adrenomedullin and Hypertension

Adrenomedullin (AM) is a multifunctional peptide which exerts numerous biological activities through the activation of AM1 (CRLR + RAMP2) and AM2 (CRLR + RAMP3) receptors. AM immunoreactivity, AM binding sites and CRLR, RAMP1, RAMP2 and RAMP3 are expressed in rat cerebellar vermis. AM binding sites are discretely and differentially distributed in the rat cerebellar cortex with higher levels detected in SHR when compared with WKY rats. In addition, there is an up-regulation of cerebellar CGRP1 (CRLR + RAMP1) and AM2 (CRLR + RAMP3) receptors and a down-regulation of AM1 (CRLR + RAMP2) receptor during hypertension associated with a decreased AM expression. These changes may constitute a mechanism which contributes to the development of hypertension, and supports the notion that cerebellar AM is involved in the regulation of blood pressure. Cerebellar AM activates ERK, increases cAMP, cGMP and nitric oxide, and decreases antioxidant enzyme activity. These effects are mediated through AM

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Cerebellum; Humans; Hypertension; Receptors, Adrenomedullin; Signal Transduction

Adrenomedullin family includes adrenomedullin (ADM), intermedin (IMD) and different peptide fragments derived from prepro-ADM or prepro-IMD. Recent researches found the interaction between different prepro-peptides or different peptide fragments, which plays a crucial role in maintaining homeostasis of cardiovascular system as well as participates in the occurrence and development of cardiovascular disease. This review intends to introduce cardiovascular effects and pathophysiological significance of adrenomedullin family peptides from function level, receptor level and signaling pathway.

Topics: Adrenomedullin; Animals; Arteriosclerosis; Cardiovascular System; Homeostasis; Humans; Hypertension; Peptide Fragments; Peptide Hormones

Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3'-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Carcinogens; Cardiovascular Diseases; Cell Transplantation; Genetic Therapy; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Molecular Sequence Data; Myocardial Infarction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Renal Insufficiency; Renin-Angiotensin System; Signal Transduction

Topics: Adiponectin; Adrenomedullin; Animals; Blood Pressure; Cardenolides; Humans; Hypertension; Metabolic Syndrome; Natriuretic Peptides; Nitric Oxide; Norepinephrine; Peptides; Renin-Angiotensin System; Saponins

Topics: Adrenomedullin; Animals; Arteriosclerosis; Connexins; Cyclooxygenase 2 Inhibitors; Endothelium-Dependent Relaxing Factors; Epoprostenol; Humans; Hypertension; Natriuretic Peptide, C-Type; Nitric Oxide; Nitric Oxide Synthase Type III; Peptides

Topics: Adrenomedullin; Animals; Calcitonin Receptor-Like Protein; Humans; Hypertension; Peptides; Polymorphism, Single Nucleotide; Receptors, Calcitonin

Topics: Adrenomedullin; Animals; Blood Pressure; Genetic Therapy; Humans; Hypertension; Kidney Diseases; Kidney Tubules; Peptides; Receptors, Adrenomedullin; Receptors, Peptide; Renal Circulation; Vasodilation

Topics: Adrenomedullin; Angiotensin II; Cardiovascular Diseases; Humans; Hypertension; Insulin Resistance; Metabolic Syndrome; Renin-Angiotensin System; Sodium Chloride

Topics: Adrenomedullin; Arteriosclerosis; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Kidney Failure, Chronic; Peptides; Radioimmunoassay; Reference Values; Shock, Septic; Specimen Handling; Systemic Inflammatory Response Syndrome

Arterial hypertension is one of the major risk factors in cardiovascular and renal disease. Advances in the study of pathophysiologic mechanisms and the relationship between several regulatory systems provide the basis for development of more selective therapeutic strategies. The increasing understanding of the role played by ETs, natriuretic peptides, AM, and leptin opens new frontiers in the care of hypertension and its complications, coronary artery disease and heart failure and other forms of cardiovascular disease.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Cardiovascular System; Endothelins; Humans; Hypertension; Leptin; Natriuretic Peptides; Peptides

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

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: Adrenomedullin; Animals; Body Fluids; Electrolytes; Gene Deletion; Hemodynamics; Humans; Hypertension; Peptides; Protein Precursors; Proteins; Receptors, Adrenomedullin; Receptors, Peptide; Vasodilation

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: Adrenomedullin; Animals; Biomarkers; Cardiovascular Physiological Phenomena; Genetic Therapy; Humans; Hypertension; Peptides; Renin-Angiotensin System

The distribution and characteristics of adrenomedullin (AM)-containing perivascular nerves in the rat mesenteric artery were investigated using immunohistochemical techniques. Many fibers containing AM-like immunoreactivity (LI) were observed in the adventitia of mesenteric arteries, which were densely innervated by calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-LI fibers. AM-LI, CGRP-LI, and NPY-LI fibers were abolished by cold storage denervation. Capsaicin pretreatment abolished AM-LI and NPY-LI fibers but not NPY-LI fibers. NPY-LI fibers but not AM-LI and CGRP-LI fibers disappeared after treatment with 6-hydroxydopamine. There were many AM-LI positive cells in the dorsal root ganglia, where AM mRNA was detected. In a double immunofluorescence study, AM-LI was found in CGRP-LI fibers, although some fibers contained AM-LI alone. The density of AM-LI fibers was lower in SHR than in WKY mesenteric arteries. These results suggest that the mesenteric artery is innervated by AM-containing perivascular nerves and AM may have a neurotransmitter role in the regulation of vascular tone.

Topics: Adrenomedullin; Age Factors; Animals; Calcitonin Gene-Related Peptide; Humans; Hypertension; Immunohistochemistry; Mesenteric Arteries; Neuropeptide Y; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Adrenomedullin (AM), a vasodilatory peptide, has recently been shown to have multipotent properties. Among its other pharmacological actions, AM has been hypothesized to protect organs from hypertension, hypoxia, or infection. In vitro studies have shown that AM has an inhibitory effect on vascular smooth muscle cell proliferation and oxidative stress, but that it enhances nitric oxide (NO) production, which in turn is thought to protect against organ damage. Recent advances in genetic engineering have made it possible to investigate the chronic effects of AM in vivo. Applying genetic engineering, it is revealed that adrenomedullin was shown to protect liver, kidney, vasculature, and heart from septic shock, ischemia and hypertension. However, speculation as to the mechanism of its organ-protective effect varies from report to report. Possible mechanisms include preservation of blood flow, interaction with NO and/or oxidative stress. And although there continue to be technical limitations to the use of these genetically modified models, their application in further investigations should help to clarify the potential efficacy of AM as a new therapeutic agent.

Topics: Adrenomedullin; Animals; Hypertension; Mice; Mice, Knockout; Oxidative Stress; Peptides

Topics: Adrenomedullin; Animals; Cardiomegaly; Humans; Hypertension; Peptides

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

This review is an attempt to highlight evidence that may implicate the cardiovascular abnormalities in the pathogenesis of hypertension. Many physiological, pharmacological, and biochemical studies have been conducted in in vitro and in vivo systems. Since blood pressure can rise in response to an increase in cardiac output and/or a rise in peripheral resistance, abnormalities may be present in one or more of the multiple factors that affect these two parameters in hypertension. These multiple factors include various neurohumoral factors. Increased levels of various vasoconstrictor neurohumoral factors have been found in patients with hypertension. Vasoconstrictor neurohumoral factors such as catecholamines, angiotensin II, and endothelin-1 induce vascular smooth muscle cells(VSMCs) proliferation and contraction. On the other hand, vasodilator neurohumoral factors such as natriuretic peptides and adrenomedulin inhibit VSMCs proliferation. Both neurohumoral factors mutually interact and develop hypertension.

Topics: Adrenomedullin; Angiotensin II; Animals; Cardiovascular System; Catecholamines; Cell Division; Endothelin-1; Humans; Hypertension; Insulin; Kallikrein-Kinin System; Muscle, Smooth, Vascular; Natriuretic Agents; Nitric Oxide; Peptides; Vasoconstriction

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

Adrenomedullin (AM) is a novel 52-aminoacid-peptide hormone, originally isolated from human phaeocromocytoma. Adrenomedullin acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood lowering properties, but its exact role is still uncertain. Adrenomedullin is considered to play an important endocrine role in various tissues maintaining the electrolyte and fluid homeostasis. Its normal plasma concentration is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases parallel to the seriousness of the disease. It is assumed that this peptide may be important under pathologic conditions compensating the effects of the vasoconstrictor molecules. Till now, investigations have proved that in diabetic angiopathies the levels and the production of vasoconstrictor factors and adrenomedullin were increased, while, those of other relaxing substances including nitrogenoxid were decreased. It is still uncertain whether increased release of adrenomedullin in diabetes is a compensatory mechanism or a coincidental event. Although, the precise role of adrenomedullin in the pathogenesis of diabetic complications is still to be elucidated, the elevated concentration of adrenomedullin in diabetes--which influences the vascular functions--let us speculate that there might be a certain interaction between adrenomedullin induction and vascular functions in diabetes. Thus, the induction of vascular adrenomedullin could be a new target of a therapeutic approach to the diabetic complications.

Topics: Adrenomedullin; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Peptides; Tissue Distribution; Vasodilator Agents

Although the biological effects of adrenomedullin (AM) and PAMP have been reported extensively in animal studies and from in-vitro experiments, relatively little information is available on responses to the hormone administered to man. This review summarizes data from the few studies carried out in man. In healthy volunteers, i.v. infusion of AM reduces arterial pressure, probably at a lower rate of administration than is required to elicit other responses. AM stimulates heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and renin whilst inhibiting any concomitant response in plasma aldosterone. Little or no increase in urine volume or sodium excretion has been observed. Patients with essential hypertension differ only in showing a greater fall in arterial pressure and in the development of facial flushing and headache. In patients with heart failure or chronic renal failure, i.v. AM has similar effects to those seen in normal subjects but also induces a diuresis and natriuresis, depending on the dose administered. Infusion of AM into the brachial artery results in a dose-related increase in forearm and skin blood flow, more prominent and more dependent on endogenous nitric oxide in healthy volunteers than in patients with cardiac failure. When infused into a dorsal hand vein, AM partially reversed the venoconstrictor action of norepinephrine. Although much more information is required to clarify the role of AM under physiological and pathophysiological circumstances, it is clear that it has prominent hemodynamic and neurohormonal effects, though generally lesser urinary effects when administered short-term in doses sufficient to raise its levels in plasma to those seen in a number of clinical disorders. The only study of PAMP in man showed that its skeletal muscle vasodilator potency, when infused into the brachial artery of healthy volunteers, was less than one hundredth that of AM, and it was without effect on skin blood flow.

Topics: Adrenomedullin; Cardiovascular Diseases; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Kidney Failure, Chronic; Peptide Fragments; Peptides; Proteins; Veins

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Humans; Hypertension; Peptides

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

Although approximately 90% of patients diagnosed with hypertension have essential hypertension, it is important that secondary hypertension is considered; diagnosed, when present; and managed either medically or surgically. Although the most common organ involved in the etiology of secondary hypertension is the kidney, disorders of the adrenal gland also play a major role. This review focuses on recent findings and controversies about the adrenal medulla and, where appropriate, on the role of the adrenal medulla in hypertension.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Adrenomedullin; Animals; Humans; Hypertension; Peptides; Pheochromocytoma; Vasodilation

"Adrenomedullin (AM)" is a novel hypotensive peptide which was discovered in human pheochromocytoma by monitoring the elevating activity of platelet cAMP. In addition, a novel 20 residues hypotensive peptide, termed "proadrenomedullin N-terminal 20 peptide" (PAMP) is processed from proadrenomedullin. By RNA blot analysis, AM mRNA was found to be highly expressed in several tissues including ventricle, lung, kidney, aorta and vascular cultured cells as well as in adrenal medulla. Both AM and PAMP shows hypotensive effects in anesthetized rats, but exhibits different hypotensive mechanism. AM possesses multiple biological effects involving in cardiovascular homeostasis. Further, plasma AM as well as PAMP concentrations significantly increased in various cardiovascular diseases including hypertension and congestive heart failure. The present review summarizes the recent advancement of AM research and demonstrated that AM and PAMP are important vasoactive peptides involved in the physiology and pathophysiology of circulation control.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Humans; Hypertension; Molecular Sequence Data; Peptide Fragments; Peptides; Proteins; Rats

Topics: Adrenomedullin; Cardiovascular Physiological Phenomena; Heart Failure; Humans; Hypertension; Peptides; Vasodilator Agents

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Blotting, Northern; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Molecular Sequence Data; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Rats

The aim of this study is to investigate the effects of endogenous vasoactive substances on the occurrence of intradialytic hypertension (IDH) in patients during maintenance hemodialysis. Thirty-four maintenance hemodialysis patients were enrolled in this trial, and 17 of them were diagnosed with IDH (defined as an increase in blood pressure of at least 10 mmHg during or immediately after a hemodialysis session), while 17 age-matched and sex-matched controls without IDH were selected for a retrospective comparison. We collected patients' blood samples before and after a dialysis session and measured the plasma levels of N-terminal fragment brain natriuretic peptide, renin, angiotensin-II, aldosterone (ALD), angiotensin-converting enzyme (ACE), endothelin-1 (ET-1), nitric oxide (NO), norepinephrine (NOR), and adrenomedullin. The post-dialysis serum ET-1 concentrations were significantly higher (4.09 ± 2.06 vs. 2.75 ± 1.34 pg/mL, P < 0.05), while the post-dialysis ratio of NO to ET-1 was lower (17.79 ± 5.65 vs. 24.78 ± 12.04, P < 0.05) in IDH patients compared with the control group. Post-dialysis ALD and NOR values were significantly lower (P < 0.01) and ACE levels were significantly higher (P < 0.01) than the pre-dialysis concentrations only in the control and not in the IDH group. All other measured factors did not differ significantly between the groups and between pre-dialysis and post-dialysis determinations. Compared with blood angiotensin-II, ALD, ACE, NOR, adrenomedullin, N-terminal fragment brain natriuretic peptide, and NO status, inappropriately elevated ET-1 plasma concentrations may play a predominant role in the pathogenesis of IDH.

Topics: Adrenomedullin; Adult; Aged; Aldosterone; Angiotensin II; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Norepinephrine; Peptidyl-Dipeptidase A; Renal Dialysis

To study the therapeutic effect of Luohuo Capsule (LHC) clinically.. Clinical trial on 90 patients were carried out adopting randomized, stratified, single-blinded and positive drug controlled method, by divided patients into the treated group (n = 60) and the control group (n = 30). The treated group was treated with LHC, which was mainly consisted of Leech, Radish seed, Water-plantain Tuber, Chuanxiong, etc. The control group was treated with Beijing Hypotensive. No. 0. The therapeutic course was 4 weeks. The diagnosis and efficacy evaluation were in accord with corresponding national standards, using the indexes including safety, clinical symptoms, blood pressure, hemorrheologic parameters, blood lipid, adrenal medullin (AdM) and plasma tissue factor pathway inhibitor (TFPI).. The total effective rate of LHC in lowering blood pressure in the treated group and the control group was 85.00% and 86.67% respectively, comparison of them showed no significant difference (P = 0.915). Most of the improvement of clinical symptoms in the treated group were better than those in the control group (P < 0.05 or P < 0.01). LHC could also improve the hemorrheologic status (P < 0.01), alleviate the blood lipids disorder (P < 0.05), and adjust AdM and TFPI (P < 0.05).. LHC is safe in treating hypertension grade I and II with no adverse reaction.

Topics: Adrenomedullin; Adult; Aged; Antihypertensive Agents; Capsules; Drugs, Chinese Herbal; Female; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Peptides; Phytotherapy; Single-Blind Method

Adrenomedullin (ADM) infusion increases salt excretion in the rat. However, there is no evidence that this substance is related to changes in salt intake in humans. In this study we sought whether the urinary excretion rate of this autacoid is related to salt intake and by the expected changes in arterial pressure in patients with mild essential hypertension. The influence of salt intake on the renal excretion of ADM was investigated in 55 hypertensive patients in a double blind, randomized and crossover study comparing a 2-week 50 mmol/day salt intake period with a 150 mmol/day salt intake period. Twenty-four-hour ADM and endothelin-1 (ET-1) excretion rate were measured by radioimmunoassay on preextracted urinary samples (intraassay confidence variable <8%). The antibodies used in these assays had minimal ADM-ET-1 cross-reactivity (<1%). Twenty-four-hour microalbuminuria was measured by nephelometry. On univariate analysis changes in urinary ADM were significantly related to those in salt excretion (r = 0.33, P = .01) as well as to changes in urinary ET-1 (r = 0.56, P = .0001). Furthermore, changes in urinary albumin excretion were related to those in urinary ET-1 (r = 0.26, P = .05), but were independent of those in urinary ADM (P = .19). In a multiple regression model including age, sex, body mass index, and changes in systolic pressure, plasma renin activity and plasma aldosterone and urine volume, salt excretion resulted as the stronger independent predictor of urinary ADM (r = 0.33, P = .01). However, changes in urinary salt lost prediction power (P = .11) for urinary ADM when urinary ET-1 was introduced into the model. In this model (multiple r = 0.31) urinary ET-1 resulted to be the only independent predictor of urinary ADM (beta = 0.56, P = .0001). This study is the first to show that the renal excretion of ADM is related to changes in salt intake and that it is tightly linked to that of ET-1. The data support the notion that these autacoids play a role in the regulation of sodium metabolism in patients with mild hypertension. The intercorrelations between ET-1, ADM, and microalbuminuria are compatible with the hypothesis that ET-1 is involved in a salt-induced increase in glomerular pressure and suggest that ADM may act as a counterregulatory factor in this situation.

Topics: Adrenomedullin; Adult; Aged; Albuminuria; Angiotensins; Cross-Over Studies; Double-Blind Method; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Natriuresis; Peptides; Radioimmunoassay; Renin; Sodium Chloride, Dietary; Vasodilator Agents

The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma.. 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of iradrenomedullin in the pheochromocytoma.. Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery.. The mean plasma adrenomedullin concentrations ( SD) in patients with pheochromocytoma (37.9 +/- 6pg/ml) were significantly higher (p<0.0001) than those in normal subjects (13.7 +/- 6.1 pg/mI) and patients with essential hypertension (22.5 +/- 9.lpg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 +/- 6 to 10.9 +/- 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide.. This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adrenomedullin; Adult; Catecholamines; Female; Hemodynamics; Humans; Hypertension; Immunohistochemistry; Male; Middle Aged; Norepinephrine; Peptides; Pheochromocytoma; Treatment Outcome

We investigated whether maternal and fetoplacental adrenomedullin, a newly discovered hypotensive peptide involved in the insulin regulatory system, is modified in diabetic pregnancy. We studied its correlation with pregnancy complications associated with this disease. Thirty-six pregnant women with diabetes (13 with type I and 23 with gestational diabetes mellitus) and in 40 uncomplicated pregnancies were included. 10 out of 36 diabetic pregnancies were complicated by gestational hypertension. In each woman, adrenomedullin concentration in maternal and fetal plasma and in amniotic fluid was assessed by specific radioimmunoassay. We found that overall mean amniotic fluid adrenomedullin concentration was higher (p < 0.05) in diabetic (14.7 +/- 1.6 fmol/ml) than in uncomplicated pregnancies (10.8 +/- 0.9 fmol/ml), whereas no differences were present in maternal and fetal plasma adrenomedullin levels between diabetic and uncomplicated pregnant women. High levels of amniotic fluid adrenomedullin were found in both type I and gestational diabetes mellitus pregnancies (13.7 +/- 1.4 and 15.6 +/- 2.2 fmol/ml, respectively). Diabetic pregnancies complicated by gestational hypertension showed lower (p < 0.05) amniotic fluid adrenomedullin concentrations than normotensive diabetic patients. These findings suggest that placental adrenomedullin production is upregulated in diabetic pregnancy, and it may be important to prevent excessive vasoconstriction of placental vessels.

Topics: Adrenomedullin; Adult; Amniotic Fluid; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Blood; Gestational Age; Humans; Hypertension; Middle Aged; Peptides; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Radioimmunoassay

Levels of adrenomedullin (AM) have been shown to be elevated in hypertension and chronic renal failure, suggesting that AM plays a role in the pathogenesis of these diseases. The objective of the present study was to investigate whether circulating AM is involved in erythropoietin (Epo)-induced hypertension in patients with renal anemia due to progressive renal disease. Following treatment with 6,000 IU of Epo once a week, the hematocrit (Ht) rose significantly from 25.9+/-4.0 to 33.4+/-3.3% (n=54, p<0.001) with an overall rate of increase in Ht of 0.43+/-0.04%/week. In response to treatment with Epo, a rise in mean blood pressure of >10 mmHg (Epo-induced hypertension) was found in 22% (12/54 cases) of the patients enrolled. There was no difference in the rate of Ht increase between patients with and without Epo-induced hypertension. There was a significant positive correlation between mature AM and serum creatinine (Cr) concentration before treatment with Epo. However, no correlation was found between the plasma concentration of total AM and serum Cr concentration. Long-term treatment with Epo did not influence plasma concentration of either mature AM or total AM in patients developing hypertension during the study period. These results suggest that circulating AM may play a role in the progression of renal disease. However, the present study does not support the notion that circulating AM is associated with the pathogenesis of Epo-induced hypertension. It is too early yet to claim that there is no AM-mediated mechanism in Epo-induced hypertension.

Topics: Adrenomedullin; Adult; Aged; Anemia; Creatinine; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Peptides

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

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

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

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

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67 +/- 10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42 +/- 14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Adrenomedullin; Adult; Aged; Antihypertensive Agents; Blood Pressure; Epinephrine; Female; Gene Expression; Heart Rate; Heart Ventricles; Humans; Hypertension; Kidney; Lung; Male; Metabolic Clearance Rate; Middle Aged; Myocardial Ischemia; Myocardium; Norepinephrine; Peptide Biosynthesis; Peptides; Pheochromocytoma; Pulmonary Artery; Pulmonary Circulation; RNA, Messenger

Hypothalamic paraventricular nucleus (PVN) is an important central site for the control of the adipose afferent reflex (AAR) that increases sympathetic outflow and blood pressure in obesity-related hypertension (OH).. In this study, we investigated the effects of nitric oxide (NO) and cardiovascular bioactive polypeptide adrenomedullin (ADM) in the PVN on AAR and sympathetic nerve activity (SNA) in OH rats induced by a high-fat diet.. The results showed that ADM, total neuronal NO synthase (nNOS) and phosphorylated-nNOS protein expression levels in the PVN of the OH rats were down-regulated compared to the control rats. The enhanced AAR in OH rats was attenuated by PVN acute application of NO donor sodium nitroprusside (SNP), but was strengthened by the nNOS inhibitor nNOS-I, guanylyl cyclase inhibitor (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and gamma-aminobutyric acid A type receptor (GABAA) antagonist Bicuculline. Moreover, PVN ADM microinjection not only decreased basal SNA but also attenuated the enhanced AAR in OH rats, which were effectively inhibited by ADM receptor antagonist ADM22-52, nNOS-I, ODQ or Bicuculline pretreatment. Bilateral PVN acute microinjection of ADM also caused greater increases in NO and cyclic guanosine monophosphate (cGMP) levels, and nNOS phosphorylation. Adeno-associated virus vectors encoding ADM (AAV-ADM) transfection in the PVN of OH rats not only decreased the elevated AAR, basal SNA and blood pressure (BP), but also increased the expression and activation of nNOS. Furthermore, AAV-ADM transfection improved vascular remodeling in OH rats.. Taken together, our data highlight the roles of ADM in improving sympathetic overactivation, enhanced AAR and hypertension, and its related mechanisms associated with receptors mediated NO-cGMP-GABAA pathway in OH condition.

Topics: Adrenomedullin; Animals; Bicuculline; Blood Pressure; gamma-Aminobutyric Acid; Hypertension; Nitric Oxide; Nitric Oxide Synthase Type I; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptors, GABA; Reflex; Sympathetic Nervous System

Adrenomedullin (ADM) is a novel cardiovascular peptide with anti-inflammatory and antioxidant properties. Chronic inflammation, oxidative stress and calcification play pivotal roles in the pathogenesis of vascular dysfunction in obesity-related hypertension (OH). Our study aimed to explore the effects of ADM on the vascular inflammation, oxidative stress and calcification in rats with OH. Eight-week-old Sprague Dawley male rats were fed with either a Control diet or a high fat diet (HFD) for 28 weeks. Next, the OH rats were randomly subdivided into two groups as follows: (1) HFD control group, and (2) HFD with ADM. A 4-week treatment with ADM (7.2 μg/kg/day, ip) not only improved hypertension and vascular remodeling, but also inhibited vascular inflammation, oxidative stress and calcification in aorta of rats with OH. In vitro experiments, ADM (10 nM) in A7r5 cells (rat thoracic aorta smooth muscle cells) attenuated palmitic acid (PA, 200 μM) or angiotensin II (Ang II, 10 nM) alone or their combination treatment-induced inflammation, oxidative stress and calcification, which were effectively inhibited by the ADM receptor antagonist ADM22-52 and AMP-activated protein kinase (AMPK) inhibitor Compound C, respectively. Moreover, ADM treatment significantly inhibited Ang II type 1 receptor (AT1R) protein expression in aorta of rats with OH or in PA-treated A7r5 cells. ADM improved hypertension, vascular remodeling and arterial stiffness, and attenuated inflammation, oxidative stress and calcification in OH state partially via receptor-mediated AMPK pathway. The results also raise the possibility that ADM will be considered for improving hypertension and vascular damage in patients with OH.

Topics: Adrenomedullin; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Calcinosis; Hypertension; Inflammation; Male; Obesity; Rats; Rats, Sprague-Dawley; Vascular Remodeling

Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal-fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditions.. To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14.. The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.. These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.

Topics: Adrenomedullin; Animals; Blood Pressure; Female; Fetal Growth Retardation; Humans; Hypertension; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Uterus

Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r =  - 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.

Topics: Adrenomedullin; Antihypertensive Agents; Chromatography, Liquid; Cross-Sectional Studies; Female; Humans; Hypertension; Pregnancy; Protein Precursors; Renal Insufficiency, Chronic; Tandem Mass Spectrometry

The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19.. We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated.. Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001).. We found that MR-proADM could represent a prognostic biomarker of COVID-19.

Topics: Adrenomedullin; Aged; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; C-Reactive Protein; Comorbidity; COVID-19; Female; Humans; Hypertension; Interleukin-6; Lung Diseases; Male; Middle Aged; Patient Selection; Prognosis; Protein Precursors; Retrospective Studies; SARS-CoV-2; Severity of Illness Index; Survival Analysis; Triage

Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160-180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.

Topics: Adrenomedullin; Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Hypertension; Male; MAP Kinase Signaling System; NADPH Oxidases; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sympathetic Nervous System

Topics: Adrenomedullin; Animals; Brain; Brain Stem; Hypertension; Hypoxia; Long-Term Potentiation; Rats; Vasoconstrictor Agents

Intermedin/adrenomedullin-2 (IMD/AM2), a member of the calcitonin gene-related peptide/AM family, plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus (PVN) of the hypothalamus on sympathetic nerve activity (SNA), and lipopolysaccharide (LPS)-induced sympathetic activation in obesity-related hypertensive (OH) rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure (MAP) in response to specific drugs. Male rats were fed a control diet (12% kcal as fat) or a high-fat diet (42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4 (TLR4) and plasma norepinephrine (NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS (0.5 µg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD (50 pmol) caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympathetic activation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However, IMD in the PVN decreased the LPS-induced ERK activation, which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover, IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.

Topics: Adrenomedullin; Animals; Blood Pressure; Hypertension; Lipopolysaccharides; Male; Neuropeptides; Obesity; Rats, Sprague-Dawley; Receptors, Adrenomedullin; Sympathetic Nervous System; Toll-Like Receptor 4

The aim of this study was to evaluate the association of ADM genetic variant and HBP among Lithuanian adolescents aged 12-15 years. This is a cross-sectional study of a randomly selected sample of 675 12-15-years-old schoolchildren who were surveyed during November 2010 to April 2012 in the baseline survey. Single-nucleotide polymorphism (SNP) of ADM gene (rs7129220) was evaluated using real-time PCR. Logistic regression analyses were used to test the associations of ADM (rs7129220) polymorphism with HBP under four inheritance models based on the Akaike Information Criterion (AIC) and to calculate the odds ratios. In the multivariate analysis, boys carrying ADM AG genotype (vs. carriers of ADM GG genotype), ADM AG + AA genotype (vs. carriers of ADM GG genotype) and ADM AG genotype (vs. carriers of ADM GG + AA genotype) had higher odds of having hypertension in codominant, dominant, and overdominant inheritance models. Girls with ADM AG + AA had increased odds of prehypertension compared to girls with the ADM GG genotype carriers in dominant inheritance model. Significant associations were observed in additive models separately for boys (hypertension) and girls (prehypertension). Our results indicate that ADM gene polymorphism was significantly associated with higher odds of HBP in Lithuanian adolescents aged 12-15 years.

Topics: Adolescent; Adrenomedullin; Age Factors; Alleles; Child; Child, Preschool; Cross-Sectional Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Lithuania; Male; Odds Ratio; Polymorphism, Single Nucleotide; Prehypertension; Prevalence; Public Health Surveillance

Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.

Topics: Adrenomedullin; Animals; Blood Pressure; Cyclic AMP; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Ion Channels; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Second Messenger Systems; Stress, Mechanical

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

What is the central question of this study? Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity; given that adrenomedullin is released during hypoxia, what are the effects of its agonism and antagonism in the RVLM after chronic intermitent hypoxia (CIH) exposure? What is the main finding and its importance? CIH exposure sensitizes adrenomedullin-dependent mechanisms in the RVLM, supporting its role as a sympathoexcitatory neuromodulator. A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension.. Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50-55 g) submitted to CIH (6% oxygen every 9 min, 8 h day

Topics: Adrenomedullin; Animals; Blood Pressure; Heart Rate; Hypertension; Hypoxia; Long-Term Potentiation; Male; Medulla Oblongata; Rats; Sleep Apnea Syndromes; Sympathetic Nervous System; Vasoconstrictor Agents

Obese children are at increased risk for abnormal cardiac structure and function. Little is known about adrenomedullin (AM), a cytokine produced in various organs and tissues, as a biomarker of cardiac hypertrophy in obese children. This study aimed to assess the plasma AM levels in a cohort of obese children and its relationship to left ventricular (LV) functions.. The study included 60 obese children and 60 non-obese children matched for age and gender as control group. Blood pressure, serum lipid profile, fasting glucose, insulin and plasma AM and the homeostatic model assessment of insulin resistance (HOMA-IR) were measured. Cardiac dimensions and LV functions were assessed using conventional echocardiography.. Compared to control subjects, obese children had higher blood pressure (P = 0.01), insulin (P = 0.001), HOMA-IR (P = 0.001), and AM (P = 0.001). Moreover, obese children had higher LV mass index (LVMI) (P = 0.001), indicating LV hypertrophy; prolonged isovolumic relaxation times (P = 0.01), prolonged mitral deceleration time (DcT) (P = 0.01) and reduced ratio of mitral E-to-mitral A-wave peak velocity (P = 0.01), indicating LV diastolic dysfunction. Laboratory abnormalities were only present in children with LV hypertrophy. In multivariate analysis in obese children with LV hypertrophy, AM levels were positively correlated with LVMI [odds ratio (OR) 1.14, 95% confidence interval (Cl) 1.08-1.13, P = 0.0001] and mitral DcT (OR 2.25, 95% CI 1.15-2.05, P = 0.01) in the presence of higher blood pressure and HOMA-IR. A cut-off value of AM at 52 pg/mL could differentiate obese children with and without left ventricular hypertrophy at a sensitivity of 94.32% and specificity of 92.45%.. Plasma AM levels may be elevated in obese children particularly those with LV hypertrophy and is correlated with higher blood pressure and insulin resistance. Measurement of plasma AM levels in obese children may help to identify those at high risk of developing LV hypertrophy and dysfunction.

Topics: Adrenomedullin; Area Under Curve; Biomarkers; Body Mass Index; Case-Control Studies; Child; Developing Countries; Echocardiography; Egypt; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Incidence; Insulin Resistance; Male; Pediatric Obesity; Reference Values; Risk Assessment; ROC Curve

Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM activates three different receptors, the AM type 1 (AM1), type 2 (AM2), and calcitonin gene-related peptide 1 (CGRP1) receptors. AM triggers several signaling pathways such as adenylyl cyclase (AC), guanylyl cyclase (GC), and extracellular signal-regulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. Cerebellar AM, AM-binding sites, and its receptor components are altered during hypertension, although it is unknown if these alterations are associated with changes in AM signaling. Thus, we assessed AM signaling pathways in cerebellar vermis of 16-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Animals were sacrificed by decapitation, and cerebellar vermis was microdissected under stereomicroscopic control. Tissue was stimulated in vitro with AM. Then the production of cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and cyclic adenosine monophosphate (cAMP) were assessed along with ERK1/2 activation and three antioxidant enzymes' activity: glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Our findings demonstrate that in the cerebellar vermis of normotensive rats, AM increases cGMP, NO, cAMP production, and ERK1/2 phosphorylation, while decreases basal antioxidant enzyme activity. In addition, AM antagonizes angiotensin II (ANG II)-induced increment of antioxidant enzyme activity. Hypertension blunts AM-induced cGMP and NO production and AM-induced decrease of antioxidant enzyme activity. Meanwhile, AM-induced effects on cAMP production, ERK1/2 activation, and AM-ANG II antagonism were not altered in SHR rats. Our results support a dysregulation of several AM signaling pathways during hypertension in cerebellar vermis.

Topics: Adrenomedullin; Animals; Catalase; Cerebellum; Cyclic GMP; Glutathione Peroxidase; Hypertension; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxide Dismutase

Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.

Topics: Adrenomedullin; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Catalase; Cerebellum; Disease Models, Animal; Glutathione Peroxidase; Hypertension; Male; Random Allocation; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Valsartan

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

Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 μg/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 μg/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 μg/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 ± 2 to 167 ± 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead-induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead-induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure.

Topics: Adrenomedullin; Animals; Antioxidants; Blood Pressure; Calcitonin Gene-Related Peptide; Doxycycline; Endothelin-1; Hypertension; Lead; Lead Poisoning; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Nitrates; Nitrites; Rats; Rats, Wistar

Cerebral blood flow autoregulation (CA) shifts to higher blood pressures in chronic hypertensive patients, which increases their risk for brain damage. Although cerebral vascular smooth muscle cells express the potent vasodilatatory peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) and their receptors (calcitonin receptor-like receptor (Calclr), receptor-modifying proteins (RAMP) 1 and 2), their contribution to CA during chronic hypertension is poorly understood. Here we report that chronic (10 weeks) hypertensive (one-kidney-one-clip-method) mice overexpressing the Calclr in smooth muscle cells (CLR-tg), which increases the natural sensitivity of the brain vasculature to CGRP and AM show significantly better blood pressure drop-induced cerebrovascular reactivity than wt controls. Compared to sham mice, this was paralleled by increased cerebral CGRP-binding sites (receptor autoradiography), significantly in CLR-tg but not wt mice. AM-binding sites remained unchanged. Whereas hypertension did not alter RAMP-1 expression (droplet digital (dd) PCR) in either mouse line, RAMP-2 expression dropped significantly in both mouse lines by about 65%. Moreover, in wt only Calclr expression was reduced by about 70% parallel to an increase of smooth muscle actin (Acta2) expression. Thus, chronic hypertension induces a stoichiometric shift between CGRP and AM receptors in favor of the CGRP receptor. However, the parallel reduction of Calclr expression observed in wt mice but not CLR-tg mice appears to be a key mechanism in chronic hypertension impairing cerebrovascular reactivity.

Topics: Adrenomedullin; Animals; Binding Sites; Brain; Calcitonin Receptor-Like Protein; Cerebrovascular Circulation; Female; Hypertension; Mice; Mice, Inbred DBA; Mice, Transgenic; Molecular Sequence Data; Rats; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptors, Calcitonin Gene-Related Peptide; Recombinant Proteins

The aim of the study is to measure the vasoactive peptides, urotensin II (UII), endothelin (ET) and adrenomedullin (ADM) in a well-characterized population of normal controls and patients with essential hypertension, and to study their association with this disease.. The contents of plasma UII, ET and ADM were measured by radioimmunoassay in 40 normal controls and 120 patients with essential hypertension. Echocardiographic examinations were performed using an ultrasonic system, and the left ventricular end diastolic diameter (LVEDd) along with the left ventricular posterior wall thickness (LVPWT) and interventricular septal thickness (IST) were determined. The left ventricular mass index (LVMI) was calculated according to the method reported by Devereux et al.. Plasma UII, ET and ADM contents were increased in patients than healthy controls (3.28 ± 1.257 pmol/L vs. 1.80 ± 0.639 pmol/L, p < 0.01), and correlated with the severity of hypertension in patients. Besides, all the three vasoactive peptides in plasma had significant correlations with SBP, IST, LVPWT, LVMI (p ≤ 0.05), while they showed insignificant associations with LVEDd (p > 0.05). UII was remarkably associated with ADM content, while the association of UII level with LVEDd and ET content were not significant.. The vasoactive peptides UII, ET and ADM may be involved in the pathophysiologic process of essential hypertension, and function as the indicators for severity of this disease.

Topics: Adrenomedullin; Aged; Echocardiography; Endothelins; Essential Hypertension; Female; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Statistics as Topic; Urotensins

Adrenomedullin (AM) and their receptor components, calcitonin-receptor-like receptor (CRLR) and receptor activity-modifying protein (RAMP1, RMP2 and RAMP3) are widely expressed in the central nervous system, including cerebellum. We have shown that AM binding sites are altered in cerebellum during hypertension, suggesting a role for cerebellar adrenomedullinergic system in blood pressure regulation. To further evaluate the role of AM in cerebellum, we assessed the expression of AM, RAMP1, RAMP2, RAMP3 and CRLR in the cerebellar vermis of 8 and 16week old spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. In addition, the effect of microinjection of AM into rat cerebellar vermis on arterial blood pressure (BP) was determined. Animals were sacrificed by decapitation and cerebellar vermis was dissected for quantification of AM, CRLR, RAMP1, RAMP2 and RAMP3 expression using western blot analysis. Another group of male, 16week old SHR and WKY rats was anesthetized, and a cannula was implanted in the cerebellar vermis. Following recovery AM (0.02 to 200pmol/5μL) or vehicle was injected into cerebellar vermis. BP was determined, before and after treatments, by non-invasive plethysmography. In addition, to establish the receptor subtype involved in AM action in vivo, animals received microinjections of AM22-52 (200pmol/5μL), an AM1 receptor antagonist, or the CGRP1 receptor antagonist, CGRP8-37 (200pmol/5μL) into the cerebellar vermis, administered simultaneously with AM or vehicle microinjection. Cannulation was verified post mortem with the in situ injection of a dye solution. Our findings demonstrated that the expression of CRLR, RAMP1 and RAMP3 was higher in cerebellum of SHR rats, while AM and RAMP2 expression was lower than those of WKY rats, both in 8 and 16week old rats. In vivo microinjection of AM into the cerebellar vermis caused a profound, dose dependent, hypotensive effect in SHR but not in normotensive WKY rats. Coinjections of a putative AM receptor antagonist, AM22-52 abolished the decreases in mean arterial pressure (MAP) evoked by AM, showing that AM acts through its AM1 receptor in the vermis to reduce MAP. These findings demonstrate a dysregulation of cerebellar AM-system during hypertension, and suggest that cerebellar AM plays an important role in the regulation of BP. Likewise; they constitute a novel mechanism of BP control which has not been described so far.

Topics: Adrenomedullin; Animals; Arterial Pressure; Blood Pressure; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Cerebellar Vermis; Hypertension; Male; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins

To investigate the association between anxiety disorders and left ventricular hypertrophy in patients with essential hypertension.. Left ventricular structure and function were assessed with echocardiography in 56 patients with essential hypertension and anxiety disorder (study group) and in 56 patients with hypertension only (control group). Serum adrenomedullin levels were also measured in these patients.. There was no statistically significant difference in the left ventricular ejection fraction between the study and the control group (54.21 ± 88.81% versus 56.01 ± 7.85%, p>0.05). The left ventricular mass index (LVMI) in study group was higher than in control group (137.05 ± 9.42 versus 123.57 ± 7.01 g/m(2), p=0.001). The plasma levels of adrenomedullin in study group was higher than in control group (25.97 ± 5.48 versus 18.32 ± 6.97 ng/L, p=0.001). Levels of plasma adrenomedullin were positively correlated with LVMI in the study (r=0.734, p<0.05) and control group (r=0.592, p<0.05).. Anxiety disorders are associated with elevated plasma adrenomedullin levels and increased left ventricular hypertrophy in patients with essential hypertension. The clinical significance of these changes requires further investigation.

Topics: Adrenomedullin; Adult; Aged; Anxiety Disorders; Case-Control Studies; Essential Hypertension; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Ultrasonography; Ventricular Function, Left; Young Adult

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide family, which shares the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N(ω)-propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene-related peptide receptor antagonist calcitonin/calcitonin gene-related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO.

Topics: Adrenomedullin; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Hypertension; Hypertrophy, Left Ventricular; Male; Miotics; Neuropeptides; Nitric Oxide; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptors, Adrenomedullin; RNA, Messenger; Sympathetic Nervous System

Adrenomedullin (AM) is a vasodilator peptide with pleiotropic effects, including cardiovascular protection and anti-inflammation. Because of these beneficial effects, AM appears to be a promising therapeutic tool for human diseases, while intravenous injection of AM stimulates sympathetic nerve activity due to short-acting potent vasodilation, resulting in increased heart rate and renin secretion. To lessen these acute reactions, we conjugated the N-terminal of human AM peptide with polyethylene glycol (PEG), and examined the biological properties of PEGylated AM in the present study. PEGylated AM stimulated cAMP production, an intracellular second messenger of AM, in cultured human embryonic kidney cells expressing a specific AM receptor in a dose-dependent manner, as did native human AM. The pEC50 value of PEGylated AM was lower than human AM, but no difference was noted in maximum response (Emax) between the PEGylated and native peptides. Intravenous bolus injection of 10nmol/kg PEGylated AM lowered blood pressure in anesthetized rats, but the acute reduction became significantly smaller by PEGylation as compared with native AM. Plasma half-life of PEGylated AM was significantly longer than native AM both in the first and second phases in rats. In summary, N-terminal PEGylated AM stimulated cAMP production in vitro, showing lessened acute hypotensive action and a prolonged plasma half-life in comparison with native AM peptide in vivo.

Topics: Adrenomedullin; Animals; Blood Pressure; Cyclic AMP; Humans; Hypertension; Kidney; Peptides; Polyethylene Glycols; Rats; Receptors, Adrenomedullin

To evaluate the significance of plasma adrenomedullin and calcitonin gene-related peptide (CGRP) concentration in patients with Type 2 diabetes mellitus who are treated for hypertension and dyslipidemia.. Plasma adrenomedullin and CGRP concentration, transthoracal echocardiography and ABPM were evaluated in 82 patients with Type 2 diabetes mellitus and 41 control subjects with no previous cardiovascular disease. All the subjects had casual blood pressure ≤140/90 mmHg or received antihypertensive medication, were treated by statin if LDL cholesterol was≥3mmol/L, by fibrates if triacylglyceroles≥2 mmol/L.. The mean age was 61±6 in patients with diabetes mellitus and 61±5 years in control subjects (p=0.9). Plasma CGRP was 3.0±1.8 in patients with diabetes mellitus and 2.3±1.0 ng/ml in control subjects (p=0.09). Plasma adrenomedullin was 2.2±0.9 in patients with diabetes mellitus and 2.8±1.1 ng/ml in control subjects (p=0.01). In patients with diabetes mellitus mass index of the left ventricle was significantly higher and the parameters of diastolic function were more deteriorated. Plasma adrenomedullin and CGRP correlated significantly negatively with serum creatinine and positively with mean 24 hours arterial blood pressure in patients with diabetes mellitus but not in control subjects. Plasma adrenomedullin concentration in patients with diabetes mellitus treated for hypertension was significantly reduced.. Despite concentration plasma adrenomedullin and CGRP modulation by cardioprotective treatment both neuropeptides remained involved in regulation of hemodynamic and metabolic parameters in patients with Type 2 diabetes mellitus. The low plasma of adrenomedullin in patients with Type 2 diabetic may be marker of the efficient intervention on cardiovascular risk factors.

Topics: Adrenomedullin; Aged; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Humans; Hypertension; Hypolipidemic Agents; Male; Middle Aged; Prognosis; Risk Factors

To investigate the effect of adrenomedullin (ADM) on renal arteriole remodeling and phosphorylation of extracellular signal-regulated protein kinases 1/2 (p-ERK1/2) in spontaneous hypertensive rats (SHR).. Male SHR (4 weeks old) were randomized into hypertensive group (SHR) and ADM-treated group (ADM) to receive subcutaneous saline and ADM injections (daily dose of 1.0 nmol/kg, 5 days a week), respectively, with age-matched Wistar-Kyota (WKY) rats as the blank control. The systolic blood pressure (SBP) was measured at the end of each week, and histological changes of the renal arterioles were observed using HE and Weigert staining; the expression of P-ERK1/2 in the arterioles was detected with immunohistochemistry and Western blotting.. At 16 and 24 weeks of age, the rats in both SHR and ADM groups showed significantly higher SBP levels than WKY rats (P<0.05), and at 24 weeks, SBP was significantly lower in ADM group than in SHR group (P<0.05). The intima thickness/lumen diameter (IT/LD) ratio of the renal arterioles increased in both SHR and ADM groups at 16 and 24 weeks as compared with that of WKY rats (P<0.05), and for arterioles with an outer diameter <40 µm, the IT/LD ratio was significantly lower at 24 weeks in ADM group than in SHR group (P<0.05). The renal expression of p-ERK1/2, which increased significantly in SHR and ADM groups at 16 and 24 weeks (P<0.05), was significantly lower in ADM group than in SHR group at 24 weeks (P<0.05).. Long-term ADM treatment can control SPB elevation in SHR rats and reduce renal arteriole remodeling by inhibiting the phosphorylation of ERK1/2.

Topics: Adrenomedullin; Animals; Arterioles; Blood Pressure; Hypertension; Kidney; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Rats; Rats, Inbred SHR; Rats, Wistar; Vascular Remodeling

The roots of adult hypertension go back to childhood. This study aimed to examine the independent effects of physical, behavioural and genetic factors identified in childhood and mid-adulthood for prediction of adult hypertension.. The study subjects were participants of the Kaunas Cardiovascular Risk Cohort study started in 1977 (n = 1082, age 12-13 years). In 2012, a total of 507 individuals (63.9% of eligible sample) participated in the 35-year follow-up survey. Health examination involved measurements of blood pressure (BP), anthropometric parameters, and interview about health behaviours. Subjects were genotyped for AGT (M235T), ACE (I/D, rs4340), ADM (rs7129220), and CACNB2 (rs12258967) genes polymorphisms. A genetic risk score was calculated as the sum of the number of risk alleles at each of four single nucleotide polymorphisms.. AGT TT genotype male carriers had the highest mean values of systolic BP in childhood. In females, ADM genotype AA was associated with the highest values of systolic and diastolic BP, while CACNB2 genotype CC carriers had the highest values of diastolic BP in childhood. Systolic and diastolic BP in childhood, gain in BMI from childhood to adulthood, and risky alcohol consumption predicted hypertension in middle-aged men. In women, genetic risk score together with diastolic BP in childhood and gain in BMI were significant predictors of adult hypertension. The comparison of four nested logistic regression models showed that the prediction of hypertension improved significantly after the addition of BMI gain. Genetic risk score had a relatively weak effect on the improvement of the model performance in women.. BP in childhood and the gain in BMI from childhood to adulthood were significant predictors of adult hypertension in both genders. Genetic risk score in women and risky alcohol consumption in men were independently related with the risk of adult hypertension.

Topics: Adolescent; Adrenomedullin; Alcohol Drinking; Angiotensinogen; Body Mass Index; Calcium Channels, L-Type; Child; Female; Follow-Up Studies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension; Lithuania; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Prevalence; Risk Factors

Adrenomodulin (ADM) is a peptide hormone secreted in response to cellular strain such as ischemia and is believed to have a beneficial effect on the cardiovascular system. However, the epidemiological relationships between ADM and measurements of haemodynamics, arteriosclerosis and atherosclerosis are not well established. The aim of this study was to investigate the association between the mid-regional part of pro-ADM (MR-proADM) and brachial pulse pressure (PP), carotid intima-media thickness (cIMT) and carotid atherosclerosis.. This study has a cross-sectional design and includes 4924 individuals (mean age 58 years, 40% men) from Malmö, Sweden, examined between 1991 and 1994. Participants underwent physical examination, measurement of MR-proADM and ultrasound of the carotid arteries.. There was a positive association between MR-proADM and brachial PP, cIMT as well as a carotid plaque score. The associations were significant after adjustment for age, sex, BMI, hypertension, diabetes, low-density lipoprotein cholesterol and smoking.. ADM is positively associated with brachial PP and both carotid IMT and plaques, suggesting a role for ADM in early haemodynamic pathophysiology related to arteriosclerosis and the atherosclerotic plaque development.

Topics: Adrenomedullin; Arteriosclerosis; Blood Pressure; Brachial Artery; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cholesterol, LDL; Cohort Studies; Cross-Sectional Studies; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Peptides; Risk Factors; Sex Factors; Smoking

Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL) detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004) and D11S1346 (at 10.6 Mb, P = 0.00000004), suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR), and adrenomedullin (ADM) are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs) within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]). For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]). Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension.

Topics: Adrenomedullin; Adult; Aged; Alleles; Chromosomes, Human, Pair 11; Disease Susceptibility; Essential Hypertension; Female; Gene Order; Genotype; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Italy; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Sex Factors; White People

Genetic factors may determine an individual's blood pressure (BP) level and risk for hypertension. This study aimed to examine the associations between genetic variants of the adrenomedullin (ADM) gene and essential hypertension, as well as BP levels, in a Chinese Han population. In this study, 2410 hypertensive patients and 2346 normal controls were recruited. Three tagging single-nucleotide polymorphisms (SNPs) based on the HapMap CHB data were selected and genotyped. No significant associations between the three SNPs of the ADM gene and hypertension status were observed. However, SNP rs4399321 was found to be associated with BP levels among the controls. GG homozygotes for this SNP had higher systolic BP (SBP) levels than carriers of the A allele (P=0.002). Particularly in non-drinkers, GG homozygotes had significantly higher SBP (116.9±0.9 vs. 113.7±0.3 mm Hg, P=0.001) and diastolic (74.0±0.7 vs. 72.6±0.2 mm Hg, P=0.046) BP levels than carriers of the A allele. Neither rs4910118 nor rs7944706 was associated with BP levels in the controls either before or after being stratified by drinking status. The results of this study showed that genetic variations in the ADM gene were not associated with the risk of hypertension in a Chinese population. However, the genotype at common variation rs4399321 may influence the BP level in normotensive subjects, especially among non-drinkers. In addition, replications in other populations and further functional studies are required to confirm and interpret the association of ADM with BP.

Topics: Adrenomedullin; Adult; Alcohol Drinking; Asian People; Blood Pressure; China; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Heterozygote; Homozygote; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

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

We asked whether plasma concentrations of endothelin-1 (ET-1) or adrenomedullin (ADM) are altered by different activity states of the renin-angiotensin-aldosterone system (RAAS). Levels of ET-1 and ADM were studied in patients with primary aldosteronism (n = 15), essential hypertension (n = 15), and adrenal insufficiency (n = 7). Effects of fludrocortisone, dexamethasone, or spironolactone treatment on ET-1 and ADM levels were also analyzed. Plasma ET-1 and ADM concentrations did not differ significantly between the patient groups. After fludrocortisone, dexamethasone, or spironolactone treatment, both ET-1 and ADM did not change significantly. The data support the hypothesis that the RAAS is not directly linked with the ET-1/ADM system.

Topics: Adrenal Insufficiency; Adrenomedullin; Adult; Anti-Inflammatory Agents; Biomarkers; Dexamethasone; Diuretics; Endothelin-1; Female; Fludrocortisone; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Spironolactone

Adrenomedullin (ADM), a peptide with vasodilatory natriuretic and diuretic properties, is secreted in many tissues and shows multidirectional activity ADM activity may play an important role in the pathophysiology of gestational hypertension (GH) and preeclampsia (PE) by involvement in compensation of failed utero-placental unit circulation.. The aim of the study was to evaluate the association of -1984A>G ADM gene polymorphism with the development of GH and PE in maternal-fetal dyads.. The study group consisted of 46 hypertensive pregnant subjects (further divided into two subgroups: 20 pregnant women with GH and 26 women with PE). 43 healthy pregnant women constituted the control group. The study and the control groups as well as the newborns were genotyped for -1984A>G ADM gene polymorphism using PCR/RLFP procedures.. Minor--1984G allele was found to be higher in both, the GH (15.00%, OR = 3.62, p = 0.05), and the PE groups (9.62, OR = 2.18, p=ns) when compared with controls (4.65%). A tendency for higher frequency of minor -1984G allele (12.50 vs. 6.98% in controls, OR = 1.91, p=ns) was observed in the newborns from the GH group. It was also noteworthy that coexistence of both heterozygous genotypes of maternal-fetal dyads (-1984AG mother/1984AG fetus) was overrepresented in the GH group (15.00 vs. 6.98%, OR = 2.35, p=ns) and in the PE group (11.54 vs. 6.98%, OR = 1.74, p=ns) when compared to controls.. The observed tendency for overrepresentation of minor -1984G ADM allele in the GH and PE women and their newborns, despite lack of statistical significance, suggests participation of this genetic variant in the pathogenesis of the mentioned conditions. Additionally the obtained results could indicate that maternal-fetal gene-gene interaction may be a potential source of adverse perinatal outcomes.

Topics: Adrenomedullin; Adult; Female; Humans; Hypertension; Hypertension, Pregnancy-Induced; Infant, Newborn; Maternal-Fetal Exchange; Pilot Projects; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Risk Factors; Young Adult

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

In subtotal nephrectomy (SN)- and salt-induced hypertension, calcitonin gene-related peptide (CGRP) plays a compensatory role to attenuate the blood pressure increase in the absence of an increase in the neuronal synthesis and release of this peptide. Therefore, the purpose of this study was to determine whether the mechanism of this antihypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide. Hypertension was induced in Sprague-Dawley rats by SN and 1% saline drinking water. Control rats were sham-operated and given tap water to drink. After 11 days, rats had intravenous (drug administration) and arterial (continuous mean arterial pressure recording) catheters surgically placed and were studied in a conscious unrestrained state. Baseline mean arterial pressure was higher in the SN-salt rats (157 ± 5 mmHg) compared with controls (128 ± 3 mmHg). Administration of CGRP (and adrenomedullin) produced a significantly greater dose-dependent decrease in mean arterial pressure in SN-salt rats compared with controls (∼2.0-fold for both the low and high doses). Interestingly, isolated superior mesenteric arterioles from SN-salt rats were significantly more responsive to the dilator effects of CGRP (but not adenomedullin) than the controls (pEC(50), SN-salt, 14.0 ± 0.1 vs. control, 12.0 ± 0.1). Analysis of the CGRP receptor proteins showed that only the receptor component protein was increased significantly in arterioles from SN-salt rats. These data indicate that the compensatory antihypertensive effects of CGRP result from an increased sensitivity of the vasculature to dilator activity of this peptide. The mechanism may be via the upregulation of receptor component protein, thereby providing a more efficient coupling of the receptor to the signal transduction pathways.

Topics: Adrenomedullin; Analysis of Variance; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Blotting, Western; Calcitonin Gene-Related Peptide; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Infusions, Intravenous; Male; Mesentery; Nephrectomy; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin Gene-Related Peptide; Sodium Chloride, Dietary; Time Factors; Vasodilation; Vasodilator Agents

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease. Elevated natriuretic peptides in LVH have spurred interest that biomarkers may play a role in screening programs. Adrenomedullin (ADM) is a 52-amino acid peptide mediating vasorelaxation, natriuresis, and diuresis. The midregional portion of proADM (MRproADM) is secreted stoichiometrically with ADM; hence, it can be used as a surrogate marker of ADM. We compared the diagnostic performance of MRproADM for the detection of LVH with N-terminal pro-B-type natriuretic peptide (NTproBNP). Two hundred fifty-three hypertensive patients were derived from a local screening study. The MRproADM and NTproBNP levels were assayed using immunoluminometric assays. The MRproADM levels were significantly elevated in patients with LVH than those without (mean [SD]: 0.73 [0.25] vs 0.59 [0.18] nmol/L, P < .001). In multivariate analyses, male sex (P < .001) and log MRproADM (P = .003) retained significance for detecting LVH. Receiver operating characteristic curve for MRproADM yielded an area under the curve of 0.71; confidence interval, 0.62-0.81; P < .001, superior to NTproBNP. An optimal cutoff value for MRproADM as an indicator of LVH was 0.50 nmol/L, with a sensitivity, specificity, and negative predictive value of 90.5%, 36.5%, and 95.1%, respectively. The high negative predictive value of the MRproADM assay allows it to be used as a rule-out test for LVH when stratifying patients into high or low risk. Patients who test positive would necessitate echocardiography, enabling better resource allocation.

Topics: Adrenomedullin; Aged; Cardiomegaly; Electrocardiography; Female; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Organ Size; Protein Precursors

Adrenomedullin 2/intermedin (AM2/IMD) is a potent vasodilator peptide with organ-protective effects and is abundantly expressed in the kidney. We examined the expression of AM2/IMD in the kidneys of rats with hypertension or chronic renal impairment using quantitative RT-PCR, radioimmunoassay, and immunohistochemistry. Kidneys of 8-wk-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were dissected into inner medulla, outer medulla, cortex, and glomerulus fractions. A rat renal impairment model was prepared by 5/6 nephrectomy in WKY rats. AM2/IMD mRNA levels were the highest in the cortex among four renal portions, and significantly lower in SHR than WKY rats in all renal portions. In the remnant kidneys of 5/6 nephrectomized rats, AM2/IMD mRNA levels were significantly decreased on days 3 and 56, whereas mRNA levels of calcitonin receptor-like receptor, receptor activity-modifying proteins-1 and -2, which form receptor for AM and AM2/IMD, were increased, compared with that in sham-operated rats. AM mRNA levels were decreased on day 3, but increased on day 56, after nephrectomy. Decreased immunoreactive AM2/IMD levels in the remnant kidneys of 5/6 nephrectomized rats on day 56 were confirmed by radioimmunoassay. The renal tubules were immunostained with anti-AM2/IMD antibody, with a decreased AM2/IMD immunostaining found in proximal tubular cells of 5/6 nephrectomized rats compared with sham-operated rats. In conclusion, intrarenal AM2/IMD expression is decreased in SHR and 5/6 nephrectomized rats. Given the organ-protective effects of AM2/IMD, the downregulation of AM2/IMD as an endogenous regulatory peptide may have a role in the progression of renal impairment.

Topics: Adrenomedullin; Animals; Calcitonin Receptor-Like Protein; Disease Models, Animal; Down-Regulation; Hypertension; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Nephrectomy; Neuropeptides; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Intermedin (IMD), also called adrenomedullin 2 (ADM2), is a 47-amino acid peptide belonging to the calcitonin/calcitonin gene-related peptide (CGRP) family. IMD has similar or more potent vasodilatory and hypotensive actions compared with adrenomedullin (ADM) and CGRP. This study was designed to explore the role of IMD and its receptor in the pathogenesis of spontaneous hypertension and cardiac hypertrophy. Radioimmunoassay was employed to determine plasma immunoreactive IMD concentration and tissue immunoreactive IMD levels in the myocardium and aorta as well as cAMP concentration in the cardiovascular tissues in 13-week-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The mRNA expression of IMD, its receptor, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP)) were determined by semi-quantitative RT-PCR. Protein levels of CRLR and RAMPs were assayed by Western blotting. Our results showed that immunoreactive IMD concentration was enhanced in the SHR myocardium, aortas and plasma. Both the mRNA and protein levels of IMD, as well as those of CRLR and RAMP 1-3 were upregulated in SHRs. IMD affected cAMP generation in the myocardium and aorta, which were not attenuated by prior addition of either CGRP(8-37) or ADM(22-52) alone. These results indicate that the elevation of IMD and its receptor in the cardiovascular tissue may play an important role in the pathogenesis of spontaneous hypertension.

Topics: Adrenomedullin; Animals; Aorta; Calcitonin Receptor-Like Protein; Hypertension; Male; Membrane Proteins; Myocardium; Neuropeptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Calcitonin; RNA, Messenger; Up-Regulation

African Americans with hypertension are prone to target-organ damage and adverse cardiovascular events. Biomarkers for early detection of target-organ damage in this ethnic group are needed. Adrenomedullin (ADM) is a circulating vasoactive peptide with vasodilatory and antiproliferative effects that has been reported to be elevated in adults with hypertension.. We investigated the associations of plasma levels of mid-regional pro-ADM (MR-proADM) with pulse pressure, left ventricular mass (LVM), and albuminuria in 1,034 African-American adults (65 +/- 9 years, 72% women) with hypertension. MR-proADM was measured by an immunoluminometric assay, LVM was assessed by 2-dimensional echocardiography, and albuminuria was assessed by urine albumin:creatinine ratio (UACR). Multivariable regression analyses were used to assess whether plasma MR-proADM was independently associated with pulse pressure, LVM indexed by height to the power 2.7 (LVMi), and UACR.. Plasma MR-proADM was significantly correlated (P < 0.001) with pulse pressure, LVMi, and UACR. In separate multivariable linear regression models that adjusted for age and sex, log MR-proADM was associated with greater pulse pressure (P = 0.007), log LVMi (P = 0.001), and log (UACR+1) (P < 0.0001). After additional adjustment for body mass index (BMI), total and high-density lipoprotein (HDL) cholesterol, smoking history, diabetes, estimated glomerular filtration rate (eGFR), history of myocardial infarction (MI) or stroke, and medication use, log MR-proADM remained significantly associated with greater pulse pressure (P = 0.001), log LVMi (P = 0.029), and log (UACR+1) (P = 0.002).. In African-American adults with hypertension, plasma MR-proADM is independently associated with pulse pressure, LVMi, and albuminuria and is a potential biomarker for target organ damage.

Topics: Adrenomedullin; Aged; Albuminuria; Black or African American; Blood Pressure; Echocardiography; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Proteomics; Ventricular Function, Left

The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.

Topics: Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Female; Hypertension; Hypertrophy; Hypotension; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; Vasculitis

To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-alpha significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-alpha, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.

Topics: Adrenomedullin; Animals; Biomarkers; C-Reactive Protein; Cyclic GMP; Endothelium, Vascular; Hydrazones; Hypertension; Immunosuppressive Agents; Interleukin-6; Male; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha; Vasculitis; Vasodilation

A pilot study was conducted to investigate blood pressure level and vasoactive factors (VFs) among age- and sex-matched normotensive (NT), prehypertensive (PH), and hypertensive (EH) subjects. The results showed that angiotensin, arginine vasopressin, and endothelin were significantly higher, while adrenomedullin and calcitonin gene-related peptide were lower in the EH group than in the PH and NT groups. Nitric oxide synthase was not different among the three groups. There was a dose-response relationship between VFs and BP status. The results suggested that changes in blood VFs might be early warning signs of the development of prehypertension to hypertension, and important biomarkers for the early prevention of prehypertension.

Topics: Adrenomedullin; Adult; Angiotensin II; Arginine Vasopressin; Blood Pressure; Calcitonin Gene-Related Peptide; Case-Control Studies; Endothelins; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Nitric Oxide Synthase; Pilot Projects

Brain injury is a major adverse event after cardiac surgery, especially when extracorporeal circuits are used. We evaluated whether cardiopulmonary bypass (CPB) affects cerebrovascular resistance and plasma concentrations of adrenomedullin (AM), a vasoactive peptide regulating cerebral blood flow.. We evaluated 50 infants (age <1 year) with congenital heart defects, matched according to a 2-year follow-up; 40 infants had no overt neurological injury, and 10 had brain damage. Blood samples were taken before surgery, during surgery before CPB, at the end of CPB, at the end of surgery, and at 12 h after surgery. Neurological outcome was evaluated before surgery, on postoperative day 7, and 2 years after surgery. We measured AM concentrations and used Doppler velocimetry to measure middle cerebral artery (MCA) pulsatility index (PI).. The highest MCA PI values and lowest AM concentrations occurred at the end of CPB and of the surgical procedure. Infants who developed abnormal neurologic sequelae had significantly (P <0.001 for both) higher MCA PI values and lower AM concentrations than patients with normal neurologic outcome at the end of CPB and after surgery. As single markers for predicting neurological abnormalities, AM (cutoff: 17.4 ng/L) achieved a sensitivity of 100% and a specificity of 73.0% and MCA PI (cutoff value: 1.8) a sensitivity of 100% and a specificity of 56.8%.. AM concentrations and MCA PI patterns change during CPB, mainly in infants with brain damage, and may be useful for early identification of infants at risk for brain damage.

Topics: Adrenomedullin; Cardiopulmonary Bypass; Case-Control Studies; Cerebrovascular Circulation; Female; Heart Defects, Congenital; Humans; Hypertension; Infant; Infant, Newborn; Male; Middle Cerebral Artery; Monitoring, Physiologic; Muscle Hypotonia; Predictive Value of Tests; Pulsatile Flow; Seizures; Syndrome

Both inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the cardiac protective peptide adrenomedullin (AM) are increased in cardiac tissues and plasma in patients with myocardial infarction (MI) and chronic heart failure. Recently they have been increasingly recognized as important factors in the pathophysiology of MI and resultant congestive heart failure. Compared with sham-operated spontaneously hypertensive rats (SHR), we investigated myocardial immunoreactivity of TNF-alpha and AM and also their mutual relations in vivo in SHR+MI. Residual myocardial depression after MI was studied also in isolated perfused hearts. In chronic experiments, 24 and 48 h after permanent ligation of the descending anterior branch of the left coronary artery, we examined hemodynamics, plasma and myocardial peptide levels. Left ventricular function was assessed in isolated perfused hearts subjected to "global ischemia and reperfusion" and after induction of "calcium paradox". Circulating and myocardial TNF-alpha concentrations increased early after MI in SHR. Studies with global ischemia and calcium paradox in isolated heart showed early myocardial depression and calcium-dependent gradual increase of left-ventricular end-diastolic pressure. In the SHR+MI myocardial AM concentrations were increased 9- and 49-fold after respective 24 h and culminated 48 h following MI. Circulating and myocardial AM was increased in SHR+MI in association with TNFalpha-induced myocardial depression. The both studied cardiac parameters displayed the beneficial effect of the enhanced myocardial AM concentration.

Topics: Adrenomedullin; Animals; Calcium; Hypertension; Male; Myocardial Infarction; Myocardium; Rats; Rats, Inbred SHR; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial oxidative stress and hypertrophic remodeling. Up-regulation of the cardiomyocyte adrenomedullin (AM) / intermedin (IMD) receptor signaling cascade is also apparent in NO-deficient cardiomyocytes: augmented expression of AM and receptor activity modifying proteins RAMP2 and RAMP3 is prevented by blood pressure normalization while that of RAMP1 and intermedin (IMD) is not, indicating that the latter is regulated by a pressure-independent mechanism.. to verify the ability of an anti-oxidant intervention to normalize cardiomyocyte oxidant status and to investigate the influence of such an intervention on expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes.. NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 35 mg/kg/day) was given to rats for 8 weeks, with/without con-current administration of antioxidants (Vitamin C (25mg/kg/day) and Tempol (25mg/kg/day)).. In left ventricular cardiomyocytes isolated from L-NAME treated rats, increased oxidative stress was indicated by augmented (3.6 fold) membrane protein oxidation, enhanced expression of catalytic and regulatory subunits of pro-oxidant NADPH oxidases (NOX1, NOX2) and compensatory increases in expression of anti-oxidant glutathione peroxidase and Cu/Zn superoxide dismutases (SOD1, SOD3). Vitamin C plus Tempol did not reduce systolic blood pressure but normalized augmented plasma levels of IMD, but not of AM, and in cardiomyocytes: (i) abolished increased membrane protein oxidation; (ii) normalized augmented expression of prepro-IMD and RAMP1, but not prepro-AM, RAMP2 and RAMP3; (iii) attenuated (by 42%) increased width and normalized expression of hypertrophic markers, skeletal-alpha-actin and prepro-endothelin-1 similarly to blood pressure normalization but in contrast to blood pressure normalization did not attenuate augmented brain natriuretic peptide (BNP) expression.. normalization specifically of augmented IMD/RAMP1 expression in NO-deficient cardiomyocytes by antioxidant intervention in the absence of blood pressure reduction indicates that these genes are likely to be induced directly by myocardial oxidative stress. Although oxidative stress contributed to cardiomyocyte hypertrophy, induction of IMD and RAMP1 is unlikely to be secondary to cardiomyocyte hypertrophy.

Topics: Adrenomedullin; Animals; Antioxidants; Blood Pressure; Cardiomegaly; Hypertension; Male; Myocytes, Cardiac; Neuropeptides; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Peptide

Topics: Adrenomedullin; Child; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension; Hypertension, Pulmonary; Male; Nitric Oxide

Adrenomedullin (AM) and intermedin (IMD; adrenomedulln-2) are vasodilator peptides related to calcitonin gene-related peptide (CGRP). The actions of these peptides are mediated by the calcitonin receptor-like receptor (CLR) in association with one of three receptor activity-modifying proteins. CGRP is selective for CLR/receptor activity modifying protein (RAMP)1, AM for CLR/RAMP2 and -3, and IMD acts at both CGRP and AM receptors. In a model of pressure overload induced by inhibition of nitric-oxide synthase, up-regulation of AM was observed previously in cardiomyocytes demonstrating a hypertrophic phenotype. The current objective was to examine the effects of blood pressure reduction on cardiomyocyte expression of AM and IMD and their receptor components. Nomega-nitro-L-arginine methyl ester (L-NAME) (35 mg/kg/day) was administered to rats for 8 weeks, with or without concurrent administration of hydralazine (50 mg/kg/day) and hydrochlorothiazide (7.5 mg/kg/day). In left ventricular cardiomyocytes from L-NAME-treated rats, increases (-fold) in mRNA expression were 1.6 (preproAM), 8.4 (preproIMD), 3.4 (CLR), 4.1 (RAMP1), 2.8 (RAMP2), and 4.4 (RAMP3). Hydralazine/hydrochlorothiazide normalized systolic blood pressure (BP) and abolished mRNA up-regulation of hypertrophic markers sk-alpha-actin and BNP and of preproAM, CLR, RAMP2, and RAMP3 but did not normalize cardiomyocyte width nor preproIMD or RAMP1 mRNA expression. The robust increase in IMD expression indicates an important role for this peptide in the cardiac pathology of this model but, unlike AM, IMD is not associated with pressure overload upon the myocardium. The concordance of IMD and RAMP1 up-regulation indicates a CGRP-type receptor action; considering also a lack of response to BP reduction, IMD may, like CGRP, have an anti-ischemic function.

Topics: Adrenomedullin; Animals; Body Weight; Hydralazine; Hydrochlorothiazide; Hypertension; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myocytes, Cardiac; Myosin Heavy Chains; Neuropeptides; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Size; Peptides; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Systole

Adrenomedullin (AM) is a multifunctional regulatory peptide, and endogenous AM is an important factor in regulating cardiovascular and renal homeostasis as a potent cardio-reno-protective factor. To illustrate the protective mechanism of adrenomedullin (AM) on the cardiovascular system by observing (1) the changes in mRNA and protein levels of AM and its receptor-calcitonin receptor-like receptor (CL) and receptor activity-modifying proteins (RAMPs)-in myocardia and aortas of spontaneously hypertensive rats (SHRs) and (2) the response of cardiovascular tissue to AM. The AM content and cyclic adenosine monophosphate (cAMP) production in myocardia and aortas were measured in SHRs and Wistar Kyoto (WKY) rats (11-week-old) by radioimmunoassay (RIA). The mRNA levels of brain natriuretic peptide (BNP), AM, CL, RAMP1, -2, -3 were determined by semi-quantitative RTPCR. Protein levels of CL, RAMP1, -2, -3 were assayed by Western blotting. SHRs had severe hypertension, and the tail-blood pressure was 76.7% higher, the ratio of heart weight to body weight (heart coefficient) 45.5% higher, and the BNP gene expression 4.5-fold higher than that of WKY rats (all p < 0.01). The AM-ir content in plasma, myocardia and aortas of SHRs increased by 42.5%, 68.3% and 80.4%, respectively (all p < 0.01) compared with WKY rats. Furthermore, the mRNA levels of AM, CL, RAMP1, RAMP2 and RAMP3 were elevated by 46% (p < 0.01), 62% (p < 0.05), 51.2% (p < 0.01), 41% (p < 0.01) and 54% (p < 0.01), respectively, in myocardia and by 72%, 87%, 155%, 53% and 74% (all p < 0.01), respectively, in aortas. The elevated mRNA level of CL, RAMP1 RAMP2 and RAMP3 correlated positively with that of AM mRNA in hypertrophic myocardia (r= 0.943, 0.621, 0.688 and 0.633, respectively, all p < 0.01) and aortas (r = 0.762, 0.892, 0.828 and 0.736, respectively, all p < 0.01). The protein levels of CL, RAMP1, RAMP2 and RAMP3 in myocardia and aortas of SHRs were increased compared with that of WKY rats. The response to AM was potentiated in myocardia and aortas in SHRs, and the production of cAMP was increased by 47% and 65% (both p < 0.01), respectively. AM-stimulated cAMP generation in myocardia and aortas was blocked by both AM(22-52), the specific antagonist of AM, and calcitonin gene-related peptide (CGRP)(8-37), the antagonist of the CGRP1 receptor. In myocardia and aortas of SHRs, the gene expressions and protein levels of AM, CL, RAMP1, RAMP2 and RAMP3 were increased, and the response to AM was potentiat

Topics: Adrenomedullin; Animals; Aorta; Blood Pressure; Blotting, Western; Calcitonin Receptor-Like Protein; Cardiomegaly; Cyclic AMP; Hypertension; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myocardium; Natriuretic Peptide, Brain; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

The hypotensive peptide adrenomedullin (AM) is assumed to act as a factor inhibitory on elevation of blood pressure and on progression of the hypertensive organ damage, and plasma AM levels are elevated in patients with hypertension. The aim of the present study is to explore whether or not a rise in plasma AM levels precedes the development of hypertension. Normotensive local residents without apparent cardiovascular or renal disease (n = 177) were divided into low and high AM groups based on the median concentration of AM in plasma (11.9 fmol/ml), and followed up for 3 years for development of hypertension. The incidence of hypertension was higher in the residents with high AM than low AM levels (27.8 vs 11.5%, P < 0.01), whereas a similar analysis of plasma levels of atrial or brain natriuretic peptides revealed no such difference. The plasma AM level was found to be a significant parameter for the development of hypertension in a univariate analysis (P < 0.01), but not in a multivariate analysis. Meanwhile, the plasma AM level was significantly (P < 0.01) correlated with age and body mass index (BMI), two variables independently significant for the development of hypertension. The present findings suggest that an elevation of the plasma AM level associated with aging and increased BMI precedes the development of hypertension in the normotensive subjects.

Topics: Adrenomedullin; Female; Humans; Hypertension; Male; Middle Aged; Regression Analysis; Risk Assessment

We examined the effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. Spontaneously hypertensive rats (SHRs) were treated with one of the following combinations for 4 weeks: tap water and vehicle [0.5% ethanol, subcutaneously (s.c.), n = 5], 1% NaCl in drinking water and vehicle (n = 8), 1% NaCl and aldosterone (0.75 microg/h s.c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 microg/kg/h s.c., n = 8). Systolic blood pressure (SBP) and left ventricular (LV) weight were higher in aldosterone-treated SHRs than vehicle- or vehicle/1% NaCl-treated SHRs. Thiobarbituric acid reactive substances (TBARS) levels and NADPH oxidase activity in LV tissues of aldosterone-treated SHRs were also higher than those of vehicle- or vehicle/1% NaCl-treated SHRs, and these changes were associated with increases in LV mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content. Treatment with adrenomedullin did not alter SBP or LV weight but attenuated aldosterone-induced increases in TBARS levels, NADPH oxidase activity, and mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content in LV tissues. These data suggest that NADPH oxidase-mediated reactive oxygen species production is involved in the pathogenesis of cardiac collagen accumulation in aldosterone-dependent malignant hypertensive rats and that the cardioprotective effects of adrenomedullin are mediated through the suppression of this pathway.

Topics: Adrenomedullin; Aldosterone; Animals; Blood Pressure; Cardiotonic Agents; Collagen; Fibronectins; Heart; Hypertension; Male; Myocardium; NADPH Oxidases; Oxidative Stress; Peptides; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sodium

Topics: Adrenomedullin; Animals; Blood Pressure; Humans; Hypertension

Hypertension frequently occurs in obese subjects. It has been reported that leptin and resistin induce endothelin-1 expression in vascular endothelial cells. Altered function of brain microvascular endothelial cells may be related to increased occurrences of stroke in hypertensive patients. In the present study, we therefore studied the effects of leptin and resistin on the expression of endothelin-1 and adrenomedullin in bovine brain microvascular endothelial cells. Northern blot analysis showed that leptin (10(-10)-10(-8) mol/l), resistin (10(-10)-10(-8) mol/l) or a combination of leptin and resistin (10(-8) mol/l for each) had no significant effects on the expression of endothelin-1 mRNA or adrenomedullin mRNA in cultured bovine brain microvascular endothelial cells. On the other hand, hypoxia induced, and tumor necrosis factor-alpha (10 ng/ml) decreased, the expression levels of endothelin-1 and adrenomedullin mRNAs, indicating that the bovine brain microvascular endothelial cells were able to respond to hypoxia and tumor necrosis factor-alpha. Consistent with the results of Northern blot analysis, immunoreactive endothelin and immunoreactive adrenomedullin concentrations in the medium were not significantly changed by the treatment with leptin, resistin, or a combination of leptin and resistin. The present study thus showed that neither leptin nor resistin affects the expression of endothelin-1 or adrenomedullin in bovine brain microvascular endothelial cells.

Topics: Adrenomedullin; Animals; Brain; Cattle; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Hypertension; Hypoxia; Leptin; Microcirculation; Peptides; Resistin; RNA, Messenger; Stroke; Tumor Necrosis Factor-alpha

We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats.. We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues.. SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system.. Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.

Topics: Adrenomedullin; Aldosterone; Animals; Collagen Type I; Disease Models, Animal; Diuretics; Gene Expression Regulation; Hypertension; Kidney; Lymphotoxin-alpha; Male; Peptides; Rats; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; RNA, Messenger

The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia.. Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89.. AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.

Topics: Actins; Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Body Weight; Cardiotonic Agents; Cell Differentiation; Cell Division; Cell Size; Collagen Type I; Connective Tissue; Fibroblasts; Heart Ventricles; Humans; Hypertension; Male; Myocytes, Cardiac; Peptides; Rats; Rats, Wistar; Recombinant Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

Adrenomedullin (AM) is a hypotensive peptide that functions as an important regulator in the cardiovascular and renal systems. The current study explored the potential therapeutic effects of delivering the human AM cDNA via a novel double-stranded adeno-associated virus vector (dsAAV) on hypertension and related complications in spontaneously hypertensive rats (SHR). A single dose of dsAAV-AM vector administered by tail vein injection into adult SHR resulted in significant reduction of systolic blood pressure at 2 weeks after gene delivery. This effect was observed through the entire duration of the experiment period (up to 16 weeks). Administration of dsAAV-AM also resulted in a decrease in total urine microalbumin content. Left ventricle and cardiomyocyte hypertrophy, fibrosis in the heart, glomerular sclerosis, and tubular injuries in the kidney were significantly reduced. Moreover, deterioration of hemodynamic variables was prevented in treated rats, as compared with the control groups. We conclude that AAV-mediated AM delivery can render a longterm and stable reduction of hypertension and protect against renal injury and cardiac remodeling in the spontaneously hypertensive rat model. Further preclinical studies are warranted for the development of a gene therapy strategy for human hypertension.

Topics: Adenoviridae; Adrenomedullin; Albuminuria; Animals; Blood Pressure; Cardiovascular Diseases; DNA Primers; Enzyme-Linked Immunosorbent Assay; Genetic Therapy; Genetic Vectors; Heart; Hypertension; Kidney; Male; Organ Size; Peptides; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction

To investigate the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand and amidating activity in the hypertrophied heart in severe hypertension.. The following four groups were studied: 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 was converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly was converted to active mature AM (AM-m) by enzymatic amidation. AM-m, AM-total (AM-T; AM-T = AM-m + AM-Gly), atrial natriuretic peptide (ANP) in the plasma and left ventricle (LV) by immunoradiometric assay, and gene expression of AM and ANP were measured.. 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 the plasma (AM-m: +31%; AM-T: +56%) and in the LV (AM-m: +84%; AM-T: +31%) were significantly higher in SHR-SP than those in WKY. The LV tissue AM-m/AM-T ratio was significantly higher in SHR-SP (93.2%) than that in WKY. The mRNA levels of AM in the LV were significantly higher in SHR-SP than those 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.. These results suggested that cardiac AM system was upregulated in the hypertrophied heart in this hypertension model. Considering that AM being as an antiremodeling autocrine and(or) paracrine factor, upregulation of the AM system may modulate the pathophysiological course in LV hypertrophy.

Topics: Adrenal Glands; Adrenomedullin; Animals; Hypertension; Hypertrophy, Left Ventricular; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Up-Regulation

We developed a transgenic (Tg) rat model that overexpresses human proadrenomedullin N-terminal 20 peptide (PAMP) only and then compared the effects of unilateral nephrectomy followed by a high salt diet for five weeks in Tg and wild-type rats. We found that systolic blood pressure was significantly lower in Tg UNX rats and cardiac hypertrophy and myocardial fibrosis was also attenuated in Tg rats. Evaluation of gene expression showed suppression of cardiac local renin-angiotensin system (RAS) in Tg rat. These results suggest that in addition to reducing blood pressure, PAMP suppresses cardiac hypertrophy through negative regulation of the local cardiac RAS.

Topics: Adrenomedullin; Animals; Animals, Genetically Modified; Blood Pressure; Cardiomegaly; Diet; Fibrosis; Humans; Hypertension; Kidney; Myocardium; Peptide Fragments; Protein Precursors; Proteins; Rats; Renin-Angiotensin System; Salts; Transgenes

In this work, we aimed to observe the changes in adrenomedullin (ADM) and its receptor-calcitonin receptor-like receptor (CL), receptor activity-modifying protein (RAMP) 1, RAMP2 and RAMP3-in cardiac ventricles and aortas of hypertensive rats, and the responsiveness of injured cardiovascular tissue to ADM, then to illustrate the protective mechanism of ADM on the cardiovascular system. Male SD rats were subjected to treatment with chronic N(G)-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. The ADM contents and cAMP production in myocardia and aortas were measured by RIA. The mRNA levels of ADM, CL, and RAMP1-3 were determined by RT-PCR. L-NNA induced severe hypertension and cardiomegaly. The ir-ADM content in plasma, ventricles and aortas in L-NNA-treated animals increased by 80%, 72% and 57% (all p<0.01), respectively. Furthermore, mRNA levels of ADM, CL, RAMP2 and RAMP3 were elevated by 91%, 33%, 50% and 72.5% (all p<0.01), respectively, in ventricles and by 95%, 177%, 74.7% and 85% (all p<0.01), respectively, in aortas. mRNA level of RAMP1 was elevated by 129% (p<0.01) in aortas but no significant difference in ventricles. The elevated mRNA levels of RAMP2 and RAMP3 were positively correlated with that of ADM in hypertrophic ventricles (r=0.633 and 0.828, p<0.01, respectively) and the elevated mRNA levels of CL, RAMP2 and RAMP3 were positively correlated with that of ADM in aortas (r=0.941, 0.943 and 0.736, all p<0.01, respectively). The response of ventricular myocardia and aortas to ADM administration potentiated, and the production of cAMP was increased by 41% and 68% (both p<0.01), respectively. ADM-stimulated cAMP generation in ventricular myocardia and aortas was blocked by administration of both ADM22-52, the specific antagonist of ADM receptor, and CGRP8-37, the antagonist of the CGRP1 receptor. The results showed an increased in cardiovascular ADM generation and an up-regulation of the gene expression of ADM and its receptor-CL, RAMP1-3 during hypertension, augmented responsiveness of ventricular myocardia and aortas of hypertensive rats to ADM, suggesting that these receptors may play a role in the cardiovascular adaptation in response to sub-chronic NO-inhibition.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Aorta; Cyclic AMP; Disease Models, Animal; Enzyme Inhibitors; Heart; Heart Ventricles; Hypertension; Intracellular Signaling Peptides and Proteins; Male; Myocardium; Nitroarginine; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Previous studies demonstrated that adrenomedullin (AM) is metabolized by neutral endopeptidases and that the renal effect of AM is augmented by the inhibition of neutral endopeptidases. We have recently shown that the long-term administration of AM has renoprotective effects.. This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved.. We studied the following four groups: control Dahl salt-resistant (DR) rats, untreated Dahl salt-sensitive (DS) rats, omapatrilat (35 mg/kg per day)-treated DS rats; and human AM (500 ng/h) plus omapatrilat-treated DS rats. After 7 weeks' treatment, blood pressure, renal function, neurohumoral factors, gene expression levels, and histological findings were examined.. DS rats were characterized by increased blood pressure, decreased renal function, abnormal histological findings, and increased gene expression of collagen I and III, transforming growth factor beta (TGF-beta), and NADPH oxidase subunits (p40phox, p47phox, and gp91phox) in the renal cortex compared with DR rats. Compared with DS rats, omapatrilat significantly decreased systolic blood pressure (-26 mmHg), improved renal function, histological findings, and messenger RNA expression levels of collagen I, collagen III, and TGF-beta. Combined treatment with omapatrilat and AM further improved renal function, histological findings, and mRNA expression levels of collagen I, collagen III, and TGF-beta, without a further reduction in blood pressure. Only combined treatment decreased mRNA levels of p40phox, p47phox, and gp91phox. There were no differences in plasma AM or atrial natriuretic peptide levels among three DS groups.. Our results suggest that combined treatment with omapatrilat and AM provides additional renoprotective effects independent of blood pressure-lowering activity partly via inhibition of gene expressions of oxidative stress and extracellular matrix.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Collagen Type I; Collagen Type III; Drug Therapy, Combination; Gene Expression; Humans; Hypertension; Kidney; Male; Oxidative Stress; Peptides; Protease Inhibitors; Pyridines; Rats; Rats, Inbred Dahl; Recombinant Proteins; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

Obstructive sleep apnea (OSA) is associated with hypertension. The vasorelaxing peptide adrenomedullin (ADM) may counteract effects of OSA-induced release of vasopressor substances.. Plasma ADM levels were measured at 9:30 PM, 2:00 AM (after 4 to 5 h of untreated OSA), and 6:00 AM (after 4 h of continuous positive airway pressure treatment) in 15 OSA patients and in 10 controls.. Baseline ADM levels were similar in the OSA and control groups (28.7 +/- 6.7 v 27.7 +/- 6.4 pg/mL, respectively), did not change overnight in either group, and were not affected by continuous positive airway pressure.. OSA does not exert any significant acute or chronic effects on plasma ADM levels.

Topics: Adrenomedullin; Adult; Body Mass Index; Continuous Positive Airway Pressure; Humans; Hypertension; Male; Middle Aged; Peptides; Polysomnography; Sleep Apnea, Obstructive

We examined whether adrenomedullin, a vasoactive peptide expressed in the heart, modulates the increase in blood pressure, changes in systolic and diastolic function, and left ventricular hypertrophy produced by long-term administration of ANG II or norepinephrine in rats. Subcutaneous administration of adrenomedullin (1.5 microg.kg(-1).h(-1)) for 1 wk inhibited the ANG II-induced (33.3 microg.kg(-1).h(-1) sc) increase in mean arterial pressure by 67% (P < 0.001) but had no effect of norepinephrine-induced (300 microg.kg(-1).h(-1) sc) hypertension. Adrenomedullin enhanced the ANG II-induced improvement in systolic function, resulting in a further 9% increase (P < 0.01) in the left ventricular ejection fraction and 19% increase (P < 0.05) in the left ventricular fractional shortening measured by echocardiography, meanwhile norepinephrine-induced changes in systolic function were remained unaffected. Adrenomedullin had no effect on ANG II- or norepinephrine-induced left ventricular hypertrophy or expression of hypertrophy-associated genes, including contractile protein and natriuretic peptide genes. The present study shows that adrenomedullin selectively suppressed the increase in blood pressure and augmented the improvement of systolic function induced by ANG II. Because adrenomedullin had no effects on ANG II- and norepinephrine-induced left ventricular hypertrophy, circulating adrenomedullin appears to act mainly as a regulator of vascular tone and cardiac function.

Topics: Adrenomedullin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Body Weight; Echocardiography; Heart; Heart Rate; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Norepinephrine; Peptides; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Proteins; Receptor, Angiotensin, Type 1; Receptors, Adrenomedullin; Receptors, Peptide; Reverse Transcriptase Polymerase Chain Reaction; Telemetry; Vasoconstrictor Agents; Vasodilator Agents

Adrenomedullin (ADM) is a multifunctional peptide with important roles in the cardiovascular system, especially in the adjustment of cardiovascular and renal homeostasis. ADM is present in plasma, organs and tissues, and its activity increases during hypertension. It remains unknown whether the clearance of this peptide is altered during hypertension. Neutral endopeptidase (NEP) is the major enzyme in ADM's degradation. We observed the activity and distribution of NEP and the expression of its mRNA in the plasma, cardiac ventricle, aorta, jejunum and kidney of spontaneously hypertensive rats (SHRs) in order to study the possible role of NEP in elevating tissue ADM concentrations during hypertension. ADM and NEP were diffuse in all tissues studied. The level of tissue ADM was generally higher in SHR tissues than in control tissues, except in the renal medulla, and its mRNA expression was higher in all tissues. Plasma NEP activity, general NEP activity and the expression of NEP mRNA in the left ventricle, aorta and jejunum in SHRs was lower than that of controls, and the level of ADM was inversely correlated with NEP activity. NEP activity and mRNA and protein expression in SHR kidneys were higher than in control kidneys; moreover, the ADM content was positively correlated with NEP activity in the renal cortex. NEP activity in the lung of SHRs did not differ from that of controls. Thus, in SHRs, the local concentration and action of ADM in the tissues may be differentially regulated by NEP.

Topics: Adrenomedullin; Animals; Aorta; Gene Expression; Hypertension; Immunohistochemistry; Jejunum; Kidney; Lung; Male; Myocardium; Neprilysin; Peptides; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY

MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.

Topics: Adrenomedullin; Animals; Blood Pressure; Cell Line; Chemical Fractionation; Chromatography, High Pressure Liquid; Cyclic AMP; Fibroblasts; Humans; Hypertension; Hypotension; Male; Matrix Metalloproteinase 2; Peptide Fragments; Peptides; Rats; Rats, Inbred Lew; Receptors, Adrenomedullin; Receptors, Peptide; Substrate Specificity; Urine; Vasoconstrictor Agents; Vasodilator Agents

This animal experiment was aimed at the questions whether high glucose concentration inhibits insulin secretion (glucose toxicity, GT) of beta-cell of islets from SHR and Wistar-Kyoto (WKY) rat and whether adrenomedullin (AM) enhances GT. Ten 6-week-old SHRs (test group) and ten 10-week-old Wistar-Kyoto rats (WKY) (control group) were selected. RAMI-1640 medium containing 5.6 mM glucose (normal glucose group) and 20 mM glucose (high glucose group) were applied. Various concentrations of AM (0, 10(-8), 10(-7), 10(-6) M) and RPMI-1640 medium containing high glucose were mixed, respectively. The isolated islets from rats were put into 12-well plates (90 islets/well). The islets were incubated in RAMI-1640 medium containing normal or high glucose for one hour. Then the supernatants from both incubations were determined by RIA for insulin. In SHR group, the insulin concentration in supernatants gained from high glucose group without AM was lower than that from normal glucose group (19.9+/-6.6 vs 60.9+/-33.6 mU/L, P<0.05). With the increment of the concentration of AM, insulin concentration in supernatants from islets incubated in high glucose and various concentrations of AM tended to be low further (19.9+/-6.6 vs 22.2+/-8.0 vs 21.5+/-5.6 vs 17.9+/-3.6 mU/L). The changing tendency in control group was the same as in SHR group. When the islets were incubated in normal glucose and high glucose medium, the insulin concentration in supernatant significantly decreased in SHR group compared with that in control group (P<0.01). The insulin secretion was inhibited by high glucose in beta-cell of islets from SHR and WKY. The results suggest GT to beta-cell of islets from SHR and WKY. AM tended to inhibit insulin secretion in a dose-dependent manner in beta-cell of islets from SHR and WKY. The inhibition of insulin secretion caused by high glucose in beta-cell of islets from SHR was more remarkable than from WKY. This may be related to secretion dysfunction in beta-cell of islets from SHR.

Topics: Adrenomedullin; Animals; Blood Glucose; Cells, Cultured; Female; Glucose; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY

In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the changes in mRNAs levels of preproadrenomedullin (ppADM) gene encoding adrenomedullin (ADM) and the essential receptor components of ADM, calcitonin receptor-like receptor (CRLR), and the receptor activity modifying protein 2 and 3 (RAMP2 and RAMP3) in the medulla oblongata, hypothalamus, midbrain, pituitary gland and adrenal gland of the stress-induced hypertensive rats. It was shown that chronic foot-shock and noise stress for 15 consecutive days induced a significant increase in systolic blood pressure (SBP) and unique changes in ppADM and its receptor components mRNAs in all areas studied. As compared with the control group, the level of ppADM mRNA, normalized against a glyceraldehydes-3-phosphate dehydrogenase (GAPDH) control, was up-regulated in the hypothalamus-pituitary-adrenal (HPA) axis, but down-regulated in the medulla oblongata and midbrain (P<0.01 and P<0.05, respectively). The relative amount of CRLR mRNA was higher in the hypothalamus than that in other areas. The level of CRLR mRNA expression was significantly increased in the medulla oblongata of the stress group (P<0.01), but decreased in the midbrain (P<0.01) as well as hypothalamus(P<0.05), as compared with that of the control group. Chronic stress for 15 consecutive days produced an increase in the level of RAMP2 mRNA expression in the medulla oblongata (P<0.01) and a decrease in the adrenal gland (P<0.01), as compared with the control. No significant stress-related changes in RAMP2 mRNA were observed in the midbrain, hypothalamus and pituitary gland. The amount of RAMP3 mRNA was relatively higher in the midbrain and hypothalamus than that in the medulla oblongata, adrenal gland and adrenal gland. Stress-induced hypertensive rats exhibited an increased RAMP3 mRNA expression in the hypothalamus and pituitary gland (P<0.01 and P<0.05, respectively) and a decrease in the adrenal gland and midbrain (P<0.05). No significant stress-related change in RAMP3 mRAN was observed in the medulla oblongata. Taken together, our results indicate that the significant changes in ppADM and its receptor components mRNAs expression in the HPA axis and autonomic centers may be related to the development of the stress-induced hypertension. Nevertheless, the pathophysiological significance of brain-derived ADM and its receptors in stress and blood pressure regulation and their roles in stress-induced hypertension st

Topics: Adrenomedullin; Animals; Brain Stem; Hypertension; Hypothalamo-Hypophyseal System; Male; Peptides; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Stress, Physiological

The aim of the study was to evaluate plasma adrenomedullin (AM) concentration in primary hyperparathyroidism (PHP) and its effect on the regulation of blood pressure. Forty-one patients with PHP (25 normotensive and 16 hypertensive), and 31 healthy subjects (HS) were included in the study. As expected the total and ionized calcium and i-PTH serum levels were significantly higher in patients with PHP than in HS (P <.001). No significant difference was found in calcium-phosphorus metabolism parameters between normotensive and hypertensive PHP patients. Serum i-PTH levels correlated positively with systolic blood pressure (SBP) (r = 0.510; P <.02), diastolic blood pressure (DBP) (r = 0.586; P <.01) and heart rate (HR) (r = 0.486; P <.043) only in hypertensive PHP patients. Overall, mean plasma AM concentrations were significantly higher in PHP patients (16.1 +/- 7.9 pg/mL) than in HS (11.3 +/- 4.8 pg/mL) (P <.003) and correlated with i-PTH (r = 0.430; P <.005). However, in hypertensive PHP patients plasma AM levels (22.5 +/- 4.7 pg/mL) were higher than in normotensive PHP patients (11.6 +/- 1.8 pg/mL) (P <.001) and correlated with DBP (r = 0.902, P <.0029). In HS no correlation was found between plasma AM values and biohumoral, hormonal, or hemodynamic parameters. In conclusion, we demonstrated that in patients with PHP, plasma AM concentrations are increased and correlate with i-PTH and blood pressure values. We suggest that increased AM levels could be a compensatory factor in the defence mechanism against further blood pressure elevation.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Blood Pressure; Calcium; Female; Heart Rate; Humans; Hyperparathyroidism; Hypertension; Male; Middle Aged; Osmolar Concentration; Parathyroid Hormone; Peptides; Reference Values

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

The peptides derived from post-translational processing of preproadrenomedullin are produced in and act on areas of the autonomic nervous system important for blood pressure regulation. We examined the role of endogenous, brain-derived adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in the central nervous system arm of the baroreflex by using passive immunoneutralization to block the actions of the endogenous peptides. Our results indicate that the preproadrenomedullin-derived peptides do not play a role in sensing changes in blood pressure (baroreflex sensitivity), but the adrenomedullin peptides do regulate the speed with which an animal returns to a normal, stable blood pressure. These findings suggest that endogenous, brain-derived AM and PAMP participate in the regulation of autonomic activity in response to baroreceptor activation and inactivation.

Topics: Adrenomedullin; Animals; Baroreflex; Blood Pressure; Hypertension; Hypotension; Male; Peptides; Phenylephrine; Rats; Rats, Sprague-Dawley; Systole; Triazenes

Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the exact mechanisms regulating cardiac AM gene expression are unknown. The aim of the present study was to characterize the role of mechanical load in regulating gene expression of AM by using two hypertensive rat strains as experimental models. Acute pressure overload was produced by arginine(8)-vasopressin (AVP, 0.05 microg/kg/min, i.v.) infusion in conscious spontaneously hypertensive rats (SHR) and double transgenic rats (dTGR) harboring both the human renin and angiotensinogen genes and in their respective normotensive strains. A significant increase in left ventricular AM mRNA levels was seen in the left ventricles of all rat strains, the increase being augmented in hypertensive strains. Direct left ventricular wall stretch in isolated, perfused rat heart preparation also activated AM gene expression. However, stretching of cultured neonatal ventricular myocytes resulted in inhibition of AM gene expression, and stretch also blocked hypoxia-induced increase in AM gene expression. The present study shows that cardiac AM gene expression is upregulated in response to pressure overload and that this upregulation may be mediated via cell types other than cardiac myocytes.

Topics: Adrenomedullin; Animals; Arginine Vasopressin; Gene Expression Regulation; Heart Ventricles; Humans; Hypertension; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peptides; Pressure; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; RNA, Messenger

Topics: Adrenomedullin; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Insulin; Male; Middle Aged; Oxidative Stress; Peptides

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

To study the effects of adrenomedullin (AM) on secretory function of pancreatic islet in spontaneously hypertensive rat (SHR) and Wistar-kyoto (WKY) rat.. Ten SHRs (test group) and ten WKY rats (control group) were used. The pancreatic islets isolated from SHR and WKY rats were put into 12-well plates. The islets were incubated in RPMI-1640 medium containing 2.8 mmol/L glucose (low glucose group) for 45 minutes. The second incubation was performed in RPMI-1640 medium containing 11.1 mmol/L glucose (high glucose group) and various concentrations of AM (0, 10(-8), 10(-7), 10(-6) mol/L, respectively) for 24 hours. The supernatants from both incubations were tested by RIA for insulin and glucagon.. The insulin concentrations in supernatants collected from the islets of WKY rats incubated in high glucose and various concentrations of AM for 24 hours were decreased in the dose dependent manner. When the islets of WKY rats and SHR were incubated in AM of high concentration (10(-6) mol/L), the insulin concentrations in supernatants decreased significantly. When the islets of SHR were incubated in high glucose and various concentrations of AM for 24 hours, the glucagon concentrations in supernatants were not significantly different.. The above results demonstrate that AM inhibits insulin secretion in beta cell of islets of WKY rats in dose dependent manner, that AM that AM of high concentration inhibits insulin secretion in beta cell of islets of SHR, and that AM has no influence on the function of alpha cell of islets. These suggest that AM may contribute to the impaired beta cell function during the development of diabetes mellitus.

Topics: Adrenomedullin; Animals; Dose-Response Relationship, Drug; Female; Glucagon; Hypertension; Insulin; Insulin Secretion; Islets of Langerhans; Male; Peptides; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats.. Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks.. Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations.. The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.

Topics: Adrenomedullin; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Heart; Hypertension; Male; Models, Cardiovascular; Neprilysin; Organ Size; Peptides; Pyridines; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin; Severity of Illness Index; Systole; Treatment Outcome; Vasoconstrictor Agents

To explore the changes in adrenomedullin (ADM) and receptor activity-modifying protein 2 (RAMP2) mRNA in myocardium and vessels in hypertension, a hypertensive rat model was prepared by administering L-NNA. Contents of ADM in plasma, myocardium and vessels were measured by radioimmunoassay (RIA). The levels of pro-ADM mRNA of myocardium and vessels were determined by competitive quantitative RT-PCR. The results showed that L-NNA induced hypertension and cardiomegaly. The ratio of heart to body weight increased by 35.5% (P<0.01). In hypertensive rats the ir-ADM in plasma, myocardium and vessels was increased by 80%, 72% and 57% (P<0.01), respectively compared with the control. The amounts of ADM mRNA in myocardium and vessels were increased by 50% and 109.2% (P<0.05), respectively, and the amounts of RAMP2 mRNA was increased by 132% and 87% (P<0.01), respectively, compared with control. The levels of ADM in myocardium and vessels were positively correlated with RAMP2 mRNA, the correlation coefficients were 0.741 and 0.885 (P<0.01), respectively. The results obtained indicate that in hypertensive rats, ADM is elevated in plasma, myocardium and ves-myocardium and vessel, and ADM and RAMP2 mRNA are up-regulated in myocardium and vessel. The ADM/RAMP2 system may play an important role in the pathogenesis of hypertension.

Topics: Adrenomedullin; Animals; Cardiomegaly; Hypertension; Myocardium; Nitroarginine; Rats; Receptor Activity-Modifying Protein 2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Adrenomedullin (AM) is a novel peptide, first isolated from human phaeochromocytoma, which elicits a long-lasting vasorelaxant activity. Recently, it has been reported that endothelial cells produce AM and that immunoreactive AM plasma levels may be elevated in human arterial hypertension, although the exact pathophysiological role of AM remains to be established. The aim of our study was to determine the relationship between the components of the enin-angiotensin-aldosterone system (RAAS) and plasma AM levels in patients with low-, medium- or high- renin essential hypertension. The study groups included 10 patients with low-renin essential hypertension (average age 42+15 years), nine patients with medium-renin essential hypertension (46+13 years), 11 patients with high-renin essential hypertension (42+14 years) and 12 healthy subjects (43+11 years). Our results demonstrated that the mean AM values of all patients with essential hypertension were 10.85+3.14 pg/ml; there was a statistical correlation (r=0.705; p<0.001) between plasma renin activity (PRA) and AM levels in hypertensives. In patients with high-renin essential hypertension, plasma AM levels (14.2+2.2 pg/ml) were significantly higher (p<0.001) than those of healthy subjects (8.7+2.1 pg/ml), patients with medium-renin essential hypertension (8.5+1.4 pg/ml), and patients with low-renin essential hypertension (9.1+1.5 pg/ml). There was no statistical difference in AM concentrations between medium- and low-renin hypertensive patients. In conclusion, we have found that, in hypertensive patients, plasma AM levels were increased only in high-renin individuals, suggesting a role of AM in this particular form of human essential hypertension.

Topics: Adrenomedullin; Adult; Aldosterone; Humans; Hypertension; Middle Aged; Peptides; Renin

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

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor beta (TGF-beta) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine -87%, creatinine clearance +114%, urinary protein excretion -59%) and histological findings (glomerular injury score -54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (-97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (-269%), aldosterone level (-82%), and renal tissue angiotensin II levels (-60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-beta (- 63%), angiotensin-converting enzyme (-137%), renin (-230%), and angiotensinogen (-38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Topics: Adrenomedullin; Angiotensin II; Animals; Creatinine; Drug Implants; Glomerulonephritis; Hormones; Hypertension; Kidney; Male; Peptides; Proteinuria; Rats; Rats, Inbred Dahl; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride; Time Factors; Transforming Growth Factor beta

Human adrenomedullin precursor is converted to glycine-extended adrenomedullin (AM-Gly), an intermediate inactive form of adrenomedullin. Subsequently, AM-Gly is converted to active form of mature adrenomedullin (AM-m). The aim of the present study was to investigate (i) whether sex or age influences plasma and urinary AM-m and AM-Gly levels in normal subjects; (ii) the daytime variability of plasma AM-m and AM-Gly levels in normal subjects; (iii) AM-m and AM-Gly levels and its ratio in plasma and urine in normal subjects, individuals with essential hypertension (HT), and chronic renal failure (CRF); and (iv) the ratio of AM-m and AM-total (T) in plasma of various veins and aorta.. We measured plasma levels and urinary excretions of AM-m, AM-Gly and AM-T (AM-m + AM-Gly) by recently developed immunoradiometric assay in normal subjects (n = 81), HT (n = 28) and CRF (n = 30). We also determined the molecular forms of plasma adrenomedullin taken from various sites during angiography in patients with suspected renovascular hypertension (n = 9).. There were no differences in plasma and urinary excretions of two molecular forms of adrenomedullin among sexes or ages in normal subjects. There was no daytime variation of plasma two molecular forms of adrenomedullin in normal subjects. Plasma AM-m, AM-Gly and AM-T levels were increased in patients with HT and CRF compared with normal subjects, whereas urinary AM-m, AM-Gly and AM-T excretions were decreased in patients with HT and CRF compared with normal subjects. Urinary AM-m: AM-T ratios were significantly higher than plasma AM-m: AM-T ratios. Plasma AM-m and AM-T levels taken from various veins were similar, and they were significantly higher than those of aorta, although there were no differences in plasma AM-Gly levels between aorta and veins.. These results suggest that in normal subjects, and individuals with HT and CRF: (i) plasma and urinary excretions of AM-m and AM-Gly are not affected by age or sex; (ii) AM-m in parallel with AM-Gly is increased; (iii) urine contains a higher percentage of active adrenomedullin than plasma; and (iv) plasma AM-m may be partly metabolized in the lung.

Topics: Adrenomedullin; Adult; Aged; Aging; Circadian Rhythm; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Reference Values; Sex Characteristics

Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues. We have cloned and sequenced the genomic DNA encoding the human AM gene and have determined that the gene is located in the short arm of chromosome 11. The 3'-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to hypertension. Genomic DNA was obtained from 272 healthy normotensive subjects (NT) age 57+/-5 years and 266 patients with essential hypertension (EH) age 53+/-11 years. The DNA was subject to PCR using a fluorescence-labeled primer, and the number of CA repeats were determined by poly-acrylamide gel electrophoresis. The averaged blood pressure was 117+/-13/73+/-9 mm Hg in NT and 170+/-23/104+/-12 mm Hg in EH. In Japanese, there existed 4 types of alleles with different CA-repeat numbers: 11, 13, 14, and 19. The frequencies of these alleles were significantly different between NT and EH (chi(2)=9.43, P=0.024). Namely, 13.5% of EH carried the 19-repeat allele, whereas the frequency was 6.2% in NT (chi(2)=7.62, P=0.007). In NT, plasma AM concentrations were not significantly different between the genotypes. In conclusion, microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to EH, although the gene expression is not likely to be affected by the genotypes.

Topics: Adrenomedullin; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Microsatellite Repeats; Middle Aged; Peptides; Polymorphism, Genetic

Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice.. Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production.. AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.

Topics: Adrenomedullin; Animals; Blood Vessels; Cardiovascular Abnormalities; Embryo Loss; Endothelium, Vascular; Female; Gene Targeting; Genes, Lethal; Genotype; Hemodynamics; Hemorrhage; Heterozygote; Homozygote; Hypertension; Inbreeding; Infusion Pumps; Injections, Subcutaneous; Male; Mice; Mice, Knockout; Nitric Oxide; Peptides; Phenotype; Recombinant Proteins; Vitelline Membrane

The aim of the study was to investigate the behavior of two endothelial vasoactive peptides, adrenomedullin (vasodilator) and endothelin-1 (vasoconstrictor), in human obesity with and without arterial hypertension.. The study was carried out on 30 obese subjects (body mass index > 27 kg/m2) divided into two groups: 15 normotensive obese patients (10 males, 5 females, mean age 42 +/- 12 years) and 15 hypertensive obese patients (9 males, 6 females, mean age 42 +/- 13 years). The control group consisted of 21 normal subjects (12 males, 9 females, mean age 38 +/- 12 years) and of 16 patients with essential hypertension (10 males, 6 females, mean age 41 +/- 12 years) but without organ damage. All studied subjects were taking a normocaloric (20-22 kcal/kg/day), normosodic (120-140 mEq/day) and normopotassic (50-60 mEq/day) diet. Between 8.00 and 9.00 a.m., a venous blood sample was taken for the determination (radioimmunoassay) of plasma adrenomedullin and endothelin-1 concentrations.. Plasma adrenomedullin levels in normal subjects (13.7 +/- 6.1 pg/ml) were similar to those in normotensive obese patients (14.8 +/- 7.2 pg/ml), whereas in hypertensive obese patients (22.5 +/- 9.1 pg/ml) and in those with essential hypertension (22.7 +/- 8.2 pg/ml) levels were significantly higher (ANOVA = 0.000, p < 0.05) than those of normal subjects and of normotensive obese patients. Moreover, endothelin-1 plasma concentrations were found to be significantly higher (ANOVA = 0.000, p < 0.05) in hypertensive obese patients (10.3 +/- 2.7 pg/ml) compared to normal subjects (6.5 +/- 2.4 pg/ml), normotensive obese patients (8.3 +/- 1.5 pg/ml) and to those with essential hypertension (8.5 +/- 2.9 pg/ml). In patients with essential hypertension, a positive correlation (r = 0.493, p < 0.05) was found between adrenomedullin and endothelin-1 plasma levels.. These results revealed that in human obesity associated with arterial hypertension there is an increased production of plasma adrenomedullin and endothelin-1 that, with their opposite vasoactive properties (vasodilation/vasoconstriction), can contribute to this pathological association.

Topics: Adrenomedullin; Adult; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension; Male; Obesity; Peptides

We investigated the potential roles of adrenomedullin (AM) in cardiovascular and renal function by somatic gene delivery. We showed that a single intravenous injection of the human AM gene under the control of cytomegalovirus promoter/enhancer induces a prolonged delay in blood pressure rise for several weeks in spontaneously hypertensive rats, Dahl salt-sensitive, DOCA-salt, and two-kidney one-clip hypertensive rats as compared to their respective controls injected with a reporter gene. Expression of the human AM transcript was identified in the heart, kidney, lung, liver and aorta of the rat after adenovirus-mediated AM gene delivery by RT-PCR followed by Southern blot analysis. Immunoreactive human AM levels were measured in rat plasma and urine following AM gene delivery. AM gene delivery induced significant reduction of left ventricular mass in these hypertensive animal models. It also reduces urinary protein excretion and increases glomerular filtration rate, renal blood flow and urinary cAMP levels. AM gene transfer attenuated cardiomyocyte diameter and interstitial fibrosis in the heart, and reduced glomerular sclerosis, tubular disruption, protein cast accumulation and renal cell proliferation in the kidney. In the rat model with myocardial ischemia/reperfusion injury, AM gene delivery significantly reduced myocardial infarction, apoptosis, and superoxide production. Furthermore, local AM gene delivery significantly inhibited arterial thickening, promoted re-endothelialization and increased vascular cGMP levels in rat artery after balloon angioplasty. Collectively, these results indicate that human AM gene delivery attenuates hypertension, myocardial infarction, renal injury and cardiovascular remodeling in animal models via cAMP and cGMP signaling pathways. These findings provide new insights into the role of AM in cardiovascular and renal function.

Topics: Adenoviridae; Adrenomedullin; Animals; Cardiomegaly; Cardiomyopathies; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Kidney Diseases; Male; Myocardial Infarction; Peptides; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Streptozocin; Tunica Intima; Ventricular Remodeling

This study was designed to investigate the pathophysiological significance of adrenomedullin (AM) concentration in volume- and pressure-overloaded cardiac hypertrophy. We measured ventricular AM concentrations and compared them with changes of alpha-actin and myosin heavy chain (MHC) mRNA isoforms after the creation of an aortocaval (AC) shunt as a volume-overload model or the injection of monocrotaline (MCT) as a pressure-overload model, respectively. The left ventricular AM levels after the creation of AC shunt and the right ventricular AM levels after the injection of MCT were significantly increased and correlated with changes of the alpha-actin and MHC mRNA isoforms. However, the ventricular AM mRNA expressions were increased and correlated with ventricular AM concentrations only in the AC shunt model. These results suggest that the ventricular AM levels are upregulated in both the volume- and pressure-overloaded cardiac hypertrophy by differential transcriptional regulation and that the ventricular AM may be a biochemical marker for the volume and pressure overload to the ventricle.

Topics: Adrenomedullin; Animals; Biomarkers; Gene Expression; Heart Ventricles; Hemodynamics; Hyperemia; Hypertension; Immunohistochemistry; Male; Myocardium; Osmolar Concentration; Peptides; Rats; Rats, Wistar; RNA, Messenger

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Topics: Adrenomedullin; Amides; Female; Humans; Hypertension; Immunoradiometric Assay; Male; Middle Aged; Peptides; Reference Values; Renal Dialysis

Excess oxidative stress is one of the major metabolic abnormalities on vascular walls in hypertension and atherosclerosis. In order to further elucidate the endothelial function under oxidative stress, the effect of hydrogen peroxide (H2O2) on expression of two novel endothelium-derived vasorelaxing peptides, C-type natriuretic peptide (CNP) and adrenomedullin (AM) from bovine carotid artery endothelial cells (BCAECs) was examined.. BCAECs were treated with H2O2 (0.1-1.0 mmol/ l) and/or an antioxidant, N-acetylcysteine (NAC) (5-10 mmol/l), and incubated for 48 h. The concentrations of CNP and AM were measured with the specific radioimmuno assays that we originally developed. CNP and AM mRNA expressions were also examined by reverse transcription-polymerase chain reaction (RT-PCR).. Treatment of BCAECs with 0.5 and 1 mmol/l H2O2 induced 9-and 10-fold increases of CNP concentration in the media. Addition of 10 mmol/l NAC significantly suppressed the effect of H2O2 by 52%. RT-PCR analysis showed that CNP mRNA expression in BCAECs was also rapidly augmented within 1 h with H2O2 (1 mmol/l) treatment, and reached a peak at 3 h to show a 10-fold increase. AM secretion from BCAECs also increased to two-fold with exposure to 0.5 mmol/l H2O2, accompanied with the augmented level of AM mRNA. NAC 10 mmol/l completely suppressed the effect of H2O2 on AM secretion.. In this study, it has been demonstrated that H2O2 augments endothelial secretion of the two endothelium-derived relaxing peptides, CNP and AM. Our findings suggest the increased secretion of CNP and AM from endothelium under oxidative stress may function to compensate the impaired nitric oxide-dependent vasorelaxation in hypertension and atherosclerosis.

Topics: Acetylcysteine; Adrenomedullin; Animals; Antioxidants; Arteriosclerosis; Base Sequence; Cattle; Cells, Cultured; DNA Primers; Endothelium, Vascular; Gene Expression; Humans; Hydrogen Peroxide; Hypertension; Natriuretic Peptide, C-Type; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peptides; RNA, Messenger; Vasodilation

Topics: Adrenomedullin; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Peptides; Risk Factors

Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery on salt-induced cardiorenal lesions in hypertensive Dahl saltsensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM) was generated by homologous recombination of E. coli. Expression of recombinant human AM was detected by a radioimmunoassay in the medium of human embryonic kidney 293 cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared with control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass and urinary protein, increased cAMP levels, and enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as glomerular sclerosis, tubular disruption, and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver, and aorta, and immunoreactive human AM levels were measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension and cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.

Topics: Adenoviridae; Adrenomedullin; Animals; Blood Pressure; Cardiomegaly; Cell Line; Cyclic AMP; Fibrosis; Genetic Therapy; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Peptides; Proteinuria; Rats; Rats, Inbred Dahl; Recombinant Proteins; Salts

Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10(-12)-10(-7) M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), (1)H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation = 69 +/- 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation = 66 +/- 7 vs. 41 +/- 13%, P < 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither (1)H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K(+) channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase.

Topics: Adenine; Adrenomedullin; Aged; Arterioles; Calcitonin Gene-Related Peptide; Coronary Circulation; Coronary Disease; Coronary Vessels; Enzyme Inhibitors; Female; Heart Failure; Humans; Hypertension; In Vitro Techniques; Male; Microcirculation; Middle Aged; Miotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; omega-N-Methylarginine; Peptide Fragments; Potassium Channels; Vasodilation; Vasodilator Agents

Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide that plays an important role in cardiorenal function. In this study, we explored the potential protective role of AM in volume-dependent hypertension by somatic gene delivery. Adenovirus containing the human AM cDNA under the control of the cytomegalovirus promoter/enhancer was administered into deoxycorticosterone acetate (DOCA)-salt hypertensive rats via tail vein injection. A single injection of the human AM gene resulted in a prolonged reduction of blood pressure with a maximal reduction of 41 mm Hg 9 days after gene delivery. Human AM gene delivery enhanced renal function, as indicated by a 3-fold increase in renal blood flow and a 2-fold increase in glomerular filtration rate (n=5, P<0.05). Histological examination of the kidney revealed a significant reduction in glomerular sclerosis, tubular injury, luminol protein cast accumulation, and interstitial fibrosis as well as urinary protein. Human AM gene delivery caused significant decreases in left ventricular weight and cardiomyocyte diameter, which were accompanied by reduced interstitial fibrosis and extracellular matrix formation within the heart. Expression of human AM mRNA was detected in the kidney, adrenal gland, heart, aorta, lung, and liver; immunoreactive human AM levels were measured in urine and plasma. Significant increases in urinary and cardiac cAMP levels were observed in DOCA-salt rats receiving the human AM gene, indicating activation of the AM receptor. These findings showed that AM gene delivery attenuates hypertension, protects against cardiac remodeling and renal damage in volume-overload hypertension, and may have significance in therapeutic applications in cardiovascular and renal diseases.

Topics: Adenoviridae; Adrenomedullin; Animals; Cardiomegaly; Cyclic AMP; Cyclic GMP; Desoxycorticosterone; Disease Models, Animal; Fibrosis; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Hypertension; Kidney Diseases; Male; Peptides; Rats; Rats, Sprague-Dawley; Systole

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

Adrenomedullin is a newly discovered 52 amino acid peptide that has a potent vasodilating action. The present study was undertaken to investigate the role of adrenomedullin in the regulation of membrane fluidity of erythrocytes in patients with essential hypertension.. We used an electron paramagnetic resonance and spin-labeling method. Adrenomedullin significantly decreased the order parameter for 5-nitroxide stearate and peak height ratio for 16-nitroxide stearate obtained from electron paramagnetic resonance spectra of erythrocyte membranes in normotensive volunteers (mean +/- SEM order parameter value: control, 0.718 +/- 0.003, n = 16; adrenomedullin at 10(-9) mol/l, 0.692 +/- 0.004, n = 16, P < 0.05; adrenomedullin at 10(-8) mol/l, 0.690 +/- 0.004, n = 16, P < 0.05; adrenomedullin at 10(-7) mol/l, 0.683 +/- 0.004, n = 16, P < 0.05). The findings showed that adrenomedullin increased the membrane fluidity of erythrocytes. In addition, the effect of adrenomedullin was significantly potentiated by prostaglandin E1 and dibutyryl cyclic AMP. In contrast, the calcium ionophore A23187 counteracted the actions of adrenomedullin. In patients with essential hypertension, who had higher order parameter values, the membrane fluidity of erythrocytes was significantly lower than in the normotensive control subjects (order parameter: 0.728 +/- 0.004 in hypertensives, n = 20; 0.692 +/- 0.002 in normotensives, n = 36, P < 0.01). The effect of adrenomedullin on membrane fluidity was more pronounced in the erythrocytes of essential hypertensive than in the erythrocytes of normotensive subjects (change in the order parameter with adrenomedullin at 10(-9) mol/l: -4.2 +/- 0.3% in hypertensives, n = 20; -1.8 +/- 0.2% in normotensives, n = 20, P < 0.05; adrenomedullin at 10(-8) mol/l: -4.5 +/- 0.3% in hypertensives, n = 20; -1.8 +/- 0.2% in normotensives, n = 36, P < 0.05).. The results of the present study demonstrate that adrenomedullin significantly increased the membrane fluidity of erythrocytes. The mechanisms were partially mediated by a prostaglandin E1- and cyclic AMP-dependent pathway which might be linked to changes in intracellular calcium kinetics. The greater effect of adrenomedullin in patients with essential hypertension suggests that the peptide might actively participate in the regulation of membrane functions in hypertension.

Topics: Adrenomedullin; Alprostadil; Bucladesine; Calcimycin; Calcium; Cyclic N-Oxides; Drug Combinations; Electron Spin Resonance Spectroscopy; Erythrocytes; Female; Humans; Hypertension; Male; Membrane Fluidity; Middle Aged; Peptides; Spin Labels; Vasodilator Agents

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

We examined the effect of adrenomedullin on the cardiovascular system of an animal model for preeclampsia. An inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester (L-NAME), was infused subcutaneously into rats at a constant rate from day 14 of pregnancy to make an animal model for preeclampsia. Adrenomedullin was continuously infused intravenously at a dose of 3 or 10 pmol/h from day 17 of pregnancy. The basal systolic blood pressure was significantly higher in the L-NAME treated rats than in the control rats. The adrenomedullin administration at day 19 of pregnancy showed a significant decrease in the blood pressure in the L-NAME treated rats than in vehicle rats during infusion. The blood pressure of normal pregnant rats did not significantly decrease by adrenomedullin infusion. The adrenomedullin decreased pup mortality of the L-NAME treated rats. Adrenomedullin attenuated the L-NAME induced hypertension and pup mortality. On the other hand, adrenomedullin administration in both pregnant rats in early gestation (5-11 days of pregnancy) and in non-pregnant rats did not show any significant effect on L-NAME-induced hypertension. The adrenomedullin mRNA level was predominantly expressed at high levels in the ovary, uterus and placenta, but at low levels in other tissues in pregnant rats in late gestation. The adrenomedullin mRNA level of the L-NAME treated rats in placenta decreased more than in the normal pregnant rats in late gestation (P < 0.05). These findings suggest that the adrenomedullin might play an important role in the regulation of the cardiovascular system of the mother and fetoplacental unit in rats.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Northern; Body Weight; Disease Models, Animal; Enzyme Inhibitors; Female; Fetus; Hypertension; Infusions, Intravenous; NG-Nitroarginine Methyl Ester; Peptides; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar; RNA, Messenger; Time Factors

The novel hypotensive peptide, proadrenomedullin N-terminal 20 peptide (PAMP), is processed from the adrenomedullin precursor. Recently, we identified PAMP-12 [PAMP(9-20)] from the porcine adrenal medulla as a major endogenous and biologically active peptide. Using a new, sensitive radioimmunoassay which recognizes the C-terminal region of PAMP-20 [PAMP(1-20)], we investigated the role of PAMP in patients with essential hypertension who had normal renal function, and whether PAMP-12 is present in humans. The mean PAMP plasma concentration, like that of adrenomedullin, was significantly higher in hypertensive [1.51 fmol/mL, standard error of the mean (SEM) 0.09 fmol/mL] than normotensive participants (1.08 fmol/mL, SEM 0.05). The increase in plasma PAMP concentration in patients with organ damage accompanied by hypertension was significantly higher than that in patients without organ damage. The PAMP concentration had a significant positive correlation with mean blood pressure and adrenomedullin concentration. The immunoreactive PAMP in human tissue and plasma was characterized by reverse-phase high-performance liquid chromatography. PAMP-12, as well as PAMP-20, was abundant in the phaeochromocytoma tissue. These findings suggest that PAMP plays some pathophysiological role against the development of essential hypertension.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Female; Humans; Hypertension; Male; Middle Aged; Peptide Fragments; Peptides; Proteins; Radioimmunoassay

The adrenomedullin (AM) peptide and the expression of AM messenger RNA (mRNA) from feto-maternal tissues of 22 normotensive pregnant women and from 7 women with pregnancy-induced hypertension (PIH) during third-trimester were examined to clarify the pathophysiological features of PIH. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patients under informed consent. The AM peptide was measured by a radioimmunoassay and the AM mRNA level was analyzed by Northern hybridization. The total immunoreactive AM (fmol/mg wet tissue) was significantly increased in the fetal membranes (1.95+/-0.20 vs. 3.03+/-0.44) and the umbilical artery (0.11+/-0.01 vs. 0.15+/-0.02) of the patients with PIH. On the other hand, the AM mRNA level was higher in the umbilical artery, and lower in the fetal membranes in the patients with PIH. The present results thus suggest that the changes in the expression of AM in fetal membrane and umbilical artery in PIH may play an important role in the fetal and maternal circulation.

Topics: Adrenomedullin; Blotting, Northern; Extraembryonic Membranes; Female; Fetus; Gene Expression; Gestational Age; Humans; Hypertension; Peptides; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; RNA, Messenger; Umbilical Arteries; Uterus

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

Topics: Adrenomedullin; Aorta; Heart Failure; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Peptides; Pulmonary Artery; Reference Values; Renal Insufficiency; Renal Veins; Time Factors

Adrenomedullin (AM), a potent vasodilator peptide, is processed from its AM precursor as glycine-extended AM (AM-gly), an intermediate form of AM. Subsequently, mature AM is converted from AM-gly by enzymatic amidation. Using two kinds of radioimmunoassay which recognize the entire AM molecule (E-AM-RIA) and C-terminal amide structure (C-AM-RIA), human plasma AM immunoreactivity was chromatographically characterized. In analyses of gel filtration and reverse phase high-performance liquid chromatography, most of the AM immunoreactivity measured by E-AM-RIA was eluted at a position identical to where mature AM and AM-gly emerged and was not recognized by C-AM-RIA. These data show that immunoreactive AM measured by E-AM-RIA is not amidated. When amidated by peptidylglycine alpha-amidating enzyme, the immunoreactive AM was converted to a form that can be detected by C-AM-RIA. These results indicate that most of the total AM immunoreactivity measured by E-AM-RIA represents immunoreactivity of AM-gly and that the concentration of immunoreactive mature AM in plasma is much lower than that of AM-gly. In practice, plasma concentration of AM-gly and mature AM in healthy volunteers was 2.7 +/- 0.18 fmol/ml and 0.48 +/- 0.05 fmol/ml, respectively. Furthermore, plasma concentration of AM-gly and total AM was significantly elevated in patients with hypertension compared to normotensive control. The present data indicate that most of circulating plasma AM immunoreactivity is occupied by AM-gly, an intermediate form of AM, which may reflect the process of production of AM in tissues.

Topics: Adrenomedullin; Chromatography, Gel; Chromatography, High Pressure Liquid; Glycine; Humans; Hypertension; Immunochemistry; Peptides; Protein Processing, Post-Translational; Radioimmunoassay; Vasodilator Agents

Adrenomedullin (AM) is a peptide with potent vasodilatory and hypotensive properties. Plasma AM levels in rats with experimentally induced hypertension, such as Dahl salt-sensitive rats and two-kidney, one-clip hypertensive rats, are higher than those in normotensive rats. We previously noted, however, that plasma AM levels in spontaneously hypertensive rats (SHR) are similar to those in Wistar-Kyoto rats. To define the role of AM in rats with severe hypertension, we investigated changes in circulating and tissue AM levels in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). The immunoreactive rat AM levels in plasma, urine, and tissue measured with a sensitive radioimmunoassay, and the AM mRNA levels in various tissues in 15-wk-old SHRSP/Izm were compared with those in age-matched Wistar-Kyoto rats (WKY/Izm). The plasma and urinary AM levels in SHRSP/Izm were significantly lower than those in WKY/Izm [plasma AM, 2.14+/-0.06 (SE) vs. 3.24+/-0.16 fmol/ml, p< 0.001; urinary AM, 16.36+/-3.21 vs. 36.12+/-6.09 fmol/ml, p< 0.01]. A negative correlation was found between the plasma AM level and the systolic blood pressure in both SHRSP/Izm and WKY/Izm. Reverse-phase high-performance liquid chromatography showed that the molecular components of plasma immunoreactive AM in SHRSP/Izm were similar to those in WKY/Izm. Furthermore, tissue AM levels in various organs in SHRSP/Izm were not lower than those in WKY/Izm. In conclusion, low levels of circulating AM may contribute to the maintenance of high blood pressure in 15-wk-old SHRSP/Izm. These low plasma AM levels may be caused by accelerated metabolism of circulating AM in SHRSP/Izm.

Topics: Adrenomedullin; Age Factors; Albuminuria; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cerebrovascular Disorders; Creatine; Gene Expression; Heart Rate; Hypertension; Male; Peptides; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

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

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are novel hypotensive peptides produced from the same precursor. A relationship between AM and the renin-angiotensin-aldosterone (RAA) axis was reported in several studies, but the response of the above two peptides to short-term modulation of the RAA axis in humans is not yet clear. Here, we assessed the responses of AM and PAMP in patients with varying RAA system status, including renovascular hypertension (RVH) and primary aldosteronism (PA).. Essential hypertension (EHT), RVH and PA patients were hospitalized and maintained on a standard diet (NaCl 10 g/day). The patients underwent a captopril (25 mg) loading test. A renin-secretion stimulating test (furosemide 1 mg/kg, i.v. +2 h of walking) and an ACTH loading test were performed for the PA patients. The plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma AM and PAMP levels were monitored before and after the loadings.. In the basal state, significantly higher concentrations of AM and PAMP were shown in the RVH patients compared to the other groups. AM and PAMP were significantly correlated with PRA but not PAC in all patients. The AM and PAMP levels were not affected by the captopril loading with or without a hypotensive reaction. The AM and PAMP levels were increased only slightly despite the large increase in PAC induced in the PA patients by the renin-secretion stimulating and ACTH loading tests.. The responses of plasma AM and PAMP to a short-term modulation of the RAA system were relatively small, despite the correlations observed between PRA and AM or PAMP.

Topics: Adrenocorticotropic Hormone; Adrenomedullin; Adult; Antihypertensive Agents; Captopril; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Peptide Fragments; Peptides; Proteins; Renin; Renin-Angiotensin System

To characterize the determinants of circulating levels of adrenomedullin (AM), the plasma levels of this peptide were measured in 58 patients with end-stage renal disease on hemodialysis. Predialysis plasma levels of AM were more than twice as high in patients on hemodialysis as compared to controls. In hemodialysis patients with heart failure (NYHA classes II-IV) or hypertensive HD patients plasma levels of AM were significantly higher than in patients with end-stage renal disease only. Plasma levels of AM were not altered immediately by hemodialysis but decreased significantly 14-20 h after hemodialysis. AM plasma levels before hemodialysis and 14-20 h after hemodialysis were correlated with the corresponding mean arterial pressure.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Body Weight; Female; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Renal Dialysis; Ultrafiltration

1. Adrenomedullin is a potent vasodilating peptide first isolated from phaeochromocytoma and adrenal medulla but also found in the heart, lungs and kidneys. It may also be a paracrine factor because endothelial and smooth muscle cells synthesize adrenomedullin as well as express the receptors. Adrenomedullin induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of nitric oxide. 2. We have developed a specific radioimmunoassay and measured the immunoreactivity of human adrenomedullin in the plasma of 58 male subjects: eight with essential hypertension, 12 with heart failure, 10 with ascites due to cirrhosis, 12 with chronic renal failure, four with hypoxia due to chronic obstructive pulmonary disease and 12 control subjects. 3. Plasma levels (mean +/- SEM) in patients with essential hypertension (16.3 +/- 1.9 pmol/l), congestive heart failure (17.5 +/- 2.8 pmol/l) and renal failure (17.7 +/- 2.5 pmol/l) were raised compared with control subjects (7.8 +/- 1.4 pmol/l, P < 0.05), confirming previous reports. 4. In addition, we observed that plasma levels of adrenomedullin were significantly raised in patients with ascites due to liver cirrhosis (15.5 +/- 1.9 pmol/l) and chronic obstructive pulmonary disease with hypoxia (20.0 +/- 1.5 pmol/l). 5. We concluded that the plasma level of adrenomedullin is raised in a variety of diseases.

Topics: Adrenomedullin; Adult; Aged; Heart Failure; Humans; Hypertension; Hypoxia; Kidney Failure, Chronic; Liver Cirrhosis; Lung Diseases, Obstructive; Male; Middle Aged; Peptides; Radioimmunoassay; Vasodilator Agents

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

Adrenomedullin (ADM), a peptide with potent vasodilatory and natriuretic actions, is elevated in patients with essential hypertension. Because pharmacological doses of ADM result in renal vasodilation and natriuresis, it has been suggested that ADM may play a modulatory role in hypertension through potential actions on renal pressure natriuresis. However, it is unclear whether elevation of plasma ADM within the pathophysiological range has similar actions. To determine the effects of pathophysiological doses of ADM on blood pressure and on the relationship between renal perfusion pressure (RPP) and renal hemodynamics and sodium excretion, renal function was determined at RPPs of 80, 105, 130, and 155 mm Hg in spontaneously hypertensive rats (SHR) infused with ADM at 50 ng x kg(-1) x min(-1) (ADM-50, n=5) and at 100 ng x kg(-1) x min(-1) (ADM-100, n=5) and in control SHR (n=5). Decreasing RPP from 155 to 80 mm Hg in control SHR decreased (P<.05) absolute sodium excretion from 0.81+/-0.25 to 0.04+/-0.02 microEq/min, fractional sodium excretion from 0.32+/-0.11% to 0.06+/-0.04%, and urine flow rate from 11.5+/-2.8 to 1.03+/-0.31 microL/min. ADM infusion elevated (P<.05) plasma ADM levels in ADM-infused SHR (679+/-47 pg/mL in ADM-50, 858+/-79 in ADM-100) compared with control (79.5+/-27.8). However, although reduction of RPP from 155 to 80 mm Hg in ADM rats decreased absolute sodium excretion (ADM-50, 0.98+/-0.10 to 0.09+/-0.04 microEq/min; ADM-100, 0.95+/-0.09 to 0.07+/-0.02 microEq/min), fractional sodium excretion (ADM-50, 0.31+/-0.03% to 0.17+/-0.04%; ADM-100, 0.33+/-0.02% to 0.09+/-0.01%), and urine flow (ADM-50, 13.6+/-1.4 to 1.73+/-0.75 microL/min; ADM-100, 13.5+/-1.5 to 1.07+/-0.16 microL/min), these decreases were not different from values found in controls. Renal plasma flow and glomerular filtration rate were also similar in control and ADM-treated SHR at each level of RPP. Thus, acute increases in ADM to levels found in pathophysiological conditions have no effect on blood pressure, pressure natriuresis, or renal autoregulation in the SHR. These findings do not support the hypothesis that ADM serves as a modulating factor in hypertension, at least in the SHR.

Topics: Adrenomedullin; Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Glomerular Filtration Rate; Hypertension; Male; Natriuresis; Peptides; Rats; Rats, Inbred SHR; Renal Circulation

It has been reported that plasma concentrations of adrenomedullin (AM), a novel vasodilator peptide, are higher in patients with essential hypertension than those in normotensive subjects. To clarify the clinical significance of increased levels of AM in patients with essential hypertension, in this study we examined the relationship between plasma concentrations of AM and the structure of the left ventricle or carotid artery. Plasma AM concentrations; renin activity; and norepinephrine, epinephrine, and creatinine concentrations in 50 patients with untreated essential hypertension without renal dysfunction and heart failure were measured. We also measured the mean wall thickness of the left ventricle and left ventricular mass index by M-mode echocardiography and intimal-medial thickness and arterial distensibility of the carotid artery by ultrasonography. Hypertensive patients were divided into two groups: hypertensives with and those without left ventricular hypertrophy. Plasma AM concentrations in hypertensive patients with left ventricular hypertrophy were significantly higher than in hypertensive patients without left ventricular hypertrophy (7.87+/-2.70 vs 5.74+/-1.65 fmol/mL, P<.01). In all hypertensive patients, plasma AM concentrations were not correlated with blood pressure, plasma renin activity, plasma norepinephrine, plasma epinephrine, or plasma creatinine concentration. Plasma AM concentrations were positively correlated with left ventricular mass index or mean wall thickness (r=.37, P=.009; r=.40, P=.004, respectively) and inversely correlated with carotid artery distensibility (r=-.33, P=.02), whereas plasma AM concentrations were not correlated with intimal-medial thickness. These results suggest that the observed elevation of plasma AM in patients with essential hypertension with normal renal function may be partly related to cardiac hypertrophy and decreased carotid artery distensibility.

Topics: Adrenomedullin; Adult; Aged; Cardiomegaly; Carotid Arteries; Female; Humans; Hypertension; Hypertrophy; Male; Middle Aged; Peptides

Rat adrenomedullin is a peptide vasodepressor that may be of importance in the pathogenesis of hypertensive disease. Because of the known link between obesity and hypertension, we hypothesized that decreased responsiveness to adrenomedullin might be seen in an obese rodent model. In this study, the in vivo vasodilator actions of exogenous adrenomedullin were compared in anesthetized lean (n = 7) and obese (fa/fa) Zucker rats (n = 8). Adrenomedullin dose dependently lowered mean arterial pressure in both phenotypes, but the half-maximal dose (ID50) was 2-fold higher in fa/fa rats (1.7 +/- 0.22 vs. 0.83 +/- 0.06 nmol/kg). Moreover, the duration of effect was markedly reduced in the fa/fa rats, to 1-2 min from about 5 min in the lean animals. There was no evidence for an increased rate of degradation of adrenomedullin in the fa/fa rats. Although the rats used in this study were not hypertensive, adrenomedullin had reduced sensitivity and duration of action. The evidence suggests possible defects at the target receptor or altered metabolism of adrenomedullin in obesity.

Topics: Adrenomedullin; Animals; Blood Pressure; Hypertension; Insulin Resistance; Male; Obesity; Peptides; Rats; Rats, Zucker; Vasodilator Agents

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Endothelium, Vascular; Heart Diseases; Humans; Hypertension; Kidney Diseases; Peptides; Vasodilator Agents

Adrenomedullin (ADM) is a potent vasoactive peptide. In this study, we explored the effects of a continuous supply of ADM by somatic gene delivery on spontaneously hypertensive rats (SHR). DNA constructs containing the human ADM cDNA fused to either the cytomegalovirus promoter (CMV-cADM) or Rous Sarcoma virus 3'-long terminal repeat (RSV-cADM) were intravenously injected into SHR through the tail vein. Expression of human ADM in SHR was identified in the kidney, adrenal gland, heart, and lung by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of ADM plasmid DNA in young adult SHR (7 wk old) caused a significant reduction in systolic blood pressure for up to 5 wk (p < 0.05). A second injection of CMV-cADM 5 wk after the first delivery resulted in a further reduction in blood pressure for another 3 wk (p < 0.001). A maximal blood pressure reduction of 22 mmHg in SHR was observed 7 wk after injection of CMV-cADM plasmid DNA (185 +/- 1.7 mmHg, n = 6, p < 0.001), and a reduction of 15 mmHg was observed after injection of RSV-cADM (192 +/- 2.7 mmHg, n = 6, p < 0.001), as compared with control rats given vector DNA (207 +/- 2.4 mmHg, n = 6). Similarly, injection of CMV-cADM plasmid DNA in adult SHR (10 wk old) resulted in a significant reduction in blood pressure for up to 6 wk. Antibodies to either human ADM or its plasmid DNA were not detected in rat sera after the second injection. These studies indicate that intravenous injection of the human ADM gene in hypertensive rats results in expression of the foreign gene and induces a long-lasting reduction in blood pressure.

Topics: Adrenomedullin; Animals; Antibody Formation; Avian Sarcoma Viruses; beta-Galactosidase; Blood Pressure; Cytomegalovirus; DNA, Complementary; DNA, Recombinant; Gene Expression; Genetic Therapy; Humans; Hypertension; Hypotension; Injections, Intravenous; Kidney; Lung; Peptides; Rats; Rats, Inbred SHR; RNA, Messenger; Spleen; Tissue Distribution; Transfection

We designed the present study to assess any changes in plasma concentrations of the novel vasorelaxant peptide adrenomedullin in patients with essential hypertension. Plasma adrenomedullin concentrations were measured in 45 patients with untreated essential hypertension, 15 patients with borderline hypertension, and 30 normotensive control subjects. After 4 weeks of effective calcium channel blocker-based antihypertensive therapy, adrenomedullin concentrations were measured again. The concentrations were higher in hypertensive patients with increased serum creatinine levels or decreased glomerular filtration rates compared with borderline hypertensive patients and normotensive subjects, although values in normotensive and hypertensive individuals overlapped. Plasma adrenomedullin concentrations were positively correlated with serum creatinine levels and inversely correlated with glomerular filtration rates in the hypertensive patients, whereas adrenomedullin values were not correlated with blood pressure level, left ventricular mass index, or left ventricular ejection fraction. Despite blood pressure control with antihypertensive therapy, plasma adrenomedullin concentrations were not changed. Reversed-phase high-performance liquid chromatographic analysis showed that a major component of immunoreactive adrenomedullin in the plasma of normotensive subjects and hypertensive patients is human adrenomedullin-(1-52). These results indicate that plasma adrenomedullin concentrations are elevated in many hypertensive patients with renal dysfunction and its major component is human adrenomedullin-(1-52).

Topics: Adrenomedullin; Adult; Antihypertensive Agents; Calcium Channel Blockers; Chromatography, High Pressure Liquid; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Osmolar Concentration; Peptides; Reference Values

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide processed from an adrenomedullin precursor. In this study, high concentrations of immunoreactive PAMP (ir-PAMP) were detected in rat cardiac atrium and adrenal gland by the radioimmunoassay (RIA) for rat PAMP. The mean plasma concentration of rat ir-PAMP was 3.8 +/- 0.3 fmol/ml. Analysis in atrium, adrenal gland and plasma with high performance liquid chromatographies showed that most ir-PAMP emerged as one major peak at the position exactly identical to that of the authentic rat PAMP. We further investigated the tissue and plasma concentrations of rat ir-PAMP in spontaneously hypertensive rat (SHR) to elucidate the role of PAMP in hypertension. The ir-PAMP concentration in heart tissue of SHR was found to be increased compared with that of the control rat. Especially, the atrial concentration of ir-PAMP of SHR (5.66 +/- 0.78 fmol/mg wet tissue) was significantly higher than that of the control (3.29 +/- 0.22 fmol/mg wet tissue). Cardiac PAMP might have a role for the protection from systemic hypertension.

Topics: Adrenal Glands; Adrenomedullin; Amino Acid Sequence; Animals; Heart Atria; Humans; Hypertension; Molecular Sequence Data; Organ Specificity; Peptide Fragments; Peptides; Proteins; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Sensitivity and Specificity

Adrenomedullin (AM), a novel hypotensive peptide, is suggested to be involved in defense mechanisms against hypertension, however, the detail mechanisms have not been clarified. To elucidate whether AM synthesis would be altered in a salt dependent hypertension, we have investigated the AM concentration and AM messenger RNA (mRNA) level in tissues of Dahl salt-sensitive rats on either low- or high-salt intake. The AM concentration in cardiac ventricle of the high-salt group was significantly higher than that of the low-salt group. The plasma AM concentration was also significantly higher in the high-salt group than in the low-salt group. Furthermore, the plasma AM concentration correlated well with the weight of left ventricle. RNA blot analysis revealed that the AM mRNA level in cardiac ventricle of the high-salt group was higher than that of the low-salt group. These results suggest that AM participates in the pathophysiology of salt dependent hypertension and plays a role in cardiac hypertrophy.

Topics: Adrenomedullin; Animals; Hypertension; Myocardium; Peptides; Rats; RNA, Messenger; Sodium Chloride, Dietary

Responses to adrenomedullin, a newly discovered hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15-52 (adrenomedullin-(15-52)) and 22-52 (adrenomedullin-(22-52)) amino acid fragments of adrenomedullin were investigated in the mesenteric vascular bed of the cat. Under constant flow conditions, injections of adrenomedullin, adrenomedullin-(15-52), and calcitonin gene-related peptide (CGRP) in doses of 0.003-1 nmol into the perfused superior mesenteric artery caused significant dose-related decreases in mesenteric arterial perfusion pressure. Mesenteric vasodilator responses to adrenomedullin and adrenomedullin-(15-52) were similar in magnitude and duration, while vasodilator responses to CGRP were greater in magnitude and longer in duration than those produced by adrenomedullin or adrenomedullin-(15-52) when these agents were injected in doses of 0.1-1 nmol. Adrenomedullin-(22-52) caused no significant change in mesenteric arterial perfusion pressure when injected in doses up to 10 nmol. These results suggest that amino acids 15-52 and the six-membered ring structure of adrenomedullin are important for the expression of vasodilator activity in the mesenteric vascular bed of the cat.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Blood Pressure; Calcitonin Gene-Related Peptide; Cats; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Injections, Intra-Arterial; Male; Mesenteric Arteries; Molecular Sequence Data; Peptide Fragments; Peptides; Recombinant Proteins; Structure-Activity Relationship; Vasodilation

1. Male, Long Evans rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters to permit assessment of the regional haemodynamic responses to human and rat adrenomedullin, to compare the responses to human adrenomedullin to those of human alpha-CGRP in the absence and presence of the CGRP1-receptor antagonist, human alpha-CGRP [8-37], and to determine the involvement of nitric oxide (NO)-mediated mechanisms in the responses to human adrenomedullin, relative to human alpha-CGRP. 2. Human and rat adrenomedullin (0.3, 1, and 3 nmol kg-1, i.v.) caused dose-dependent hypotension and tachycardia, accompanied by increases in renal, mesenteric and hindquarters flows and vascular conductances. At the lowest dose only, the hypotensive and mesenteric vasodilator effects of rat adrenomedullin were significantly greater than those of human adrenomedullin. 3. Human alpha-CGRP at a dose of 1 nmol kg-1 caused hypotension, tachycardia and increases in hindquarters flow and vascular conductance, but reduction in renal and mesenteric flows, and only transient vasodilatations in these vascular beds. These effects were substantially inhibited by human alpha-CGRP [8-37] (100 nmol kg-1 min-1), but those of human adrenomedullin (1 nmol kg-1) were not; indeed, the mesenteric haemodynamic effects of the latter peptide were enhanced by the CGRP1-receptor antagonist. 4. In the presence of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 183 nmol kg-1 min-1), there was only a slight, but significant, inhibition of the hindquarters hyperaemic vasodilator effect of human adrenomedullin, but not that of human alpha-CGRP. 5. These results indicate that the marked regional vasodilator effects of human (and rat) adrenomedullin are largely independent of NO and, in vivo, do not involve CGRP1-receptors.

Topics: Adrenomedullin; Angiotensin II; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Calcitonin Gene-Related Peptide; Catheterization, Peripheral; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Humans; Hypertension; Hypotension; Laser-Doppler Flowmetry; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Peptides; Random Allocation; Rats; Regional Blood Flow; Renal Circulation; Tachycardia; Vasopressins

The effects of rat adrenomedullin, a novel vasorelaxant peptide, on systemic and regional hemodynamics were examined in conscious Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR). The intravenous infusion of adrenomedullin at rates of 1.67 and 5 micrograms/kg per min decreased the mean arterial pressure in a dose-dependent fashion in both types of rats. Adrenomedullin at a rate of 5 micrograms/kg per min increased the heart rate and cardiac output. As a result, the total peripheral resistance significantly decreased. With regards to the regional hemodynamics, adrenomedullin significantly increased the flow rates in the lungs, heart, spleen, kidneys, adrenal glands and small intestine of SHR. The flow rates in the brain and skin did not change and the flow rates in the skeletal muscle and testis were decreased. These regional hemodynamic changes were also observed in SD rats and there was no qualitative difference in the regional responses to adrenomedullin between SHR and SD rats. Thus, adrenomedullin predominantly increased the flow rates in organs in which adrenomedullin gene was highly expressed. It therefore seems that adrenomedullin may act as a local vasodilatory hormone rather than as a circulatory hormone.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Hypertension; Infusions, Intravenous; Peptides; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Regional Blood Flow; Species Specificity; Vascular Resistance

1. The haemodynamic effects of rat adrenomedullin (AM), a novel hypotensive peptide, were examined in anesthetized 16-18 week old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). 2. An intravenous injection of rat AM dose-dependently reduced the mean blood pressure (MBP) with a concomitant fall in total peripheral resistance index (TPRI) and an increase in cardiac index (CI) in both strains of rats. Percent changes in MBP, TPRI and CI were not different between SHR and WKY. 3. The plasma half-life of rat AM in SHR was similar to that in WKY when it was administered at the dose of 1.0 nmol/kg. 4. These findings indicate that AM has a potent vasorelaxant activity in both SHR and WKY. The haemodynamic responsiveness to exogenous AM and its pharmacokinetics in SHR were comparable with those in WKY.

Topics: Adrenomedullin; Amino Acid Sequence; Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Hypertension; Male; Molecular Sequence Data; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

Adrenomedullin is a novel hypotensive peptide recently discovered in human pheochromocytoma. In the present study, we measured the plasma immunoreactive adrenomedullin of healthy subjects and patients with various diseases. Immunoreactive adrenomedullin was found to circulate in blood of the healthy subjects at a considerable concentration (3.3 +/- 0.3 fmol/ml). Plasma adrenomedullin was significantly increased in the patients with congestive heart failure (5.4 +/- 0.3 fmol/ml), essential hypertension (5.3 +/- 0.4 fmol/ml) and renal disease (4.9 +/- 0.4 fmol/ml). In healthy volunteers physical exercise significantly increased the plasma adrenomedullin concentration. The increase of adrenomedullin was inversely related to systolic blood pressure. These findings indicate that adrenomedullin participates in the circulation control in both physiological and diseased conditions. Although the exact origin of circulating adrenomedullin is still unknown, it is thought to be released rapidly by acute exercise, thereby regulating the cardiovascular system by its vasodilating activity.

Topics: Adrenomedullin; Antihypertensive Agents; Exercise; Heart Diseases; Humans; Hypertension; Kidney Diseases; Male; Peptides; Radioimmunoassay; Reference Values

Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from the pheochromocytoma tissue of humans. To examine the pathophysiological role of AM in primary aldosteronism (PA), the plasma concentration of AM in patients with PA was measured with a specific radioimmunoassay and compared to that in age- and sex-matched healthy normotensive subjects. In addition, the concentrations of AM as well as catecholamines in the plasma from both the adrenal vein and the inferior vena cava (IVC) were measured to determine whether or not the circulating AM in these PA patients is supplied from the adrenal medulla, which contains a much higher concentration of AM than any other human tissue does. The plasma concentration of AM in the PA patients (4.57 +/- 0.32 fmol/mL, n = 6) was significantly (P < .01) higher than that in the healthy subjects (3.06 +/- 0.20 fmol/mL, n = 12). A significant positive correlation (r = 0.62, P < .01) was observed between the mean blood pressure and the plasma AM level. The AM concentration in plasma from the adrenal vein was almost the same level as that from the IVC although the concentrations of both epinephrine and norepinephrine in the adrenal vein were much higher than those in the IVC. Therefore, it seems unlikely that the plasma AM in the PA patients is mainly supplied from the adrenal medulla. Judging from the potent hypotensive activity of AM, the present findings suggest that AM participates in defense mechanisms acting against the elevation of blood pressure in the patients with PA.

Topics: Adrenal Glands; Adrenomedullin; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Osmolar Concentration; Peptides; Radioimmunoassay; Veins; Vena Cava, Inferior

Human adrenomedullin (hADM) is a newly isolated peptide with hypotensive activity in normotensive rats. The objective of this study was to investigate the effect of hADM(13-52) on hypertensive animals. hADM(13-52) induced a dose-dependent decrease in the blood pressure of spontaneously hypertensive rats and renal hypertensive rats. This result suggests that hADM is a novel antihypertensive peptide. In isolated rat aortic arteries, hADM(13-52) produced nitric oxide dependent relaxation and inhibited endothelin 1 and angiotensin II release. These in vitro effects may represent the molecular mechanisms underlying the hypotensive action of hADM in vivo.

Topics: Adrenomedullin; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Endothelins; Humans; Hypertension; In Vitro Techniques; Male; Nitric Oxide; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Vasodilator Agents

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

A specific and sensitive radioimmunoassay for adrenomedullin has been developed. Half-maximal inhibition of binding of radioiodinated adrenomedullin was observed at 4 fmol/tube. The radioimmunoassay recognized the entire adrenomedullin molecule and has little crossreactivity with adrenomedullin fragment peptides. Adrenomedullin-like immunoreactivity was found to circulate in human plasma at considerable concentration (3.3 +/- 0.39 fmol/ml). The immunoreactivity of adrenomedullin was eluted at almost the same position as synthetic adrenomedullin on gel-filtration chromatography and reverse-phase high-performance liquid chromatography, suggesting that circulating adrenomedullin recognized by the present radioimmunoassay is identical or very similar to authentic adrenomedullin. Plasma immunoreactive adrenomedullin significantly increased in patients with hypertension, with a progressive rise proportionate to disease severity.

Topics: Adrenomedullin; Antihypertensive Agents; Chromatography, High Pressure Liquid; Humans; Hypertension; Immune Sera; Peptides; Radioimmunoassay