/- 6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137 +/- 6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102 +/- 3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 micrograms/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats. ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Denervation; Desoxycorticosterone; Diuresis; Hypertension; Kidney; Natriuresis; Rats; Rats, Sprague-Dawley; Sodium Chloride

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged

Ventricular hypertrophy is characterized by augmentation of the synthesis and storage of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). To evaluate in vitro the cellular mechanisms of immunoreactive ANP (IR-ANP) and BNP (IR-BNP) release from ventricular cardiocytes, we measured the secretory response to graded passive myocardial stretch in isolated atrialectomized perfused hypertrophied hearts of 14- to 18-month-old spontaneously hypertensive rats. At this age, the ventricular levels of both IR-ANP and IR-BNP were markedly higher in spontaneously hypertensive (182 +/- 27 and 32 +/- 3 pmol/ventricle, respectively) than in age-matched normotensive Wistar-Kyoto rats (35 +/- 4 and 12 +/- 1 pmol/ventricle, respectively; P < 0.001), whereas the differences between the strains in atrial levels of these peptides were small. The release of natriuretic peptides from ventricles in response to stretch was examined by increasing the volume of the intraventricular balloon for 10 min. Stretching of the hypertrophied ventricles produced a rapid transient (from 1-5 min) increase in both IR-ANP and IR-BNP secretion. As left ventricular pressure rose from 0 to 26 +/- 1 mm Hg, IR-ANP and IR-BNP release into the perfusion fluid increased 1.8 +/- 0.4- and 2.5 +/- 0.2-fold, respectively. Infusion of staurosporine, known to inhibit protein kinase-C activity in heart cells, blocked the stretch-induced increase in IR-ANP release (F = 3.10; P < 0.001, by analysis of variance), but had no effect on basal ventricular IR-ANP secretion (F = 0.87; P = NS). An L-type calcium channel antagonist, diltiazem, had no significant effect on basal (F = 1.20; P = NS) or stretch-stimulated (F = 1.47; P = NS) IR-ANP release from hypertrophied rat myocardium. Chromatographical analysis revealed that the ventricles primarily release the active processed 28- and 45- amino acid ANP- and BNP-like peptides, respectively, both before and during stretch. This study indicates that stretch stimulates both ANP and BNP secretion from hypertropic ventricular myocytes. The results further suggest that protein kinase-C may be involved in stretch-induced ventricular ANP release, whereas the influx of extracellular calcium may not be necessary.

Topics: Alkaloids; Animals; Atrial Natriuretic Factor; Biomechanical Phenomena; Chromatography, High Pressure Liquid; Heart; Heart Ventricles; Hemodynamics; Hypertension; Kinetics; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Staurosporine

1. The effects of a high calcium diet (2.5%) on blood pressure, electrolyte balance, plasma and tissue atrial natriuretic peptide (ANP), cytosolic free Ca2+ concentration ([Ca2+]i), and arterial smooth muscle responses were studied in one-kidney deoxycorticosterone (DOC)-NaCl hypertensive Wistar rats. 2. Calcium supplementation for 8 weeks markedly attenuated the development of DOC-NaCl hypertension and the associated cardiac hypertrophy, and prevented the DOC-NaCl-induced sodium-volume retention as judged by reduced plasma Na+, and decreased plasma and ventricular ANP concentrations in high calcium-fed DOC-NaCl rats. However, calcium supplementation did not affect the DOC-NaCl-induced rise in platelet [Ca2+]i. 3. Smooth muscle contractions of isolated mesenteric arterial rings in response to depolarization by K+ (20-30 mM) were enhanced in DOC-NaCl-treated rats, this enhancement being abolished by concurrent oral calcium loading. The Ca2+ entry blocker nifedipine (10 nM) inhibited the contractions induced by K+ (30-125 mM) more effectively in DOC-NaCl rats than in controls, while the inhibition in calcium-loaded DOC-NaCl rats was significantly greater than in controls only with 30 mM K+. 4. The contractions of mesenteric arterial rings induced by omission of K+ from the organ baths were used to evaluate cell membrane permeability to ions. In chemically denervated rings the onset of the gradual rise in contractile force in K(+)-free medium occurred earlier, and the rate of the contraction was faster in DOC-NaCl-treated rats than in controls and high calcium-fed DOC-NaCl rats. Smooth muscle relaxation induced by 0.5 mM K+ upon K(+)-free contractions was clearly slower in DOC-NaCl rats than in controls and calcium-supplemented DOC-NaCl rats. 5. The functions of arterial smooth muscle Na+, Ca2+ exchange and Ca(2+)-ATPase were evaluated by the aortic contractions elicited by low Na+ medium, and the subsequent relaxation responses induced by Ca(2+)-free solution (in the presence of 5 mM caffeine, 1 microM nifedipine and 10 microM phentolamine). The rate of aortic low Na+ contractions (evaluating Ca2+ influx via Na+, Ca2+ exchange), as well as that of subsequent relaxations was slower in DOC-NaCl-treated rats than in controls, whether the relaxation was induced in normal (144.0 mM) or low (1.2 mM) organ bath Na+ concentration (reflecting Ca2+ extrusion by both Ca(2+)-ATPase and Na+, Ca2+ exchange, and by Ca(2+)-ATPase alone, respectively). However, in calcium-s

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Platelets; Blood Pressure; Body Weight; Calcium, Dietary; Cell Membrane; Cell Membrane Permeability; Desoxycorticosterone; Heart; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Wistar; Water-Electrolyte Balance

1 The effects of long-term angiotensin-converting enzyme inhibition with quinapril on arterial function were studied in spontaneously hypertensive rats, Wistar-Kyoto rats serving as normotensive controls. 2 Adult hypertensive animals were treated with quinapril (10 mg kg-1 day-1) for 15 weeks, which reduced their blood pressure and the concentrations of atrial natriuretic peptide in plasma and ventricular tissue to a level comparable with that in normotensive rats. 3 Responses of mesenteric arterial rings in vitro were examined at the end of the study. Compared with normotensive and untreated hypertensive rats, responses to noradrenaline were attenuated in hypertensive animals on quinapril, both force of contraction and sensitivity being reduced. Quinapril also attenuated maximal contractions but not sensitivity to potassium chloride. Nifedipine less effectively inhibited vascular contractions in normotensive and quinapril-treated than in untreated hypertensive rats. 4 Arterial relaxation responses by endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitrite, isoprenaline) mechanisms were similar in normotensive and quinapril-treated rats and more pronounced than in untreated hypertensive rats. 5 Cell membrane permeability to ions was evaluated by means of potassium-free solution-induced contractions of endothelium-denuded denervated arterial rings. These responses were comparable in normotensive and quinapril-treated rats and less marked than in untreated hypertensive rats. 6 Intracellular free calcium concentrations in platelets and lymphocytes, measured by the fluorescent indicator quin-2, were similar in normotensive and quinapril-treated rats and lower than in untreated hypertensive rats. 7 In conclusion, quinapril treatment improved relaxation responses and attenuated contractions in arterial smooth muscle of hypertensive rats. These changes may be explained by diminished cytosolic free calcium concentration, reduced cell membrane permeability, and alterations in dihydropyridine-sensitive calcium channels following long-term angiotensin-converting enzyme inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Calcium; Cardiomegaly; Hypertension; In Vitro Techniques; Isoquinolines; Male; Mesenteric Arteries; Muscle, Smooth; Muscle, Smooth, Vascular; Norepinephrine; Organ Size; Quinapril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrahydroisoquinolines

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cilazapril; Diabetes Mellitus, Type 1; Glomerular Filtration Rate; Humans; Hypertension; Middle Aged; Natriuresis

Plasma endothelin concentrations were evaluated in 53 chronic, congestive heart failure (CHF) patients with or without history of systemic hypertension, as well as in 9 with hypertension only and in 22 healthy control subjects. Plasma renin, aldosterone and atrial natriuretic peptide, as well as clinical and hemodynamic data were determined. In patients with CHF, big endothelin-1 was, independent of hypertension history, significantly greater than in hypertensive patients with normal cardiac function and in control subjects (both p < 0.0001). Patients with severe CHF had significantly greater big endothelin-1 values than did those with moderate CHF. During 12-month follow-up, 11 patients with CHF underwent heart transplantation, and 9 died; these patients had significantly greater big endothelin-1 concentrations than did the 33 clinically stable patients (p < 0.001). Big endothelin-1 and atrial natriuretic peptide correlated with right atrial pressure, pulmonary capillary wedge pressure, left ventricular ejection fraction, effort capacity and severity of CHF (New York Heart Association functional class).

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Case-Control Studies; Endothelins; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Prognosis; Renin

To evaluate the atrial natriuretic peptide response to angiotensin II (Ang II) infusion in non-modulating hypertension, we studied 31 men with essential hypertension. These patients were subdivided into groups of low renin patients (n = 8), non-modulators (n = 11), and modulators (n = 12) according to their renin profile and ability to modulate renin and aldosterone responses to a graded infusion of Ang II (1.0 and 3.0 ng/kg per minute) on a low Na+ intake (10 mmol Na+ per day). During basal conditions, plasma atrial natriuretic peptide was higher (p < 0.05) in low renin patients (16.34 +/- 2.67 fmol/mL) than in both modulators (10.59 +/- 4.29 fmol/mL) and non-modulators (9.85 +/- 2.64 fmol/mL). During Ang II infusion, plasma atrial natriuretic peptide significantly increased in both low renin (27.67 +/- 2.61 fmol/mL at 60 minutes, p < 0.01) and modulating (20.36 +/- 3.07 fmol/mL at 60 minutes, p < 0.05) patients, whereas it did not change in non-modulators (13.94 +/- 4.39 fmol/mL, NS). After 5 days on a high sodium intake (200 mmol Na+ per day), plasma atrial natriuretic peptide rose in modulating (20.61 +/- 2.31 fmol/mL, p < 0.01 versus low sodium intake), non-modulating (20.11 +/- 6.48 fmol/mL, p < 0.01 versus low sodium intake), and low renin (26.13 +/- 3.81 fmol/mL, p < 0.001 versus low sodium intake) hypertensive patients. When the Ang II infusion was repeated with a high sodium intake, plasma atrial natriuretic peptide increased again in low renin and modulating patients, whereas it did not change in non-modulators.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Diet, Sodium-Restricted; Hormones; Humans; Hypertension; Kidney; Male; Middle Aged; p-Aminohippuric Acid; Renin; Sodium

Neutral metalloendopeptidase (NEP) inhibitors delay atrial natriuretic factor (ANF) catabolism and potentiate biological responses to ANF. We describe biochemical and pharmacological profiles of a novel NEP inhibitor, SCH 42354 (N-[2(S)-(mercaptomethyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine and its orally active ethylester prodrug, SCH 42495. SCH 42354 selectively inhibited hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nmol/L, respectively) in vitro. Plasma levels of exogenous ANF were augmented and ANF clearance from plasma was delayed by oral SCH 42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats were higher in SCH 42495-treated rats. Diuretic and natriuretic effects of ANF were increased in rats treated with SCH 42495. Oral doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reductions in blood pressure in DOCA-Na hypertensive rats of 22 +/- 6, 43 +/- 7, and 62 +/- 12 mm Hg, respectively, which were not associated with increases in heart rate. These doses did not alter urine flow, salt excretion, or plasma ANF. SCH 42495 produced significant elevation of urinary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 42495 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of SCH 42495 significantly decreased cardiac output and did not lower systemic vascular resistance, a profile similar to that of ANF. The hypotensive response to SCH 42495 was not ascribable to ACE inhibition. Pithed rat preparations revealed no interaction of the drug with autonomic cardiovascular function. The antihypertensive effect of SCH 42495 likely results from potentiation of endogenous ANF via NEP inhibition.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Autonomic Nervous System; Bradykinin; Desoxycorticosterone; Drug Synergism; Hemodynamics; Hypertension; Kidney; Male; Metalloendopeptidases; Methionine; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Mutant Strains; Sodium Chloride

To investigate the involvement of brain natriuretic peptide in the circulation of pregnant women with pregnancy-induced hypertension.. We determined the plasma levels of brain and atrial natriuretic peptides in a cross-sectional study of 36 normal pregnant women and 17 women with pregnancy-induced hypertension.. During normal pregnancy, the plasma brain natriuretic peptide level was similar to that in nonpregnant women, but the plasma atrial natriuretic peptide level in the second trimester was significantly higher than that in nonpregnant women (P < .05). In women with severe pregnancy-induced hypertension, the plasma brain natriuretic peptide level was eight times higher than that in normal pregnant women in the third trimester; the plasma atrial natriuretic peptide level in the same patients was three times higher than that in normal pregnancy. The plasma brain natriuretic peptide level showed a positive correlation with the mean blood pressure (r = 0.62, P < .001).. The present findings suggest that brain natriuretic peptide is increased in the plasma of women with pregnancy-induced hypertension and that brain natriuretic peptide, in concert with atrial natriuretic peptide, participates in maintaining homeostasis of the maternal circulation.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Urea Nitrogen; Cross-Sectional Studies; Female; Humans; Hypertension; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

SCH 34826, i.e., (S)-N-(N-(2,2[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]-2-oxo-1-(phenyl-methyl)ethyl)-phenylalanyl)-beta-alanine, is a potent and selective inhibitor of neutral endopeptidase 24.11 (NEP), an enzyme that degrades the atrial natriuretic peptide (ANP). The effects of SCH 34826 on hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs) were evaluated following 1 month of treatment by measuring the blood pressure, cardiac weight, and left ventricular fibrosis. Adult SHRs were treated with SCH 34826 at 10, 30, or 100 mg/kg given orally twice daily or with vehicle. The systolic blood pressure (SBP) and heart rate (HR) were recorded weekly by the tail-cuff method. Cardiac structural damage was determined by morphometric analysis. Over the dose range examined, the drug produced no significant changes in either blood pressure or heart rate. Despite the lack of antihypertensive activity, SCH 34826 at 100 mg/kg reduced both the cardiac mass (-10%) and the amount of fibrotic tissue present in the left ventricle (-42%). These data indicate that chronic inhibition of NEP by SCH 34826 interacts with mechanisms underlying myocardial hypertrophy and cardiac remodeling.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Dioxolanes; Dipeptides; Hemodynamics; Hypertension; Male; Microscopy, Electron; Myocardium; Neprilysin; Rats; Rats, Inbred SHR; Ventricular Function, Left

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Bradykinin; Cyclic GMP; Desoxycorticosterone; Diuresis; Hypertension; Kidney; Kininogens; Male; Natriuresis; Neprilysin; Rats; Rats, Wistar; Sulfhydryl Compounds; Thiorphan

To examine whether atrial natriuretic factor (ANF) is secreted adequately in the early phase of myocardial infarction, plasma ANF concentration and clinical parameters, including hemodynamic variables, were studied in 118 patients with acute myocardial infarction (AMI). The patients were divided into 2 subgroups according to the absence (group A, n = 41) or presence (group B, n = 77) of a history of valvular heart disease, previous myocardial infarction, hypertension, or renal failure. Although no significant difference in atrial pressure after the infarction was found between the 2 groups, the plasma ANF level was significantly lower in group A than in group B (76 +/- 6 vs. 185 +/- 26 pg/ml; mean +/- SEM, p < 0.01). Plasma ANF was correlated with pulmonary capillary wedge pressure in group B (r = 0.54, p < 0.001), whereas no relationship with hemodynamic parameters was observed in group A. In 56 of the 118 patients (group A, n = 18; group B, n = 38), the pulmonary arterial plasma level was significantly higher in group A (p < 0.05), whereas the difference was not significant in group B. Seven of the 8 expired cases among these 56 patients had peripheral plasma ANF levels of more than 150 pg/ml, which were higher than those in pulmonary arterial plasma. These observations suggest firstly that the plasma level of ANF is lower in patients with a new onset of myocardial infarction compared to those with a history of cardiac or renal diseases, and secondly that stimulated ANF release originates not only from the right side of the heart, but also from additional site(s), particularly in patients with chronic ventricle overload and a poor prognosis.

Topics: Atrial Function, Right; Atrial Natriuretic Factor; Female; Heart Valve Diseases; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Pulmonary Wedge Pressure; Risk Factors

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cells, Cultured; Endothelins; Glomerular Mesangium; Humans; Hypertension; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides, Cyclic; Rats

The relationship between plasma atrial natriuretic peptide (ANP), renin-angiotensin-aldosterone system and left ventricular mass in essential hypertension was assessed.. Immunoreactive ANP in 10 normal subjects and 20 untreated patients with mild to moderate essential hypertension was compared with echocardiographic measurement of cardiac size, function and blood pressure. Venous plasma concentrations of ANP were also studied in relation to urinary sodium and potassium excretion, as well as the renin-angiotensin-aldosterone system.. Plasma ANP was higher in hypertensive patients (25.3 +/- 13.3 pg/ml; p = 0.003) than normotensive subjects (11.1 +/- 2.7 pg/ml). In hypertensive patients, plasma ANP was inversely related to plasma renin activity (PRA) (r = -0.6; p = 0.009). No relationship was found between ANP and blood pressure, nor between the indices of left ventricular mass and function or urinary electrolytes.. This study showed that circulating ANP is, in average, significantly increased in hypertensive patients, consistent with previous reports. Our data do not support a direct link between left ventricular mass and increased plasma ANP levels in hypertensive patients. Whether the inverse relationship between ANP and PRA in this pathologic state is a direct one or merely a secondary association has not been clearly established.

Topics: Adult; Aged; Atrial Natriuretic Factor; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Renin

The aim of this study was to investigate atrial natriuretic peptide (ANP) gene expression in the central nervous system (CNS) during hypertension.. We measured and compared immunoreactive atrial natriuretic peptide (irANP) and ANP messenger RNA (mRNA) in the hypothalamus and brainstem of 17-week-old spontaneously hypertensive rats (SHR) with those of age-matched Wistar-Kyoto (WKY) rats using ribonuclease (RNase) protection assay for ANP mRNA and a specific radioimmunoassay for irANP.. RNase protection assay revealed that the concentrations of ANP mRNA in the hypothalamus and brainstem of SHR were higher than those of WKY rats. IrANP concentrations in the hypothalamus and brainstem of SHR were determined by a specific radioimmunoassay and found to be higher than those of WKY rats. Elevated mRNA levels in the hypothalamus and brainstem of SHR indicated that increased level of irANP in the CNS resulted from increased synthesis of ANP.. We propose that increased synthesis of brain ANP in SHR may reflect a compensatory mechanism induced by hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Brain Stem; Gene Expression; Hypertension; Hypothalamus; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

To investigate the renal, haemodynamic and neurohormonal responses to low-dose infusions of atrial natriuretic factor (ANF) in hypertensive humans.. Ten patients with mild-to-moderate essential hypertension received incremental infusions of 3 and 6 ng/kg per min ANF or vehicle alone whilst on a constant dietary sodium intake. A 90-min basal clearance period was followed by two 2-h infusion periods, with urine collection in the last 90 min of each period. In each of the three clearance periods, glomerular filtration rate (GFR), renal tubular function, and the activity of the renin-angiotensin and sympathetic nervous systems were determined.. The renal sites of ANF action were established by simultaneous measurements of 51Cr-ethylenediaminetetraacetate lithium and sodium clearances. Plasma concentrations of neurohormones were measured by radioimmunoassays.. Plasma ANF concentrations increased by 1.6- and 2.5-fold during the lower and higher ANF infusion rates, respectively. Plasma cyclic guanosine monophosphate concentrations increased in parallel. ANF caused no changes in supine systolic and diastolic blood pressure or in heart rate. In contrast, haematocrit values increased progressively across the study. The renal effects of ANF administration were characterized by an unaltered GFR and significant increases in the renal clearances of lithium (a marker of end-proximal fluid delivery) and sodium when compared with vehicle infusions, whereas urine flow did not change. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly. Plasma concentration of active renin decreased during ANF infusions, but no significant changes in plasma levels of renin substrate, angiotensin I, angiotensin II or aldosterone were observed. A subtle activation of the sympathetic nervous system was indicated by a moderate increase in plasma noradrenaline during the ANF infusions.. These results indicate that even small increases in plasma ANF, as can be found during physiological conditions, induce natriuresis in patients with essential hypertension by enhancing fluid delivery from the proximal tubules, in addition to impairing distal fractional sodium reabsorption. With minor exceptions, the ANF infusions caused qualitatively and quantitatively similar renal, haemodynamic and endocrine effects in the hypertensive patients as in a previously studied group of normotensive subjects.

Topics: Adult; Atrial Natriuretic Factor; Female; Hematocrit; Humans; Hypertension; Kidney; Kidney Function Tests; Lithium; Male; Natriuresis; Renin-Angiotensin System; Sympathetic Nervous System

To seek possible correlations between plasma atrial natriuretic factor (ANF) and left ventricular diastolic function (LVDF) in hypertensive patients.. Since LVDF abnormalities can be detected in patients with normal left ventricular mass, we studied a group of hypertensive patients without left ventricular hypertrophy.. Untreated hypertensive patients (n = 23) and normotensive control subjects (n = 19) were studied. LVDF indices were obtained by M-mode and pulsed Doppler echocardiography. Blood samples for plasma ANF were taken in the recumbent position from subjects on normal-sodium intake.. Plasma ANF levels were significantly higher in hypertensive patients than in normotensive subjects. All indices for systolic function were normal in both normotensive subjects and hypertensive patients. Left atrial diameter was significantly higher for hypertensive patients than for normotensive subjects. Considering LVDF, all indices for ventricular filling were found to be altered, on average, in hypertensive patients, the only exception being peak early velocity. In addition, significant correlations were found between plasma ANF and the pulsed Doppler parameters of left ventricular filling, peak atrial velocity and the peak early:peak atrial velocity ratio. Overall correlations between plasma ANF and left atrial diameter, and between left atrial diameter and left ventricular mass index were also observed.. The high levels of plasma ANF observed in our hypertensive patients and their correlation with the LVDF indices (which mainly reflect the atrial contribution to ventricular filling) could be the result of an increased atrial stretch due to diastolic ventricular dysfunction. This may exist in hypertensive patients before the development of ventricular hypertrophy.

Topics: Adult; Atrial Natriuretic Factor; Cardiomegaly; Echocardiography; Echocardiography, Doppler; Female; Humans; Hypertension; Male; Systole; Ventricular Function, Left

Left ventricular function (LVF) after reversal of left ventricular hypertrophy (LVH) with antihypertensive therapy is still controversial. The present study was undertaken in spontaneously hypertensive rats (SHR) to determine whether LVF of the regressed heart with lisinopril is normally maintained.. We compared cardiac function of SHR after reversal of LVH induced by lisinopril with that observed in control SHR and also with effects after a 4-week washout period.. Administration of lisinopril began at 15 weeks of age and continued for 20 weeks. Cardiac index, renal blood flow, leg muscle blood flow, plasma renin activity, atrial natriuretic peptide level, and norepinephrine concentration were determined.. Lisinopril decreased body weight, blood pressure and left ventricular weight and increased leg muscle blood flow; cardiac index and renal blood flow were unaltered. Although norepinephrine concentration was unchanged, plasma renin activity increased and atrial natriuretic peptide decreased in treated SHR. Peak left ventricular pumping ability during volume loading was comparable in the two groups. After a 4-week washout period, left ventricular mass and blood pressure increased but remained lower than controls; cardiac index at rest and during volume loading was similar in the two groups.. These data indicate that LVF of the regressed heart induced by lisinopril was well preserved at rest, during volume loading and also after spontaneous recurrence of hypertension in SHR.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Enalapril; Hemodynamics; Hypertension; Lisinopril; Male; Norepinephrine; Rats; Rats, Inbred SHR; Renin; Ventricular Function, Left

We have previously demonstrated that dietary NaCl supplementation is associated with increased circulating atrial natriuretic peptide (ANP) levels in Wistar-Kyoto (WKY) rats but not in spontaneously hypertensive rats (SHR), and that replacement with exogenous ANP prevents NaCl-sensitive hypertension in NaCl-sensitive SHR (SHR-S). The current study tested the hypothesis that chronic administration of the neutral endopeptidase (NEP) inhibitor Sch 34826 prevents NaCl sensitive hypertension in SHR-S by increasing endogenous ANP. Male SHR-S received Sch 34826 (90 mg/kg/day) or vehicle by gavage for 4 weeks beginning immediately before the initiation of 1% or 8% NaCl diets at age 7 weeks. Sch 34826 prevented the increase in arterial pressure in response to 8% NaCl in SHR-S, but had no effect on blood pressure in 1% NaCl fed SHR-S; plasma ANP levels were increased by 63 and 68% in the 1% and 8% NaCl groups, respectively, in response to Sch 34826. To examine the mechanism(s) of the antihypertensive effect of Sch 34826 in NaCl-supplemented SHR-S, a single dose (90 mg/kg) of Sch 34826 or vehicle was administered by gavage to SHR-S that had consumed 1% or 8% NaCl diets for 3 weeks. Sch 34826 abolished the NaCl-induced increase in blood pressure 3 h after treatment in 8% NaCl fed SHR-S, but had no effect in SHR-S fed the 1% NaCl diet. This effect was associated with increased urine volume and urinary sodium, ANP, and cyclic GMP in 8% NaCl fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Analgesics; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dioxolanes; Dipeptides; Hypertension; Male; Protease Inhibitors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Sodium Chloride

The effects of graded supine ergometry on blood pressure, heart rate, and plasma hormones were studied in 14 hypertensive heart transplant recipients before and after 2 weeks and 6 months of enalapril (20 mg/day) plus furosemide (20-80 mg/day) alone or combined with verapamil (120-360 mg/day). Each time, measurements were obtained at rest and at 25 and 50 W exercise. Antihypertensive therapy normalized blood pressure, while heart rate and the blood pressure response to exercise remained unaltered. Pretreatment resting plasma renin activity and catecholamine levels were normal, while atrial natriuretic factor and cyclic guanosine monophosphate concentrations were elevated. All hormones increased significantly with exercise. During treatment, plasma renin activity increased and atrial natriuretic factor and cyclic guanosine monophosphate levels decreased significantly, with a blunted exercise response; concentration of catecholamines increased significantly, with augmented exercise response. Thus, the chosen regimen allowed effective, lasting BP control in hypertensive transplant patients but was associated with significant changes in plasma hormones. Whereas the rise in plasma renin activity may be attributed to converting enzyme inhibition, the decreases in atrial natriuretic factor and cyclic guanosine monophosphate and increases in catecholamine levels seem to indicate marked changes in resting and particularly exercise hemodynamics during antihypertensive therapy.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Drug Therapy, Combination; Enalapril; Epinephrine; Exercise Test; Female; Follow-Up Studies; Furosemide; Heart Rate; Heart Transplantation; Hormones; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Postoperative Complications; Renin; Verapamil

The first human studies using relatively high-doses of ANF revealed similar effects as observed in the preceding animal reports, including effects on systemic vasculature (blood pressure fall, decrease in intravascular volume), renal vasculature (rise in GFR, fall in renal blood flow), renal electrolyte excretion (rises in many electrolytes), and changes in release of a number of different hormones. Whether all these changes are the result of direct ANF effects or secondary to a (single) primary event of the hormone remains to be determined. Certainly, it has been proven that more physiological doses of ANF fail to induce short-term changes in many of these parameters leaving only a rise in hematocrit, natriuresis and an inhibition of the RAAS as important detectable ANF effects in humans. This leads us to hypothesize that ANF is a "natriuretic" hormone with physiological significance. The primary function in humans is to regulate sodium homeostasis in response to changes in intravascular volume (cardiac atrial stretch). Induction of excess renal sodium excretion and extracellular volume shift appear to be the effector mechanisms. The exact mechanism of the natriuresis in humans still needs to be resolved. It appears however, that possibly a small rise in GFR, a reduction in proximal and distal tubular sodium reabsorption, as well as an ensuing medullary washout, are of importance. The pathophysiological role of ANF in human disease is unclear. One may find elevated plasma irANF levels and/or decreased responses to exogenous ANF in some disease states. Whether these findings are secondary to the disease state rather than the cause of the disease remains to be resolved. Therapeutic applications for ANF, or drugs that intervene in its production or receptor-binding, seem to be multiple. Most important could be the antihypertensive effect, although areas such as congestive heart failure, renal failure, liver cirrhosis and the nephrotic syndrome cannot be excluded. Although the data that have been gathered to date allowed us to draw some careful conclusions as to the (patho)physiological role of ANF, the exact place of ANF in sodium homeostatic control must still be better defined. To achieve this, we will need more carefully designed low-dose ANF infusion, as well as ANF-breakdown inhibitor studies. Even more promising, however, is the potential area of studies open to us when ANF-receptor (ant)agonists become available for human use.

Topics: Animals; Atrial Natriuretic Factor; Edema; Humans; Hypertension; Kidney; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

1. Disturbances of sodium and water homoeostasis may contribute to the close association between diabetes, hypertension and proteinuria. We therefore studied the patterns of two natriuretic hormones, plasma atrial natriuretic peptide and urinary dopamine, in 165 Chinese patients with non-insulin-dependent diabetes mellitus controlled by diet or oral hypoglycaemic agents on two occasions over a 6-week period. Patients were divided into three groups based on the mean value of two 24h urinary albumin excretion measurements. In group 1, 88 patients had normoalbuminuria (urinary albumin excretion < or = 30 mg/day), in group 2, 48 patients had microalbuminuria (urinary albumin excretion between 30 and 300 mg/day), and in group 3, 29 patients had macroalbuminuria (urinary albumin excretion > or = 300 mg/day). 2. The supine systolic blood pressure (mean +/- SD) was higher in patients with abnormal albuminuria (group 1: 140.9 +/- 27.4 mmHg; group 2: 158.1 +/- 26.4 mmHg; group 3: 166.7 +/- 23.9 mmHg; F = 13.1, P < 0.001, analysis of variance). Urinary sodium output was similar in these three groups of patients. The geometric means (anti-logarithm of 95% confidence interval logarithm) of plasma atrial natriuretic peptide concentrations increased with increasing proteinuria [group 1: 33.3 (29.9-37.1) pg/ml; group 2: 39.1 (34.2-44.6) pg/ml; group 3: 50 (38.6-54.7) pg/ml; F = 4.24, P < 0.01; analysis of variance], whereas those of urinary dopamine output were related inversely to proteinuria [group 1: 1291.7 (1167.2-1437.0) nmol/day; group 2: 1142.3 (975.9-1337.2) nmol/day; group 3: 982.7 (775.7-1245) nmol/day; F = 3.10, P < 0.05, analysis of variance].(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dopamine; Humans; Hypertension; Middle Aged; Proteinuria

To examine the relation between plasma atrial natriuretic peptide (ANP) and the natriuresis of fasting.. ANP, aldosterone and renin were examined during natriuresis of fasting in 25 obese essential hypertensive patients and nine overweight normotensive subjects placed on a supervised 500-KCal diet composed of 50% carbohydrates, 30% fat and 20% protein, and unlimited salt. Twenty-four-hour urinary electrolytes were measured on days 0, 4, 7 and 10 of the diet.. Urinary sodium concentration nearly doubled in the patients on day 4, and increased 1.4-fold in the normotensive controls. Plasma ANP rose nearly threefold in the hypertensives on day 4 and nearly doubled in the normotensives. Patients and controls showed similar patterns of natriuresis and ANP secretion during the diet.. We conclude that there is a clear association between ANP levels and natriuresis of fasting.

Topics: Adolescent; Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Fasting; Female; Humans; Hypertension; Male; Middle Aged; Natriuresis; Obesity; Sodium

Experimental and clinical studies seem to prove that both endogenous opioids and atrial natriuretic peptide (ANP) are involved in blood pressure regulation. This raised the question, whether these two factors are functionally interrelated to each other. We tried to answer this question by assessing plasma ANP levels in 15 patients with II degrees essential hypertension and in 15 healthy subjects under water immersion (WI) conditions. In all subjects two WI tests were performed--one without pretreatment with naloxone, and a second one after blockade of opioid receptors by this opioid receptor antagonist. Parallel to ANP, plasma renin activity (PRA), aldosterone (ALD) and vasopressin (AVP) were assessed. In hypertensive patients significantly higher basal plasma ANP levels were found than in control subjects. WI induced a significant increase of plasma ANP in both examined groups which became markedly reduced after blockade of opioid receptors by naloxone. Naloxone did not influence the WI induced decrease of PRA, ALD and AVP respectively. From results presented in this study we conclude, that a.) opioid receptors seem to influence regulation of ANP secretion both in healthy normotensive subjects and patients with essential hypertension, and b.) that WI induced alterations of ANP on the one side and of PRA, ALD and AVP on the other side are not interrelated.

Topics: Adult; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Hypertension; Immersion; Male; Naloxone; Receptors, Opioid; Renin; Renin-Angiotensin System

To assess the existence of an altered circulating pattern of calcitonin gene-related peptide (CGRP) in hypertension.. The 24 h variation in plasma CGRP was measured and compared in 10 patients affected by uncomplicated essential hypertension and in nine age- and sex-matched healthy volunteers. The diurnal variations in blood pressure, atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma aldosterone and plasma cortisol were also assessed.. Recumbency studies were performed under standardized, drug-free conditions beginning at 0800 h. Venous samples were drawn every 4 h for 24 h and hormone levels were assessed with specific radioimmunoassays. The blood pressure was measured every 15 min with a SpaceLabs 90207 monitor.. The mean 24-h plasma CGRP concentrations were significantly lower in the hypertensive group than in the control group. In both groups a circadian rhythm was present with the same pattern, but at a lower level in hypertension. A temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the elevations of ANP, PRA, and plasma aldosterone and cortisol was apparent in both groups. The nocturnal rise in the CGRP and ANP concentrations coincided with the blood pressure and the heart rate falls.. Our data show that CGRP is lower than normal but maintains its circadian variability and its relationship with the diurnal variations in blood pressure and other hormones known to be active on the cardiovascular system.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Calcitonin Gene-Related Peptide; Case-Control Studies; Circadian Rhythm; Female; Humans; Hydrocortisone; Hypertension; Male; Renin

Glomerular hyperfiltration is thought to play a pivotal role in causing renal damage in essential hypertension. An increase in glomerular filtration rate can be experimentally induced by an acute oral protein load through still unclarified mechanisms, although hormonal factors have been postulated; in already hyperfiltering nephrons, the capacity to further increase glomerular filtration rate upon stimulation with an acute protein load (i.e. renal functional reserve) would conceivably be reduced, even in the presence of apparently normal renal function. The present study aimed at assessing whether renal functional reserve is preserved and/or is affected by different antihypertensive drugs in essential hypertensive patients without signs of renal function impairment; moreover, we tried to highlight changes in the plasma levels of natriuretic and antinatriuretic hormones potentially involved in the modulation of renal hemodynamics under the chosen experimental conditions. Renal hemodynamic parameters, plasma renin activity, aldosterone and atrial natriuretic factor were measured in fourteen essential hypertensives submitted to an acute oral protein load, alone or with a concomitant administration of either nifedipine or enalapril, as compared with a control carbohydrate meal. Glomerula filtration rate and renal plasma flow rose slightly but not significantly following an acute oral protein load as compared with a carbohydrate meal; no changes were noted in plasma atrial natriuretic factor levels, whereas plasma renin activity decreased. When nifedipine was administered together with the protein meal, both glomerular filtration rate and renal plasma flow increased significantly; there were also, parallel increases in plasma renin activity and atrial natriuretic factor. Administration of enalapril was associated with a decrease in both glomerular filtration rate and renal plasma flow; plasma renin activity showed an expected marked rise, whereas the plasma levels of atrial natriuretic factor were only slightly but not significantly reduced and plasma aldosterone fell. In conclusion, our data suggest that in our patients renal functional reserve was blunted. Clear-cut hyperfiltration was brought about by administration of nifedipine together with a protein meal, whereas enalapril completely abolished even the small increase in glomerular filtration rate seen after protein meal alone. The concomitant alterations in plasma renin activity, aldosterone and atrial

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Circulation; Renin

The aim was to investigate vascular receptors for atrial natriuretic factor (ANF) in spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats (WR) at different ages.. Relaxation and guanylate cyclase responses of blood vessels to atrial natriuretic factor were investigated, as was the binding of 125I-ANF to vascular membranes and ANF receptor subtypes, using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in reducing conditions, after solubilisation and irreversible binding of 125I-ANF.. Vascular relaxation responses of aorta showed an increased sensitivity to ANF in four week old SHR [pD2 = 8.9 (SEM 0.1) v 8.5(0.1) in WKY rats, p < 0.05] while sensitivity was similar for the three strains at older ages. Production of cyclic GMP in mesenteric arteries in response to 100 nmol.litre-1 ANF was greater (p < 0.05) in SHR than in WKY rats at four weeks of age, but was similar in older rats. The density of binding sites for ANF in mesenteric arteries, however, was lower in SHR at four weeks (p < 0.01), and increased in older rats, becoming similar to that of normotensive rats at 12 weeks of age. Affinity of ANF sites was similar in all strains. The proportion of high and low molecular weight ANF binding peptides in solubilised blood vessel membranes on SDS-PAGE was similar in all strains except in four week old SHR, in which binding to the high molecular weight band (presumably the guanylate cyclase containing receptor) was increased relative to the low molecular weight band (non-cyclase-coupled receptor) in comparison to other strains and ages.. Activity of guanylate cyclase in response to occupancy of ANF receptors may be increased in young SHR. Normal relaxation of blood vessels in response to ANF in older SHR could result in failure to counteract the increased vasoconstrictor activity present in these rats, which could play a role in the increase in blood pressure.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Vessels; Cyclic GMP; Guanylate Cyclase; Hypertension; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Atrial Natriuretic Factor

Previous studies from our laboratory have shown that spontaneously hypertensive rats have increased atrial natriuretic peptide stores and reduced norepinephrine release from nerve terminals in the anterior hypothalamus. We have postulated that atrial natriuretic peptide inhibits norepinephrine release in anterior hypothalamus, reducing excitation of sympathoinhibitory neurons, increasing sympathetic outflow, and elevating blood pressure in this model. The current study tested the hypothesis that atrial natriuretic peptide messenger RNA (mRNA) transcript levels are increased in anterior hypothalamus of spontaneously hypertensive rats compared with normotensive Wistar-Kyoto rats. Atrial natriuretic peptide mRNA in hypothalamic regions was measured by the quantitative polymerase chain reaction technique using a p-SELECT mutant atrial natriuretic peptide RNA as an internal standard. Atrial natriuretic peptide mRNA from hypothalamic regions of spontaneously hypertensive and Wistar-Kyoto rats and the internal standard were coamplified in a single reaction in which the same primers were used. Since the polymerase chain reaction product of the internal standard contained a new EcoRI restriction site, it could be distinguished from the atrial natriuretic peptide mRNA product by EcoRI digestion after the polymerase chain reaction. We found regional inhomogeneity of atrial natriuretic peptide mRNA in the hypothalamus of spontaneously hypertensive and Wistar-Kyoto rats, but we found no significant differences in atrial natriuretic peptide mRNA levels in anterior, posterior, or ventral hypothalamic areas between spontaneously hypertensive rats and Wistar-Kyoto rats fed normal (1%) or high (8%) salt diets. These data do not support the hypothesis that increased atrial natriuretic peptide stores in anterior hypothalamus of spontaneously hypertensive rats are related to increased gene transcription.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Diet, Sodium-Restricted; Hypertension; Hypothalamus; Male; Molecular Sequence Data; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA

Sixteen patients with initial diastolic blood pressure greater than or equal to 120 mm Hg were treated for 1 year with extended-release nifedipine [nifedipine-GITS (gastrointestinal therapeutic system)]. Serial changes in left ventricular mass index and associated alterations in left ventricular systolic function, left ventricular filling, plasma renin activity, atrial natriuretic peptide, and catecholamines were evaluated. Blood pressure was significantly reduced from 200 +/- 8/122 +/- 3 mm Hg (mean +/- SEM) to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. Eleven patients (69%) required only nifedipine-GITS for blood pressure control and 5 (31%) required the addition of chlorthalidone. After 6 months, the left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thicknesses were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001), respectively. Prevalence of left ventricular hypertrophy decreased from 63 to 25%. Left ventricular fractional shortening increased from 34 to 42% (p less than 0.05) and the relationship between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction, the peak velocity of early filling increased from 58 to 63 cm/s (p = 0.07), the peak velocity of late filling did not change, and the ratio of late to early peak velocity of left ventricular filling significantly decreased (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Cardiomegaly; Chlorthalidone; Delayed-Action Preparations; Drug Therapy, Combination; Echocardiography, Doppler; Electrocardiography; Epinephrine; Hemodynamics; Humans; Hypertension; Middle Aged; Nifedipine; Norepinephrine; Renin

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.

Topics: Animals; Atrial Natriuretic Factor; Binding Sites; Clonidine; Cyclic GMP; Enalapril; Hypertension; Hypertrophy; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Possible counterregulatory neurohumoral and hemodynamic responses to carvedilol (a new vasodilating nonselective beta-receptor blocker) were studied in 19 men with essential hypertension (age range, 34-59 years; mean age, 44 years). Intra-arterial pressure, cardiac output (Cardio-green), heart rate, and the vasoactive peptides norepinephrine, epinephrine, and atrial natriuretic peptide (ANP) were measured at rest supine and sitting and during 100-W bicycle exercise before and 2 h after administration of 25 mg carvedilol. The same protocol was followed after 9 months of chronic carvedilol treatment (mean dose, 52 mg/day). Carvedilol induced both acute and chronic reductions (at rest supine, 11%) in mean arterial pressure, due in part to reduction in cardiac output (5%) and in part to reduction in total peripheral resistance (5%). At rest supine, carvedilol induced a reduction in ANP (27%) that could be viewed as a counterregulatory response to decrease in cardiac output, preventing excessive blood pressure reduction. ANP decreased (18%) when the patient sat up from the supine position and increased (67%) during exercise, but no further change was seen after acute or chronic carvedilol treatment. With the patient in the sitting position, norepinephrine was 110% higher than at rest supine; during 100-W exercise, norepinephrine increased 368%. A further increase (38-86% in the three situations, respectively) was seen after the first dose of carvedilol. Epinephrine showed similar but less marked changes. Neither extracellular fluid volume nor plasma volume (isotope dilution techniques) changed significantly during the study, but the acute blood pressure response to carvedilol was directly related to changes in extracellular fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Fluids; Carbazoles; Cardiac Output; Carvedilol; Catecholamines; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Physical Exertion; Propanolamines

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.

Topics: Amino Acid Oxidoreductases; Animals; Aorta; Arginine; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Organ Size; Rats; Rats, Inbred Strains

The cardiac natriuretic peptide family includes atrial natriuretic factor and brain or B-type natriuretic peptide, also known as iso-atrial natriuretic factor (isoANF). Although these peptides contribute to cardiovascular homeostasis, their respective roles remain unclear. To study regulation of atrial natriuretic factor and isoANF gene expression during progression of hypertension, we developed a quantitative polymerase chain reaction protocol to measure their transcript level in spontaneously hypertensive rat (SHR) hearts. At the onset of hypertension, atrial natriuretic factor transcripts in 5-week-old SHR were 50% of those of age-matched Wistar-Kyoto (WKY) rats, whereas the level of isoANF transcripts was similar in atria and twofold higher in ventricles. Because atria are the major sites of atrial natriuretic factor gene expression and ventricles contribute predominantly to cardiac isoANF synthesis, total atrial natriuretic factor messenger RNA (mRNA) in the hearts of 5-week-old SHR was about 50% of that in WKY rats, and total isoANF mRNA content was already higher than in control rats. In left ventricles and ventricular septa, progression of hypertension led to a maximal increase of twofold and fourfold in atrial natriuretic factor and isoANF mRNA levels, respectively, with no detectable change in right ventricles. In the atria of older SHR, atrial natriuretic factor and isoANF mRNA levels were comparable to those of age-matched controls. These data indicate that, although increased blood pressure stimulates both atrial natriuretic factor and isoANF gene expression, regulation of the two natriuretic peptide genes is not temporally coordinated in all cardiac compartments. Furthermore, isoANF mRNA is already induced in the ventricles at the onset of the hypertensive stage, and in older SHR, the isoANF gene is hyperresponsive to progression of hypertension compared with atrial natriuretic factor. Thus, isoANF might represent a very sensitive marker of cardiac changes in hypertension.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Hypertension; Isomerism; Male; Molecular Probes; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA; Transcription, Genetic

Aim of this study was to assess the relationship between plasma concentration of atrial natriuretic factor (ANF) and its two-dimensional echocardiographic (left ventricular mass, left atrium diameter) and humoral (plasma renin and aldosterone) variables in essential hypertension (EH). We evaluated 32 patients with uncomplicated mild to moderate EH and 10 controls. They were studied in the supine position after 7 days of constant dietary sodium intake and were off therapy since at least 3 weeks. ANF values overlapped between EH patients and controls (27.8 +/- 11.5 vs. 19.5 +/- 7.4 pg/ml, p = NS). In EH, no significant correlation was found between ANF values and left ventricular mass (r = 0.29), left atrial diameter (r = 0.04), mean arterial blood pressure (r = 0.26), plasma renin activity (r = 0.00), and aldosterone (r = 0.26). In EH, ANF values overlapped between the 15 patients with hypertrophy and the 17 patients with normal ventricular mass: 30.3 +/- 17 vs. 25.6 +/- 10.6 pg/ms (p = NS). We conclude that there is a substantial overlap in plasma ANF values between mild to moderate uncomplicated EH and controls, and left ventricular hypertrophy is not a major independent stimulus to ANF release in EH.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Echocardiography; Female; Humans; Hypertension; Male; Middle Aged; Renin

Aim of the study was to evaluate the effect of cardiopulmonary receptors activation and deactivation on antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP) incretion in hypertensive and normotensive subjects. Twenty-one male subjects, 7 normotensives and 14 mild hypertensives, 7 without and 7 with left ventricular hypertrophy (LVH) were admitted to the study. Each subject underwent selective loading and unloading of cardiopulmonary receptors, by application of a positive (LBPP) or negative (LBNP) pressure to the lower body. Blood samples were taken for measurement of ANP, ADH, PRA, immunoreactive renin, aldosterone, noradrenaline and adrenaline. ADH plasma concentration increased during cardiopulmonary receptors inhibition, but this increase became statistically significant (p less than 0.05) at a step of LBNP (-40 mm Hg), in which an involvement of the sinoaortic receptors cannot be excluded. ANP plasma levels increased progressively during LBPP (p less than 0.05 at least). These changes were significantly reduced in hypertensive patients with LVH.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Cardiomegaly; Hemodynamics; Hormones; Humans; Hypertension; Lower Body Negative Pressure; Male; Middle Aged; Pressoreceptors; Pressure; Vasopressins

To assess the relation of the two natriuretic hormones, atrial natriuretic peptide (ANP) and digitalis-like natriuretic factor (DLF), to hypertension, levels of ANP and DLF were measured under basal conditions and after salt and water loading in 31 normal subjects and 36 and 57 patients with Stage I or II essential hypertension (EH). DLF levels were higher in normal women than men; in EH-II patients, DLF levels were elevated among men but subnormal in women (P less than .02) and rose with water loading in both genders. In all groups ANP levels tended to be higher in women. Water loading increased ANP levels in EH-I patients (P less than .001) and caused less marked increases of ANP in control and EH-II women and men. ANP also tended to increase with salt loading. Both DLF and ANP were related to blood pressure in the subject groups (r = 0.75 to 0.96 and r = 0.27 to 0.75, respectively) and were also related to each other (r = 0.20 to 0.47). The role of ANP and DLF in hypertension are likely to be compensatory and directed against water-electrolyte metabolism disorders associated with elevated arterial pressure.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Digitalis; Female; Humans; Hypertension; Male; Middle Aged; Plants, Medicinal; Plants, Toxic; Renin-Angiotensin System

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Combined Modality Therapy; Female; Hemodynamics; Homeostasis; Humans; Hydrotherapy; Hypertension; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Reference Values; Water-Electrolyte Balance