cyclic-gmp and Heart-Failure

Cyclic nucleotide phosphodiesterases (PDEs) modulate the neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple PDE isozymes with different enzymatic properties and subcellular localization regulate local pools of cyclic nucleotides and specific functions. This organization is heavily perturbed during cardiac hypertrophy and heart failure (HF), which can contribute to disease progression. Clinically, PDE inhibition has been considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as new potential targets to treat HF, each having a unique role in local cyclic nucleotide signalling pathways. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF.

Topics: Cardiomegaly; Cyclic GMP; Heart Failure; Humans; Myocytes, Cardiac; Nucleotides, Cyclic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Topics: Cyclic GMP; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Lung; Nitric Oxide; Soluble Guanylyl Cyclase

Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF.

Topics: Angiotensin Receptor Antagonists; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Heart; Heart Failure; Humans; Myocardium; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Vasodilator Agents

Evidence exists that heart failure (HF) has an overall impact of 1-2 % in the global population being often associated with comorbidities that contribute to increased disease prevalence, hospitalization, and mortality. Recent advances in pharmacological approaches have significantly improved clinical outcomes for patients with vascular injury and HF. Nevertheless, there remains an unmet need to clarify the crucial role of nitric oxide/cyclic guanosine 3',5'-monophosphate (NO/cGMP) signalling in cardiac contraction and relaxation, to better identify the key mechanisms involved in the pathophysiology of myocardial dysfunction both with reduced (HFrEF) as well as preserved ejection fraction (HFpEF). Indeed, NO signalling plays a crucial role in cardiovascular homeostasis and its dysregulation induces a significant increase in oxidative and nitrosative stress, producing anatomical and physiological cardiac alterations that can lead to heart failure. The present review aims to examine the molecular mechanisms involved in the bioavailability of NO and its modulation of downstream pathways. In particular, we focus on the main therapeutic targets and emphasize the recent evidence of preclinical and clinical studies, describing the different emerging therapeutic strategies developed to counteract NO impaired signalling and cardiovascular disease (CVD) development.

Topics: Cyclic GMP; Heart; Heart Failure; Humans; Nitric Oxide; Stroke Volume

Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.

Topics: Animals; Cyclic AMP; Cyclic GMP; Heart Failure; Humans; Myocardial Contraction; Myocytes, Cardiac; Phosphoric Diester Hydrolases; Second Messenger Systems; Signal Transduction

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanosine Monophosphate; Guanylate Cyclase; Heart Failure; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Retrospective Studies; Sildenafil Citrate; Soluble Guanylyl Cyclase; Tadalafil; Vasodilator Agents

Heart failure is associated with an impaired NO-soluble guanylyl cyclase (sGC)-cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload.. Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies.. Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts.. Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression.. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

Topics: Animals; Cyclic GMP; Heart Failure; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase; Ventricular Remodeling

The anti-cancer agent doxorubicin (DOX) has high cardiotoxicity that is linked to DOX-mediated increase in oxidative stress, mitochondrial iron overload, DNA damage, autophagy, necrosis, and apoptosis, all of which are also associated with secondary tumorigenicity. This limits the clinical application of DOX therapies. Previous studies have attributed DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the production of reactive oxygen species (ROS), which seem to be independent of its anti-tumor DNA damaging effects. Chemo-sensitization of soluble guanylate cyclase (sGC) in the cyclic guanosine monophosphate (cGMP) pathway induces tumor cell death despite the cardiotoxicity associated with DOX treatment. However, sGC-cGMP signaling must be activated during heart failure to facilitate myocardial cell survival. The sGC pathway is dependent on nitric oxide and signal transduction via the nitric oxide-sGC-cGMP pathway and is attenuated in various cardiovascular diseases. Additionally, cGMP signaling is regulated by the action of certain phosphodiesterases (PDEs) that protect the heart by inhibiting PDE, an enzyme that hydrolyses cGMP to GMP activity. In this review, we discuss the studies describing the interactions between cGMP regulation and DOX-mediated cardiotoxicity and their application in improving DOX therapeutic outcomes. The results provide novel avenues for the reduction of DOX-induced secondary tumorigenicity and improve cellular autonomy during DOX-mediated cardiotoxicity.

Topics: Cyclic GMP; Doxorubicin; Heart Failure; Humans; Signal Transduction; Soluble Guanylyl Cyclase

The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.

Topics: Aminobutyrates; Biphenyl Compounds; Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitric Oxide; Pyrimidines; Soluble Guanylyl Cyclase; Stroke Volume

Cyclic guanosine monophosphate (cGMP), an intracellular second messenger molecule synthesized by guanylated cyclases (GCs), controls various myocardial properties, including cell growth and survival, interstitial fibrosis, endothelial permeability, cardiac contractility, and cardiovascular remodeling. These processes are mediated by the main cGMP effector protein kinase G (PKG) activation of which exerts intrinsic protective responses against the adverse effects of neurohormonal stimulation and pathological cardiac stress. Therapeutic strategies that enhance cGMP levels and PKG activation have been used for heart failure, which can be executed by reducing natriuretic peptide (NP) proteolysis, enhancing cGMP synthesis, or blocking cGMP hydrolysis. Among these, reducing NP clearance with neprilysin inhibitor combined with angiotensin receptor blocker has been shown to greatly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) compared to the prognosis of patients on standard therapy using angiotensin-converting enzyme inhibitors. Moreover, in a recent phase III clinical trial, soluble GC-derived cGMP generation was shown to have potential efficacy in the management of HFrEF. Despite the clinical significance of cGMP/PKG signaling activated by either soluble or particulate GCs in heart failure, the differential signaling events downstream of intracellular cGMP, which are precisely controlled not only by PKG activation but also by the changes in its targeting and compartmentalization depending on the pathophysiology of heart disease, are not yet completely understood. Hitherto, the importance of the latter PKG regulatory mechanisms in developing therapeutic strategies has not been elucidated. Further investigation of redox-based PKG modulation will aid in the successful development of clinical therapies and could also lead to the establishment of improved personalized treatments for patients with heart failure.

Topics: Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart; Heart Failure; Humans; Stroke Volume

Cyclic GMP (cGMP) represents a classic intracellular second messenger molecule. Over the past 2 decades, important discoveries have identified that cGMP signaling becomes deranged in heart failure (HF) and that cGMP and its main kinase effector, protein kinase G, generally oppose the biological abnormalities contributing to HF, in experimental studies. These findings have influenced the design of clinical trials of cGMP-augmenting drugs in HF patients. At present, the trial results of cGMP-augmenting therapies in HF remain mixed. As detailed in this review, strong evidence now exists that protein kinase G opposes pathologic cardiac remodeling through regulation of diverse biological processes and myocardial substrates. Potential reasons for the failures of cGMP-augmenting drugs in HF may be related to biological mechanisms opposing cGMP or because of certain features of clinical trials, all of which are discussed.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Guanylate Cyclase; Heart Failure; Humans; Molecular Targeted Therapy; Myocardium; Nitric Oxide; Phosphoric Diester Hydrolases; Second Messenger Systems

Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Guanylate Cyclase; Heart Failure; Humans; Molecular Targeted Therapy; Myocardial Contraction; Myocardium; Natriuretic Peptides; Nitric Oxide; Phosphoric Diester Hydrolases; Second Messenger Systems; Ventricular Function, Left; Ventricular Remodeling

Coronary artery disease is a major underlying etiology for heart failure. The role of coronary microvascular disease, and endothelial dysfunction, in the pathophysiology of heart failure is poorly appreciated. Endothelial dysfunction, induced by oxidative stress, contributes to the development of heart failure. Alterations of endothelial function and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure with both reduced and preserved ejection fraction. Indeed, an altered endothelium dependent vasodilatation, causing repeated episodes of ischemia/reperfusion, can induce a chronic stunned myocardium with systolic dysfunction and an increased diastolic stiffness with diastolic dysfunction. Moreover, the altered NO-cGMP pathway directly affects myocardial homeostasis. Endothelial dysfunction is associated with worse prognosis and higher rate of cardiovascular events. Potential therapeutic strategies targeting the NO-cGMP pathway in patients with HF will be discussed in this review article. Although clinical data are still inconclusive, the NO-cGMP pathway represents a promising target for therapy.

Topics: Cyclic GMP; Endothelium, Vascular; Heart Failure; Humans; Microcirculation; Muscle, Skeletal; Myocardium; Nitric Oxide; Prognosis; Signal Transduction; Ventricular Dysfunction, Left

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

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

The nitric oxide (NO)-protein kinase G (PKG) pathway has been known for some time to be an important target for cardioprotection against ischaemia/reperfusion injury and heart failure. While many approaches for reducing infarct size in patients have failed in the past, the advent of novel drugs that modulate cGMP and its downstream targets shows very promising results in recent preclinical and clinical studies. Here, we review main aspects of the NO-PKG pathway in light of recent drug development and summarise potential cardioprotective strategies in which cGMP is the main player.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Activation; Enzyme Activators; Heart Failure; Humans; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Signal Transduction

The underlying cause of cardiac hypertrophy, fibrosis, and heart failure has been investigated in great detail using different mouse models. These studies indicated that cGMP and cGMP-dependent protein kinase type I (cGKI) may ameliorate these negative phenotypes in the adult heart. Recently, evidence has been published that cardiac mitochondrial BKCa channels are a target for cGKI and that activation of mitoBKCa channels may cause some of the positive effects of conditioning in ischemia/reperfusion injury. It will be pointed out that most studies could not present convincing evidence that it is the cGMP level and the activity cGKI in specific cardiac cells that reduces hypertrophy or heart failure. However, anti-fibrotic compounds stimulating nitric oxide-sensitive guanylyl cyclase may be an upcoming therapy for abnormal cardiac remodeling.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Fibrosis; Heart Failure; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Second Messenger Systems; Ventricular Remodeling

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

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

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3',5'- monophosphate (cAMP) and cyclic guanosine 3',5'- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotides can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE subtypes - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart and summarizes experimental and clinical data that have explored the utility of targeted PDE inhibition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Diseases; Heart Failure; Humans; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Topics: Benzoates; Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Soluble Guanylyl Cyclase; Stroke Volume

Inhibitors of PDE3, a family of dual-specificity cyclic nucleotide phosphodiesterases, are used clinically to increase cardiac contractility by raising intracellular cAMP content in cardiac myocytes and to reduce vascular resistance by increasing intracellular cGMP content in vascular smooth muscle myocytes. When used in the treatment of patients with heart failure, PDE3 inhibitors are effective in the acute setting but increase sudden cardiac death with long-term administration, possibly reflecting pro-apoptotic and pro-hypertrophic consequences of increased cAMP-mediated signaling in cardiac myocytes. cAMP-mediated signaling in cardiac myocytes is highly compartmentalized, and different phosphodiesterases, by controlling cAMP content in functionally discrete intracellular microcompartments, regulate different cAMP-mediated pathways. Four variants/isoforms of PDE3 (PDE3A1, PDE3A2, PDE3A3, and PDE3B) are expressed in cardiac myocytes, and new experimental results have demonstrated that these isoforms, which are differentially localized intracellularly through unique protein-protein interactions, control different physiologic responses. While the catalytic regions of these isoforms may be too similar to allow the catalytic activity of each isoform to be selectively inhibited, targeting their unique protein-protein interactions may allow desired responses to be elicited without the adverse consequences that limit the usefulness of existing PDE3 inhibitors.

Topics: Animals; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Heart Failure; Humans; Myocardial Contraction; Myocytes, Cardiac; Myocytes, Smooth Muscle; Phosphodiesterase 3 Inhibitors; Phosphorylation; Protein Isoforms; Signal Transduction

Cyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families that are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP, controlling specific cell functions in response to various neurohormonal stimuli. In the myocardium, the PDE3 and PDE4 families predominate, degrading cAMP and thereby regulating cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in humans, but their use is limited to acute heart failure and intermittent claudication. PDE5 inhibitors, which are used with success to treat erectile dysfunction and pulmonary hypertension, do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence however that these PDE, as well as other PDE families including PDE1, PDE2 and PDE9, may play important roles in cardiac diseases, such as hypertrophy and heart failure (HF). After a brief presentation of the cyclic nucleotide pathways in cardiac myocytes and the major characteristics of the PDE superfamily, this review will focus on the potential use of PDE inhibitors in HF, and the recent research developments that could lead to a better exploitation of the therapeutic potential of these enzymes in the future.

Topics: Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Heart; Heart Failure; Humans; Molecular Targeted Therapy; Myocardial Ischemia; Myocardial Reperfusion Injury; Phosphodiesterase Inhibitors

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Drug Design; Heart Failure; Humans; Molecular Targeted Therapy; Second Messenger Systems; Stroke Volume; Ventricular Function, Left

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO-sGC-cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO-sGC-cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO-sGC-cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

Topics: Cyclic GMP; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Nitric Oxide; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Treatment Outcome

The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology.. Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease.. Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress.. Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.

Topics: Animals; Arginase; Autocrine Communication; Biopterins; Calcium Signaling; Cyclic GMP; Diabetes Mellitus; Disease Progression; Enzyme Activation; Enzyme Induction; Heart Diseases; Heart Failure; Humans; Hypertension; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase; Paracrine Communication; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Signal Transduction; Superoxides

Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.

Topics: Cyclic GMP; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Signal Transduction

Cyclic guanosine monophosphate (cGMP) and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart. Growing evidence supports a positive impact on a variety of cardiac disease conditions from the suppression of cGMP hydrolysis. The latter is regulated by members of the phosphodiesterase (PDE) superfamily, of which cGMP-selective PDE5 has been best studied. Inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischemic injury, and cardiotoxicity. Clinical trials have begun exploring their potential to benefit dilated cardiomyopathy and heart failure with a preserved ejection fraction. This review discusses recent developments in the field, highlighting basic science and clinical studies.

Topics: Carbolines; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Fibrosis; Heart; Heart Failure; Humans; Hypertrophy; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Transforming Growth Factor beta; TRPC Cation Channels; Ventricular Remodeling

Cyclic GMP is a ubiquitous second messenger that regulates a wide array of physiologic processes such as blood pressure, long bone growth, intestinal fluid secretion, phototransduction and lipolysis. Soluble and single-membrane-spanning enzymes called guanylyl cyclases (GC) synthesize cGMP. In humans, the latter group consists of GC-A, GC-B, GC-C, GC-E and GC-F, which are also known as NPR-A, NPR-B, StaR, Ret1-GC and Ret2-GC, respectively. Membrane GCs are activated by peptide ligands such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), guanylin, uroguanylin, heat stable enterotoxin and GC-activating proteins. Nesiritide and carperitide are clinically approved peptide-based drugs that activate GC-A. CD-NP is an experimental heart failure drug that primarily activates GC-B but also activates GC-A at high concentrations and is resistant to degradation. Inactivating mutations in GC-B cause acromesomelic dysplasia type Maroteaux dwarfism and chromosomal mutations that increase CNP concentrations are associated with Marfanoid-like skeletal overgrowth. Pump-based CNP infusions increase skeletal growth in a mouse model of the most common type of human dwarfism, which supports CNP/GC-B-based therapies for short stature diseases. Linaclotide is a peptide activator of GC-C that stimulates intestinal motility and is in late-stage clinical trials for the treatment of chronic constipation. This review discusses the discovery of cGMP, guanylyl cyclases, the general characteristics and therapeutic applications of GC-A, GC-B and GC-C, and emphasizes the regulation of transmembrane guanylyl cyclases by phosphorylation and ATP.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Bone Development; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Guanylate Cyclase; Heart Failure; Humans; Mice; Molecular Targeted Therapy; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide

Compounds that inhibit the catalytic activity of cyclic nucleotide phosphodiesterases are used as therapeutic agents to increase intracellular cAMP and/or cGMP content in cells or tissues of interest. In patients with heart failure, inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases are used to raise intracellular cAMP content in cardiac muscle, with inotropic actions. These drugs are effective in acute applications, but their long-term use has been complicated by an increase in cardiovascular mortality in clinical trials. Inhibitors of enzymes in the PDE5 family have been used to raise cGMP content in cardiac muscle in animal models of pressure overload, chronic β-adrenergic receptor stimulation, ischemic injury, and doxorubicin toxicity, and have been shown to have antihypertrophic and cardioprotective actions. Recent experimental results raise some question as to the likely applicability of these findings to humans, in whose hearts PDE5 is present at much lower levels than those seen in animal models, and raise the possibility of PDE1, a dual-specificity phosphodiesterase present at high levels in human myocardium, as an alternative target for inotropic and cardioprotective actions.

Topics: Animals; Cyclic AMP; Cyclic GMP; Heart Failure; Humans; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors

Endothelial dysfunction associated with decreased nitric oxide (NO) bioactivity is a major feature of vascular diseases such as atherosclerosis or diabetes. Sodium nitroprusside (SNP)-induced relaxation is entirely dependent on cyclic guanosine monophosphate (cGMP) and preserved in atherosclerosis, suggesting that smooth muscle response to NO donor is intact. However, NO gas activates both cGMP-dependent and -independent signal pathways in vascular smooth muscle cells, and oxidative stress associated with vascular diseases selectively impairs cGMP-independent relaxation to NO. Sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), which regulates intracellular Ca(2+) levels by pumping Ca(2+) into store, is a major cGMP-independent target for NO. Physiological levels of reactive nitrogen species (RNS) S-glutathiolate SERCA at Cys674 to increase its activity, and the augmentation of RNS in vascular diseases irreversibly oxidizes Cys674 or nitrates tyrosine residues at Tyr296-Tyr297, which are associated with loss of function. S-glutathiolation of various proteins by NO can explain redox-sensitive cGMP-independent actions, and oxidative inactivation of target proteins for NO can be associated with the pathogenesis of cardiovascular diseases. Oxidative inactivation of SERCA is also implicated with dysregulation of smooth muscle migration, promotion of platelet aggregation, and impairment of cardiac function, which can be implicated with restenosis, pathological angiogenesis, thrombosis, as well as heart failure. Analysis of posttranslational oxidative modifications of SERCA and the preservation of SERCA function can be novel strategies against cardiovascular diseases associated with oxidative stress.

Topics: Animals; Antioxidants; Atherosclerosis; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetic Angiopathies; Endothelium, Vascular; Glutathione; Heart Failure; Humans; Mice; Models, Animal; Muscle, Smooth, Vascular; Nitric Oxide; Oxidative Stress; Protein Processing, Post-Translational; Rabbits; Rats; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tyrosine; Vasodilation

Group II pulmonary hypertension (PH) commonly occurs in the setting of a pressure-overloaded left ventricle (LV) which is also conducive to the development of heart failure with preserved ejection fraction. Population trends and a high prevalence of underlying causative conditions, such as essential hypertension or aortic stenosis, have increased the awareness of the pressure-overloaded LV and associated group II pulmonary hypertension. Patients often exhibit poor exercise tolerance and signs of heart failure indistinguishable from systolic heart failure; but effective medical treatments in this area have been lacking. Recent preclinical work has shed light on how the down-regulated nitric oxide - cyclic GMP pathway (within the myocardium and pulmonary vasculature) contributes to the pathophysiology of these associated conditions. This article will discuss the impact of the nitric oxide - cyclic GMP pathway on the pathogenesis of the pressure-overloaded LV and group II pulmonary hypertension, and will also introduce the potential therapeutic value of modulating this pathway.

Topics: Antihypertensive Agents; Aortic Valve Stenosis; Cardiomyopathies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diastole; Heart Failure; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Signal Transduction; Stroke Volume; Systole; Ventricular Dysfunction, Left; Ventricular Remodeling

Left ventricular (LV) remodelling remains an important treatment target in patients after myocardial infarction (MI) and chronic heart failure (CHF). Accumulating evidence has supported the concept that beneficial effects of current pharmacological treatment strategies to improve the prognosis in these patients, such as angiotensin-converting enzyme (ACE) inhibition, angiotensin type 1 receptor blocker therapy, and beta-blocker therapy, are related, at least in part, to their effects on LV remodelling and dysfunction. However, despite modern reperfusion therapy after MI and optimized treatment of patients with CHF, LV remodelling is observed in a substantial proportion of patients and is associated with an adverse clinical outcome. These observations call for novel therapeutic strategies to prevent or even reverse cardiac remodelling. Recent insights from experimental studies have provided new targets for interventions to prevent or reverse LV remodelling, i.e. reduced endothelial nitric oxide (NO) synthase-derived NO availability, activation of cardiac and leukocyte-dependent oxidant stress pathways, inflammatory pathway activation, matrix-metalloproteinase activation, or stem cell transfer and delivery of novel paracrine factors. An important challenge in translating these observations from preclinical studies into clinical treatment strategies relates to the fact that clinical studies are designed on top of established pharmacological therapy, whereas most experimental studies have tested novel interventions without concomitant drug regimens such as ACE inhibitors or beta-blockers. Therefore, animal studies may overestimate the effect of potential novel treatment strategies on LV remodelling and dysfunction, since established pharmacological therapies may act, in part, via identical or similar signalling pathways. Nevertheless, preclinical studies provide essential information for identifying potential novel targets, and their potential drawbacks, and are required for developing novel clinical treatment strategies to prevent or reverse LV remodelling and dysfunction.

Topics: Adrenergic beta-Antagonists; Angiogenesis Inducing Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Cyclic GMP; Drugs, Investigational; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Matrix Metalloproteinase Inhibitors; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitric Oxide; Protease Inhibitors; Signal Transduction; Stem Cell Transplantation; Treatment Outcome; Ventricular Remodeling

Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.

Topics: Animals; Cyclic GMP; Enzyme Activators; Enzyme Inhibitors; Guanylate Cyclase; Heart Failure; Humans; Natriuretic Peptides; Nitric Oxide; Phosphodiesterase Inhibitors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase

Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes-which differ with respect to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation-have been identified. Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways in heart failure.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Heart Failure; Hemodynamics; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential beneficial effects were demonstrated in experimental models of congestive heart failure and left ventricular hypertrophy. Some of the observed effects resemble the basic mechanisms of ischaemic pre-conditioning, mimicking both acute and delayed effects. Other effects may be due to action on systemic and cardiac haemodynamics. Mechanisms and signalling pathways, characterized in some of the experimental models, appear to be complex: for instance, the rate of cyclic guanosine monophosphate (cGMP) synthesis and the functional compartmentalization of intracellular cGMP metabolism as well as interaction with ss-adrenergic and nitric oxide signalling may influence effects in different experimental settings. In this review, we discuss mechanisms, signalling pathways, and experimental limitations and touch on considerations for translation into potentially useful applications in the clinical arena.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

Natriuretic peptides such as brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are commonly used in the diagnosis and evaluation of heart failure. However, their utility in patients with chronic kidney disease (CKD) is less clear as renal dysfunction itself can be associated with elevated concentrations of these biomarkers. Given the high prevalence of left ventricular hypertrophy and left ventricular systolic dysfunction in patients with CKD, diagnosis or exclusion of heart failure becomes important in this population. Most studies to date indicate that upward adjustment of diagnostic cut points preserves the usefulness of both BNP and NT-proBNP in the CKD patient, with similar clinical performance of each biomarker. We review the role of natriuretic peptide in heart failure in the setting of chronic renal disease.

Topics: Biomarkers; Chronic Disease; Cyclic GMP; Heart Failure; Humans; Kidney Diseases; Natriuretic Peptides; Renal Dialysis

Nitric oxide (NO) produced by endothelial NO synthase (NOS) in low concentrations is a unique messenger molecule with key homeostatic functions concerning the prevention of pathological vascular and tissue changes such as increases in blood pressure, platelet degranulation, mononuclear cell infiltration, cell proliferation and extracellular matrix protein accumulation. This is in contrast to high levels of NO derived from inducible NOS which act as detrimental effector molecules and free radicals in immune response. Deficiency in NO's protective signaling actions is a major characteristic in numerous experimental and human disease situations. The main function of the NO signaling pathway is activation of the soluble guanylate cyclase (sGC) enzyme with subsequent generation of cyclic guanosine monophosphate (cGMP) as a second messenger and downstream mediator. In the past, attempts to overcome deficiency in endothelial NO effects were focused primarily on increasing the supply with the NO precursor L-arginine or on the use of directly NO-releasing compounds. The clinical impact of these strategies, however, was rather limited. Recent state-of-the-art studies have revealed that NO signaling is highly regulated at the transcriptional level and that deficiency in NO signaling correlates closely with pathological changes. In parallel efforts, novel pharmacological compounds which specifically enhance NO/cGMP signaling have been developed and have demonstrated remarkable efficacy in experimental disease settings. In this review, we summarize the current state of knowledge on the impairment of NO/cGMP signaling and about its pharmacological stimulation. In the first part, experimental renal fibrosis, i.e. the tandem rat model of acute anti-thy1 glomerulonephritis and progressive anti-thy1 renal fibrosis will serve as a paradigm for introducing this new and exciting field. In the second part, we will address the most recent findings on NO signaling in non-renal diseases. Together, these results point out that deficiency in NO/cGMP is a common key pathway as well as a novel therapeutic target in a number of diseases.

Topics: Animals; Atherosclerosis; Cyclic GMP; Fibrosis; Glomerulonephritis; Heart Failure; Humans; Hypertension, Pulmonary; Kidney; Kidney Diseases; Liver Cirrhosis; Nitric Oxide; Nitric Oxide Synthase Type III; Signal Transduction; Thrombosis

The concept of the heart as an endocrine organ has been attractive since the discovery of atrial natriuretic peptide. This review focuses on the second discovered natriuretic peptide from the heart - B-type natriuretic peptide (BNP), widely used as a tool in the diagnosis of heart failure (HF). Controversy remains regarding its use as a therapeutic agent in HF. This article places into perspective some of the debate and provides insights into the therapeutics of BNP and the importance of its second messenger 3'5' cyclic guanosine monophosphate, which also is the second messenger for nitric oxide and is modulated by renal phosphodiesterases.

Topics: Cyclic GMP; Heart Failure; Humans; Kidney; Natriuretic Peptide, Brain

Natriuretic peptides (NPs) secreted by the heart in response to volume overload are pleiotropic molecules with vasodilating, diuretic, natriuretic, antiproliferative, and antifibrotic actions. Functioning of the NP system is altered in congestive heart failure (CHF), suggesting that support of the NP system might be beneficial in treatment of acute and chronic CHF. Several approaches alone or in combination with other pharmacologic therapies have been shown to enhance function of the NP system: direct administration of native and designer NPs, inhibition of degradation of NPs and their second messenger (cyclic guanosine monophosphate ), and stimulation of cGMP generation. Despite increasing numbers of studies using NPs in therapy of acute and chronic CHF, several controversies regarding safety, efficacy, and dosing of NPs need to be addressed. Moreover, further research is warranted to identify the stages and etiologies of CHF that may profit from NP therapy.

Topics: Acute Disease; Chronic Disease; Cyclic GMP; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Prognosis; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome

The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an approximately 38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3 exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Signaling; Captopril; Cyclic GMP; Gene Expression; Heart Failure; Humans; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myosin-Light-Chain Phosphatase; Vasoconstriction

Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation-contraction coupling (ECC), and here we discuss the evidence that NO may modulate the function of the ryanodine receptor Ca(2+) release channel (RyR2) on the cardiac sarcoplasmic reticulum (SR). Both constitutive isoforms of NOS have been shown to co-immunoprecipitate with RyR2, suggesting that the channel may be a target protein for NO. eNOS gene deletion has been shown to abolish the increase in spontaneous Ca(2+) spark frequency in cardiomyocytes exposed to sustained stretch, whereas the effect of nNOS-derived NO on RyR2 function remains to be investigated. Single channel studies have been performed with RyR2 reconstituted in planar lipid bilayers and exposed to various NO donors and, under these conditions, NO appears to have a dose-dependent, stimulatory effect on channel open probability (P(open)). We discuss whether NO has a direct effect on RyR2 via covalent S-nitrosylation of reactive thiol residues within the protein, or whether there are downstream effects via cyclic nucleotides, phosphodiesterases, and protein kinases. Finally, we consider whether the proposed migration of nNOS from the SR to the sarcolemma in the failing heart may have consequences for the nitrosative vs. oxidative balance at the level of the RyR2, and whether this may contribute to an increased diastolic Ca(2+) leak, depleted SR Ca(2+) store, and reduced contractility in heart failure.

Topics: Animals; Calcium; Cyclic GMP; Heart; Heart Failure; Humans; Myocardial Contraction; NADPH Oxidases; Nitric Oxide; Oxidation-Reduction; Ryanodine Receptor Calcium Release Channel; Superoxides

A mainstay of therapy for congestive heart failure has been the use of potent diuretic agents, such as furosemide, that target the kidney to enhance sodium and water excretion. Although furosemide is widely used to treat the symptoms of acute decompensated heart failure (ADHF), the consequent activation of the renin-angiotensin-aldosterone system may limit the natriuretic response by reducing the glomerular filtration rate. In addition, excessive diuresis may reduce cardiac preload and result in systemic hypotension, which reduces renal perfusion pressure and prerenal azotemia and raises levels of blood urea nitrogen. In order to preserve and/or enhance renal function in ADHF, especially with agents such as conventional diuretics and vasodilators, an understanding of intrarenal factors that may protect the kidney may provide a direction for optimal use of current therapies and also lead to newer therapeutic strategies. Vasodilators, especially those that are linked to cGMP activation, may provide an alternative approach.

Topics: Acute Disease; Cyclic GMP; Diuretics; Furosemide; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Renin-Angiotensin System; Risk Factors; Sodium Potassium Chloride Symporter Inhibitors; Vasodilator Agents

One of the major conceptual advances in the understanding of the pathogenesis of heart failure has been the insight that myocardial dysfunction and heart failure may progress as the result of the sustained over-expression of nitric oxide (NO) metabolites locally and in blood modulated by inducible nitric oxide synthase (iNOS). This by virtue of their deleterious effects is sufficient to contribute to disease progression by provoking left ventricular (LV) remodeling, hypertrophy and progressive LV dysfunction. Recently, tumor necrosis factor-alpha (TNF-alpha) has also been identified in this setting of heart failure. Analogous to the situation with NO, the over-expression of TNF-alpha is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between TNF-alpha and the NO have been recognized in the cardiovascular system for over a decade, the nature and importance of the interactions between these biologically active molecules in cardiac hypertrophy has become apparent only in the recent times. Therefore, we focused on the prevailing updated evidence which suggests that there is a functionally significant cross-regulation between NO and TNF-alpha signaling in blood thus playing a part in cardiac hypertrophy and failure. The discussions presented here will have a bearing on the therapeutic potential via inhibitors of these pathways in reducing cardiomyocyte hypertrophy and the LV dysfunction.

Topics: Animals; Cyclic GMP; Disease Progression; Heart Failure; Humans; Nitric Oxide; Tumor Necrosis Factor-alpha; Up-Regulation

Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.

Topics: Atrial Natriuretic Factor; Cardiovascular Agents; Clinical Trials as Topic; Cyclic GMP; Drug Therapy, Combination; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments; Receptors, Atrial Natriuretic Factor; Snake Venoms; Treatment Outcome

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5'-guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by promoting vasodilation and inhibiting vascular smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In pathophysiological states with endothelial dysfunction this signaling pathway is impaired. Activation of sGC has traditionally been achieved with nitrovasodilators; however, these drugs are associated with the development of tolerance and potentially deleterious cGMP-independent actions. In this review the actions of BAY 41-2272, the prototype of a new class of NO-independent sGC stimulators, in cardiovascular disease models is discussed. BAY 41-2272 binds to a regulatory site on the alpha-subunit of sGC and stimulates the enzyme synergistically with NO. BAY 41-2272 had antihypertensive actions and attenuated remodeling in models of systemic arterial hypertension. It also unloaded the heart in experimental congestive heart failure. BAY 41-2272 reduced pulmonary vascular resistance in acute and chronic experimental pulmonary arterial hypertension. Furthermore, BAY 41-2272 inhibited platelet aggregation in vitro and leukocyte adhesion in vivo. These findings make direct sGC stimulation with BAY 41-2272 a promising new therapeutic strategy for cardiovascular diseases and warrant further studies. Finally, the significance of the novel NO- and heme-independent sGC activator BAY 58-2667, which activates two forms of NO-insensitive sGC, is briefly discussed.

Topics: Animals; Antihypertensive Agents; Benzoates; Cardiovascular Diseases; Cell Adhesion; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heme; Humans; Hypertension; Hypertension, Pulmonary; Inflammation; Leukocytes; Nitric Oxide; Platelet Aggregation; Pyrazoles; Pyridines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilator Agents

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with beta-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adrenergic beta-Antagonists; Animals; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Coronary Circulation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Drug Therapy, Combination; Drugs, Investigational; Enzyme Activation; Forecasting; Half-Life; Heart Failure; Humans; Hypertension, Pulmonary; Isoenzymes; Multicenter Studies as Topic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phosphorylation; Prospective Studies; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Pulmonary Circulation; Randomized Controlled Trials as Topic; Rats; Treatment Outcome; Vasodilator Agents

Levels of cyclic guanosine 3',5'-monophosphate (cGMP) are elevated in plasma and urine from patients with some cardiovascular diseases and some types of cancer.. This paper is based on studies of cGMP as a biomarker.. It is well documented that cGMP levels are elevated in plasma in patients with heart failure and various leukaemias and in urine from patients with gynaecological cancers. Because of great interindividual variation in levels, cGMP is less suitable in primary diagnostics, but appears to be a sensitive marker in individual follow up in some diseases.

Topics: Biomarkers; Biomarkers, Tumor; Cardiovascular Diseases; Cyclic GMP; Female; Heart Failure; Humans; Leukemia; Male; Neoplasms

Topics: Asthma; Biomarkers; Cyclic GMP; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hyperparathyroidism; Liver Diseases; Myocardial Infarction; Neoplasms; Nitric Oxide; Radioimmunoassay; Reference Values; Specimen Handling

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Cardiopulmonary Bypass; Chronic Disease; Cyclic GMP; Glomerular Filtration Rate; Heart Failure; Humans; Intraoperative Care; Myocardial Infarction; Natriuresis; Renin-Angiotensin System; Urination; Vasodilation

The availability of selective inhibitors of the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5) has created increasing interest in unlocking the therapeutic potential of PDE5 inhibition in cardiovascular diseases that are marked by dysfunction of nitric oxide (NO)-cGMP signaling. Pulmonary arterial hypertension (PAH) and heart failure (HF) are characterized by pulmonary arterial vasoconstriction that is thought to be caused by relative deficiencies of vasodilators such as NO and exaggerated production of vasoconstrictors such as endothelin. PDE5 is abundant in the pulmonary vasculature where it catabolizes cGMP, the second messenger of NO. Inhibition of PDE5 has been shown to lower pulmonary vascular resistance in PAH and HF by augmenting local cGMP. This review outlines the therapeutic potential of PDE5 inhibition for the treatment of PAH and HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

The endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in c

Topics: Atrial Natriuretic Factor; Cyclic GMP; Heart; Heart Failure; Humans; Kidney; Natriuretic Peptide, Brain; Protease Inhibitors; Vasodilation

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

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

The prognostic importance of levels of urinary excretion of cyclic GMP (cGMPu), the second messenger of the atrial natriuretic factor (ANF) was studied in different cardiac pathologies in 31 patients (19 males and 12 females, average age 66 +/- 15 years) and compared with 31 control subjects of the same age (+/- 4 years) and sex. In the control group, the average cGMPu was 0.35 +/- 0.17 mumoles/24 hours/m2, and, with respect to urinary creatinine, increased with age (r = 0.54, p = 0.002). In the 16 patients with cardiac failure, the cGMPu was very high (1.03 +/- 0.59 mumoles/24 hours/m2, p less than 0.001) without any significant correlation with NYHA functional class although it fell after treatment. After myocardial infarction (8 cases including 3 with cardiac failure), the cGMPu was also high (0.49 +/- 0.33 mumoles/24 hours/m2) but it did not differ significantly from the control values in the 9 atrial arrhythmias without cardiac failure. The cGPMu was related to the cardiothoracic ratio but not to any blood gas parameter or echocardiographic measurement. In conclusion, the cGMPu is more stable and easier to measure than the ANF. It would seem to be a sensitive marker of cardiac failure complicating the most common cardiac pathologies observed in clinical practice.

Topics: Adult; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Atria; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction

The renin-angiotensin and cardiac natriuretic systems were studied by measuring plasma renin activity, plasma concentrations of active renin, angiotensinogen, atrial natriuretic hormone and urinary cyclic GMP in 37 patients with moderate to severe cardiac failure. The plasma sodium and osmolality were chosen as markers of hydroelectrolytic imbalance and plasma concentrations of préalbumin and retinol-binding protein as indicators of the degree of hepatocellular dysfunction. Plasma renin activity (PRA) plasma concentration of active renin, atrial natriuretic hormone and urinary cyclic GMP were higher in patients in NYHA Class IV than in those in Classes II-III, whilst plasma sodium, angiotensinogen, prealbumin and retinol-binding protein concentrations were lower in Class IV patients than in patients in Classes II-III. The plasma angiotensinogen concentrations were negatively correlated with PRA (r = -0.41, p less than 0.02), active renin (r = -0.45, p = 0.005), the atrial natriuretic factor (r = -0.36, p less than 0.05) and positively correlated with prealbumin (r = 0.54, p less than 0.001) and retinol-binding protein (r = 0.60, p less than 0.0001). In NYHA Class IV patients the decreased circulating renin substrate led to an underestimation of plasma concentrations of active renin by measurement of PRA. On the other hand, direct radio-immunometric measurement of active renin allows true estimation of circulating active renin, independently of plasma angiotensinogen concentrations and thereby reliably reflects activation of the renin system. The serum sodium was negatively correlated with active renin (r = -0.66, p less than 0.0001) in these patients not receiving converting enzyme inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Arginine Vasopressin; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Renin; Renin-Angiotensin System; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Sodium

Sinorphan is a powerful inhibitor of enkephalinases or endopeptidases 24-11, enzymes implicated in the degradation of the atrial natriuretic factor (ANF). In healthy volunteers, it increases plasma concentrations of endogenic ANF and increases diuresis and natriuresis. In order to study the tolerance and biological effects of pharmacological increase of plasma concentrations of endogenic ANF in severe congestive cardiac failure, 12 patients (in functional Classes III or IV of the NYHA classification) were given a single oral dose of 10, 20 or 40 mg of Sinorphan. Sinorphan was clinically well tolerated. The diastolic blood pressure decreased slightly (- 10 +/- 9 mmHg) but significantly (p less than 0.05). Systolic blood pressure and heart rate were unchanged. Despite spontaneously high plasma ANF concentrations (on average 15 times higher than normal subjects), Sinorphan induced an additional increase of 80 to 100% of plasma ANF concentration compared to the initial values (p less than 0.01) with no dose-dependent response for the dosages used. The inhibition of plasma endopeptidase activity attained 47% at the 30th minute. Urinary cyclic GMP excretion increased by 30% at the second hour (p less than 0.05). In addition, a statistically non significant tendency to increase diuresis and natriuresis was observed. These results show that Sinorphan increases plasma ANF concentrations by inhibition of its degradation in severe congestive cardiac failure and that this increase seems to be associated with potentially beneficial biological changes. The concept of endopeptidase inhibition should constitute a new therapeutic approach in cardiac failure, a situation in which the ANF seems to exert a favourable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Cyclic GMP; Diuresis; Female; Heart Failure; Humans; Male; Middle Aged; Natriuresis; Neprilysin; Thiorphan

Cardiac overload is associated with an overexpression of the atrial natriuretic-factor (ANF) gene in experimental models and in man. Sites of ANF gene overexpression are the atria but also the ventricular myocardium. This recruitment phenomenon of the ventricle to synthesise and secrete ANF is directly dependent on the increase in stress-stretch relationship in each cardiocyte. Therefore, the levels of plasma ANF and its second messenger, cyclic glycophosphate mutase in plasma and urine appear as markers of congestive heart failure in animal models and in man. Particularly, plasma ANF has been recognized recently as independent prognostic factor in congestive heart failure.

Topics: Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Humans

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

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

The normal control of cardiovascular function exerted by the sympathetic nervous system is disturbed in congestive heart failure. The failing pump function of the heart evokes an increase in sympathetic activity which may be reflected in increased levels of plasma noradrenaline. However, these levels are generally below the concentrations needed to activate the adrenergic effector systems, indicating that the cardiovascular consequences of the increased sympathetic activity is not mediated by circulating noradrenaline. In the failing human heart there is a decrease in beta-adrenoceptor density which is related to decreasing ventricular function. This finding suggests that the myocardium is exposed to high concentrations of noradrenaline, inducing downregulation of the receptor number, despite the fact that in the failing heart the noradrenaline stores are reduced. In heart failure the plasma noradrenaline concentration was found to be directly related to mortality and was suggested to provide a better guide to prognosis than other commonly measured indexes of cardiac performance.

Topics: Adrenergic Agonists; Animals; Cyclic AMP; Cyclic GMP; Heart Failure; Humans; Muscle, Smooth, Vascular; Norepinephrine; Prognosis; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Regional Blood Flow; Sodium-Potassium-Exchanging ATPase; Stimulation, Chemical

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Glomerular Filtration Rate; Heart Failure; Humans; Natriuretic Peptide, Brain; Sodium; Tadalafil

Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF).. PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome.. Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks.. NCT02554890 clinical.trials.gov.

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biomarkers; Biphenyl Compounds; Cyclic GMP; Drug Combinations; Enalapril; Female; Heart Failure; Hemodynamics; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Tetrazoles; Treatment Outcome; Troponin; Valsartan

Heart failure (HF) patients are at an increased risk of thrombotic events. Here, we investigated the effects of exercise training on platelet function and factors involved in its modulation in HF.. Thirty HF patients were randomized to 6 months of supervised exercise training or to a control group that remained sedentary. Exercise training consisted of 30 min of moderate-intensity treadmill exercise, followed by resistance and stretching exercises, performed three times a week. Blood was collected before and after the intervention for platelet and plasma obtainment.. Peak VO2 increased after exercise training (18.0 ± 2.2 vs. 23.8 ± 0.5 mlO2/kg/min; p < 0.05). Exercise training reduced platelet aggregation induced by both collagen and ADP (approximately -6%; p < 0.05), as well as platelet nitric oxide synthase activity (0.318 ± 0.030 vs. 0.250 ± 0.016 pmol/10(8) cells; p < 0.05). No difference in the above-mentioned variables were observed in the control group. No significant difference was observed in intraplatelet cyclic guanosine monophosphate levels among groups. There was a significant increase in the activity of the antioxidant enzymes superoxide dismutase and catalase in plasma and platelets, resulting in a decrease in both lipid and protein oxidative damage. Systemic levels of the inflammatory markers C-reactive protein, fibrinogen, and tumour necrosis factor α were also reduced in HF after training.. Our results suggest that regular exercise training is a valuable adjunct to optimal medical management of HF, reducing platelet aggregation via antioxidant and anti-inflammatory effects, and, therefore, reducing the risk of future thrombotic events.

Topics: Antioxidants; Biomarkers; Blood Platelets; Brazil; Cyclic GMP; Exercise Therapy; Female; Heart Failure; Humans; Inflammation; Inflammation Mediators; Lipids; Male; Middle Aged; Motor Activity; Muscle Stretching Exercises; Nitric Oxide Synthase; Oxidative Stress; Oxygen Consumption; Platelet Aggregation; Platelet Function Tests; Predictive Value of Tests; Prospective Studies; Recovery of Function; Resistance Training; Risk Factors; Thrombosis; Time Factors; Treatment Outcome

The progression of heart failure is affected by several factors, including chronic stimulation of the β-adrenoceptor. This clinical study was designed to measure the effects of thoracic epidural analgesia (TEA) on the plasma levels of norepinephrine (NE), cAMP, and cGMP in patients with heart failure and assess the clinical implication of TEA.. Forty patients with heart failure were randomly assigned to TEA (TEA plus standard care) and control groups (standard care). The plasma concentrations of cAMP, cGMP, brain natriuretic peptide (BNP), and NE were measured using ELISA before treatment, the second and fourth weeks of treatment.. The plasma concentrations of cAMP, cGMP, BNP, and NE in the TEA group were significantly reduced by the fourth week compared to their initial concentrations (P < 0.01, for all parameters) and the control group (P < 0.05, P < 0.05, P < 0.01, and P < 0.05, respectively). The values for left ventricular end diastolic diameter (LVEDD), ejection fraction (EF), and fractional shortening (FS) in the TEA group improved significantly compared to their initial values and the control group. However, the changes in levels for these indices in the control group were no statistical significant compared to the initial levels.. TEA can effectively decrease the plasma concentrations of cAMP and cGMP and improve cardiac function in patients with heart failure. The decreased levels of NE and cAMP occurred before the improvement in cardiac function, indicating that the abnormal epidural signal transduction can be corrected in patients with heart failure.

Topics: Analgesia, Epidural; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Humans; Male; Norepinephrine; Signal Transduction; Thoracic Vertebrae; Treatment Outcome; Ultrasonography

Natriuretic peptides exert vasodilatory, natriuretic, and diuretic effects and inhibit renin and aldosterone secretion. Carperitide, a recombinant alpha-human atrial natriuretic peptide (hANP), is used for the treatment of cardiac failure. Patients with renal failure often require renal replacement therapy, and little is known about the pharmacokinetics of carperitide when used for renal replacement therapy.. Eleven patients who received continuous carperitide infusion and needed continuous venovenous hemofiltration (CVVHF) for acute renal failure were observed. The plasma hANP concentration was noted and the hANP clearance during CVVHF was calculated. The results indicated that infused hANP was removed by CVVHF. Although the clearance of hANP by CVVHF was relatively lower than the expected whole body clearance, CVVHF slightly reduced plasma hANP and cyclic guanosine monophosphate concentrations and increased arterial pressure.. CVVHF affects the pharmacology of infused hANP in critically ill patients. Some caution with respect to blood pressure may be necessary when carrying out CVVHF for critically ill patients receiving continuous infusion of natriuretic peptides.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Failure; Hemofiltration; Humans; Middle Aged; Recombinant Proteins

Carperitide is used to treat acute decompensated heart failure (ADHF), but its effects on long-term prognosis have not been studied.. A multicenter randomized controlled study of 49 patients with ADHF was performed to clarify the drug's effects on long-term prognosis. Low-dose carperitide (0.01-0.05 microg x kg(-1 ) x min(-1)) was infused for 72 h as the initial treatment (n=26), whereas in the control group (n=23), standard medical treatment other than carperitide was given without limitation. Anti-aldosterone drugs were prohibited in both groups. During carperitide infusion, significant increases of the atrial natriuretic peptide and cyclic GMP levels and a significant decrease in the heart-type fatty acid-binding protein/serum creatinine ratio were observed, suggesting inhibition of myocyte cell membrane damage. On the other hand, no significant differences in the plasma brain natriuretic peptide, troponin T, and creatinine levels were noted in either group. During 18-month follow-up, significant reductions of death and rehospitalization occurred in the carperitide vs control group (11.5% vs 34.8%; p=0.0359). Cox regression analysis revealed that randomization to carperitide (p=0.020), pretreatment systolic blood pressure >or=140 mmHg (p=0.043), and beta-blocker therapy (p=0.016) were independent predictors for freedom from cardiac events.. Acute-phase low-dose carperitide infusion improved the long-term prognosis of patients with ADHF.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Creatinine; Cyclic GMP; Fatty Acid-Binding Proteins; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Remission Induction; Troponin T

Strategies to preserve renal function and enhance diuretic responsiveness during therapy for heart failure (HF) are needed. We hypothesized that brain natriuretic peptide (nesiritide) added to standard HF therapy would preserve renal function and enhance diuretic responsiveness.. Patients with HF with underlying renal dysfunction who were admitted with volume overload were randomized to standard therapy with nesiritide (2 mug/kg bolus; 0.01 mug/kg/min for 48 hours) or without nesiritide. Patients requiring intravenous vasodilator or inotropic therapy for rapid symptom relief were ineligible. In all patients, diuretics were administered according to a standardized dosing algorithm.. Patients (n = 72) had a mean creatinine level of 1.75 +/- 0.59 mg/dL. Patients receiving nesiritide had a lesser increase in creatinine (P = .048) and blood urea nitrogen (P = .02), but a greater reduction in blood pressure (P < .01). Nesiritide did not enhance diuretic responsiveness (P = .57) but increased 3'5' cyclic guanosine monophosphate and decreased endothelin more (P < .05 for both). There were no differences in the change in atrial natriuretic peptide, N-terminal pro-brain natriuretic peptide, plasma renin activity, angiotensin II, and aldosterone between groups.. When used as adjuvant "renal protective" therapy in patients with HF with renal dysfunction, the recommended dose of nesiritide reduced blood pressure, did not seem to worsen renal function, and suppressed endothelin but did not enhance diuretic responsiveness or prevent activation of the renin-angiotensin-aldosterone system.

Topics: Aged; Algorithms; Blood Urea Nitrogen; Creatinine; Cyclic GMP; Diuresis; Drug Administration Schedule; Drug Therapy, Combination; Endothelium; Female; Heart Failure; Humans; Kidney; Male; Mineralocorticoid Receptor Antagonists; Natriuretic Agents; Natriuretic Peptide, Brain; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume; Time Factors

The effect of beta-blockade on the cardiac natriuretic peptides is poorly understood but could contribute to their beneficial treatment effect and may be relevant to clinical use of plasma brain natriuretic peptide (BNP)/N-terminal pro brain natriuretic peptide (NTproBNP) measurements in risk stratification and in titration of anti-heart failure therapy.. Sixteen men with mild, stable heart failure (NYHA class II to III; left ventricular ejection fraction <40%) underwent serial blood sampling for plasma natriuretic peptide levels and received infusions of atrial natriuretic peptide (ANP) and BNP before and 6 weeks after the introduction and uptitration of metoprolol or 6 weeks unchanged therapy in a randomized, parallel-group design. Plasma natriuretic peptides (BNP, NTproBNP, ANP, and NTproANP) were increased by metoprolol (P<0.01 for all). The natriuretic responses to ANP and BNP infusions were sustained with the introduction of metoprolol despite reduced renal perfusion pressure. The levels of the noninfused natriuretic peptide were increased by both ANP and BNP infusions, and this effect was enhanced by metoprolol. The early plasma half-life (t(1/2)alpha) of BNP was prolonged by metoprolol (5.6+/-0.45 to 11+/-1.3 versus 5.7+/-0.8 to 6.6+/-1.3 minutes in control subjects; P=0.019).. Plasma cardiac natriuretic peptide levels increase significantly with the introduction of metoprolol in heart failure as a result of effects on secretion and clearance. Natriuretic responses to NP infusions are sustained with beta-blockade despite reduced renal perfusion pressure. Clinicians should be aware that the introduction of metoprolol causes a rise in plasma BNP/NTproBNP that is unrelated to deterioration in clinical status and must be considered when measurements are undertaken for risk stratification or titration of treatment.

Topics: Adrenergic beta-Antagonists; Aged; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Humans; Male; Metoprolol; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Stroke Volume; Time Factors; Treatment Outcome

Both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind preferentially to the natriuretic peptide A receptor. Therefore, we hypothesized that the positive inotropic and lusitropic effects of ANP might be blunted in patients with moderate congestive heart failure and high BNP levels. Micromanometers and conductance catheters were used to obtain relatively load-insensitive left ventricular pressure-volume analysis in order to compare the myocardial and load-altering actions of ANP in 20 patients with low and high plasma BNP levels. In the low-BNP group (plasma BNP levels <230 pg/ml), ANP infusion significantly decreased end-systolic pressure and end-diastolic pressure and volume, increased end-systolic elastance, and shortened left ventricular relaxation. By contrast, in the high-BNP group (plasma BNP levels >230 pg/ml), the effect of ANP infusion on LV contractility was blunted but its beneficial effects on LV diastolic function and LV-arterial coupling remained. Thus, ANP infusion may improve LV diastolic function even in patients with moderate heart failure and high plasma BNP levels.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Coronary Angiography; Cyclic GMP; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Radioimmunoassay; Stroke Volume; Ventricular Function, Left; Ventricular Pressure

The significance of antioxidant therapy in heart failure has not been fully examined. This study evaluated whether vitamin C has beneficial effects on renal function or augments the renal effects of furosemide in patients with heart failure.. There were 2 protocols. In protocol 1, plasma level of thiobarbituric acid-reactive substances (TBARS) and renal function were assessed before and after intravenous infusion of vitamin C or placebo in 8 patients with moderate congestive heart failure (CHF) treated with enalapril. In protocol 2, a randomized crossover study was performed in patients with moderate CHF treated with either an ACE inhibitor (enalapril) (n = 10) or an angiotensin II receptor antagonist (losartan) (n = 9) and in asymptomatic patients with impaired left ventricular function treated with enalapril (n = 8). TBARS and renal function were assessed before and after intravenous infusion of furosemide alone, coinfusion of furosemide with placebo and vitamin C, or coinfusion of furosemide with vitamin C and a kallikrein inhibitor (nafamostat mesilate).. In protocol 1, although vitamin C reduced TBARS, it did not affect renal function. In protocol 2, TBARS was higher in patients with moderate CHF than in asymptomatic patients. Vitamin C augmented natriuretic effect of furosemide (from 179 +/- 98 to 192 +/- 104 micromol/min, P <.01) only in patients with moderate CHF treated with enalapril but not in the other 2 groups. Nafamostat mesilate prevented this augmentation.. In patients with CHF treated with enalapril, counteraction of the increased oxidative stress by vitamin C may contribute to the augmented natriuretic effect of furosemide through the renal kinin-nitric oxide pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid; Cross-Over Studies; Cyclic GMP; Drug Therapy, Combination; Enalapril; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Oxidative Stress

In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure. Patients with chronic heart failure (n=142; mean age=57 years) received oral treatment with the ET(A) antagonist darusentan (either 30, 100, 300 mg/day or placebo) on top of standard therapy over a period of 21 days in a randomized, double-blind, placebo-controlled, multicentre study. Plasma concentrations of ANP, BNP and cGMP were determined before randomization and after 21 days of treatment. In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly. The improved cGMP:BNP ratio might reflect the ability of chronic ET(A) receptor blockade to facilitate the generation of the second messenger cGMP, which points towards a favourable modulation of the natriuretic peptide effector system, in addition to haemodynamic improvement in heart failure patients.

Topics: Atrial Natriuretic Factor; Cardiac Output; Cyclic GMP; Double-Blind Method; Drug Administration Schedule; Endothelin Receptor Antagonists; Heart Failure; Humans; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyrimidines; Receptor, Endothelin A; Vasodilator Agents

Three specific receptors for the cardiac natriuretic peptide system have been identified to date. Down-regulation of the biologically active binding sites (i.e. NPR-A and NPR-B) could explain the blunted response to cardiac natriuretic hormones observed in heart failure (HF), but not the increased metabolic clearance rate. Variations in the ratio between biological and clearance (NPR-C) receptors in target tissue may explain this increase.. The aim of this study was to investigate the regulation of NPR-C receptors on platelets, in patients with HF.. Eighteen patients with HF (NYHA class: I-II, n=8; III-IV, n=10) and 18 age-matched healthy subjects were studied. The affinity constant (K(d)) and density (B(max)) of binding sites were derived by saturation assays on platelet suspensions using 125I-ANP as radioligand.. B(max) increased as a function of the severity of disease: 21.3+/-3.3 fmol/10(9) cells in class III-IV, 11.7+/-2.2 in class I-II, and 11.6+/-1.1 in controls, respectively (P=0.0179 for class III-IV vs. controls and P=0.0451 vs. NYHA I-II).. The increase in density of 'clearance' receptors in severe HF is theoretically consistent with the reduction in cardiac natriuretic peptide biological activity, as well as the increase in metabolic clearance rate. This suggests that clearance receptor blockade may be of potential therapeutic value in HF.

Topics: Adult; Aged; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Blood Platelets; Chronic Disease; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Receptors, Atrial Natriuretic Factor; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Up-Regulation

To evaluate the effects of an angiotensin (Ang II) type 1 receptor antagonist on immune markers in patients with congestive heart failure (CHF).. Ang II stimulates production of immune factors via the Ang II type 1 receptor in vitro, and the long-term effects of Ang II type 1 receptor antagonists on plasma markers of immune activation are unknown in patients with CHF.. Twenty-three patients with mild to moderate CHF with left ventricular dysfunction were randomly divided into two groups: treatment with Ang II type 1 receptor (candesartan cilexetil) (n = 14) or placebo (n = 9). We measured plasma levels of immune factors such as tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). We also measured plasma levels of the neurohumoral factors such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP), a biological marker of ANP and BNP.. Plasma levels of TNFalpha, IL-6, sICAM-1 and sVCAM-1 were increased in the 23 CHF patients compared with normal subjects and significantly decreased after 14 weeks of candesartan cilexetil treatment, but did not change in the placebo group. Plasma levels of BNP, which is a marker of ventricular injury, significantly decreased, and the molar ratio of plasma cGMP to cardiac natriuretic peptides (ANP + BNP) was significantly increased after candesartan cilexetil treatment, but did not change in the placebo group.. These findings suggest that 14 weeks of treatment with an Ang II type 1 receptor antagonist (candesartan cilexetil) decreased plasma levels of the immune markers such as TNFalpha, IL-6, sICAM-1 and sVCAM-1 and that it improved the biological compensatory action of endogenous cardiac natriuretic peptides in patients with mild to moderate CHF.

Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Benzimidazoles; Biomarkers; Biphenyl Compounds; Cell Adhesion Molecules; Cyclic GMP; Female; Heart Failure; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Natriuretic Peptide, Brain; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Stroke Volume; Tetrazoles; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are secreted from the heart and are thought to be equally important factors in the regulation of vascular tone in health and in congestive heart failure (CHF). However, no studies directly compare vasodilator effects of these peptides in healthy subjects and in patients with CHF.. Plethysmography was used to determine the vasodilatory effects of BNP and to compare these to the effects of ANP in patients with CHF (n = 15) and age-matched healthy subjects (n = 16). Graded doses of ANP and BNP (8, 16, 32, and 48 pmol/min per 100 ml of tissue volume for both) were administered randomly into the brachial artery. Forearm blood flow (FBF) was measured, and cyclic GMP (cGMP) spillover was calculated.. Responses in FBF to both peptides in CHF were significantly lower than those of healthy subjects (BNP p < 0.05; ANP p < 0.01). Similarly, forearm spillover of cGMP was significantly lower in CHF than in healthy subjects (BNP p < 0.05; ANP p < 0.01). When vascular responses in healthy subjects were compared between BNP and ANP, BNP-induced changes in FBF (p < 0.05) and forearm cGMP spillover (p < 0.01) were significantly less than changes induced by ANP. In CHF, though, FBF change and cGMP spillover induced by the two peptides were not significantly different.. These results suggest that the metabolism and action of these natriuretic peptides in CHF may differ from the healthy state.

Topics: Aged; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Forearm; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Plethysmography; Regional Blood Flow; Vasodilation

Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.. Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 microg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (micromol/L), and platelet cGMP level (pmol/10[9] platelets) were comparable in the two groups (placebo group: MPAP, 48+/-6; PCWP, 24+/-4; cGMP, 0.76+/-0.12; vitamin E, 18.2+/-1.2; vitamin C: MPAP, 49+/-7; PCWP, 24+/-4; cGMP, 0.71+/-0.16; vitamin E, 18.6+/-1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26+/-5; PCWP, 15+/-4; vitamin C: MPAP, 26+/-4; PCWP, 16+/-4), and platelet cGMP was significantly increased (placebo group: 2.42+/-0.24; vitamin C: 2.26+/-0.26). However, at 18 hours after titration, in the placebo group, MPAP (44+/-5) and PCWP (23+/-4) were increased, and platelet cGMP (0.85+/-0.20) and plasma vitamin E levels (12.4+/-1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31+/-6), PCWP (17+/-5), platelet cGMP (2.49+/-0.23), and plasma vitamin E levels (17.6+/-1.4) were maintained for 18 hours after the titration period.. These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

Topics: Aged; Ascorbic Acid; Blood Platelets; Blood Pressure; Cyclic GMP; Double-Blind Method; Drug Tolerance; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Nitroglycerin; Vitamin E

This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibitors with and without a sulfhydryl group on intracellular production of cGMP, forearm blood flow, and neurohormonal factors during continuous transdermal application of nitroglycerin in patients with chronic heart failure. Platelet cGMP level and forearm blood flow were measured before and 5 min after sublingual administration of nitroglycerin (NTG) in 20 patients with chronic heart failure during the following 4 phases: (1) baseline phase; (2) NTG phase (1 week after NTG tape 10 mg/day); (3) CPT phase (1 week after both captopril 37.5 mg/day and NTG tape 10 mg/day); and (4) ENL phase (1 week after both enalapril 5 mg/day and NTG tape 10 mg/day). The platelet GMP level before sublingual NTG and forearm blood flow were significantly higher during the 3 phases with NTG tape than during the control phase. The percent increases in platelet cGMP level and forearm blood flow after sublingual NTG were significantly lower during the NTG phase than during the baseline phase. In contrast, concomitant application of ACE inhibitors maintained the percent increase in platelet cGMP level and forearm blood flow. These results indicate that concomitant therapy with ACE inhibitors may be helpful in preventing the attenuation of intracellular cGMP production in patients with chronic heart failure during continuous transdermal application of NTG.

Topics: Administration, Cutaneous; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Platelets; Blood Pressure; Body Weight; Chronic Disease; Cyclic GMP; Drug Tolerance; Female; Forearm; Heart Failure; Heart Rate; Hematocrit; Humans; Male; Middle Aged; Nitrates; Nitroglycerin; Norepinephrine; Regional Blood Flow; Renin; Systole; Vasodilator Agents

This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure.. The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties.. To evaluate the effect of carvedilol on nitrate tolerance, 40 patients with chronic heart failure were randomized to four groups that received either carvedilol (2.5 mg once a day [carvedilol group, n=10]), metoprolol (30 mg once a day [metoprolol group, n=10]), doxazosin (0.5 mg once a day [doxazosin group, n=10]) or placebo (placebo group, n=10). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0); 3 days after carvedilol, metoprolol, doxazosin or placebo administration (day 3); and 3 days after application of a 10-mg/24-h NTG tape concomitantly with carvedilol, metoprolol, doxazosin or placebo (day 6).. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual NTG on day 0 and day 3 among the four groups. On day 6, %FBF and %cGMP were significantly lower in the metoprolol, doxazosin and placebo groups than on day 0 and day 3, but these parameters in the carvedilol group were maintained.. These results indicated that carvedilol may prevent nitrate tolerance in patients with chronic heart failure during continuous therapy with NTG.

Topics: Adrenergic Antagonists; Aged; Blood Flow Velocity; Blood Platelets; Blood Pressure; Carbazoles; Carvedilol; Chronic Disease; Cyclic GMP; Double-Blind Method; Doxazosin; Drug Hypersensitivity; Drug Therapy, Combination; Female; Follow-Up Studies; Forearm; Heart Failure; Heart Rate; Humans; Male; Metoprolol; Middle Aged; Nitroglycerin; Propanolamines; Vasodilator Agents

Decrease in lung compliance is one of the major causes of respiratory failure. We investigated whether amrinone could improve lung compliance.. We selected 20 consecutive patients with respiratory failure due to severe cardiogenic pulmonary edema to receive mechanical ventilation. Patients were administered a bolus injection (1 mg.kg-1) over 10 min followed by continuous intravenous infusion (10 micrograms.kg-1.min-1) of amrinone. Lung compliance, blood gas values, hemodynamic parameters, and sample plasma amrinone levels were assessed over a 120-min period after the onset of the continuous infusion of amrinone.. Ten min following amrinone infusion, dynamic compliance (Cdyn) and static compliance (Cst) increased from 30 +/- 11 to 36 +/- 12 ml/cm H2O and from 37 +/- 12 to 42 +/- 13 ml/cm H2O, respectively (P < 0.01). Plasma amrinone levels reached a therapeutic level as vasodilator and positive inotropic effects at 10 min after amrinone infusion. The significant change in mean pulmonary artery pressure and pulmonary artery wedge pressure occurred later than the change in compliance of respiratory system. However, there were significant correlations between the mean pulmonary artery pressure and Cdyn (r = 0.36, P < 0.01) and Cst (r = 0.44, P < 0.01), as well as between plasma amrinone levels and Cdyn (r = 0.30, P < 0.05) and Cst (r = 0.41, P < 0.01).. Amrinone-induced improvement in lung compliance was considered mainly to be due to an increase in the number of functioning lung units by improvement of the hemodynamics and a direct positive effect of amrinone on respiratory muscle contraction.

Topics: Aged; Amrinone; Blood Gas Analysis; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Lung Compliance; Male; Myocardial Contraction; Pulmonary Edema; Respiration, Artificial; Respiratory Mechanics; Vasodilator Agents

The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously.. Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 microgram/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3 +/- 1.6 to 25.9 +/- 1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1 +/- 1.1 to 13.2 +/- 1.3 mm Hg; mean right atrial pressure decreased from 10.9 +/- 1 to 4.8 +/- 1.0 mm Hg; mean arterial pressure decreased from 85.2 +/- 2.0 to 74.9 +/- 1.7 mm Hg; and cardiac index increased from 2.0 +/- 0.1 to 2.5 +/- 0.1 L/min per square meter (all P < .01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90 +/- 38 versus 67 +/- 27 mL/h and 2.6 +/- 2.4 versus 1.4 +/- 1.2 mEq/h, respectively, both P < .05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change.. Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure.

Topics: Blood Pressure; Creatinine; Cyclic GMP; Double-Blind Method; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Placebos; Potassium; Pulmonary Artery; Pulmonary Wedge Pressure; Sodium; Stroke Volume; Vascular Resistance

Our primary objective was to compare the effects of three different doses of candoxatrilat with the effects of placebo on urinary volume in patients with moderately severe heart failure. The effects of candoxatrilat on urinary composition, neuroendocrine indexes and renal hemodynamic function were also studied.. Candoxatrilat, a neutral endopeptidase inhibitor, reduces degradation of atrial natriuretic peptide and provokes diuresis in patients with mild heart failure, but the renal effects have not been studied in patients with moderately severe heart failure in a placebo-controlled study.. In a double-blind crossover trial, the effects of intravenous boluses of saline vehicle (placebo) and 50, 100 and 200 mg of candoxatrilat were compared on separate days in 12 patients with heart failure. Urinary output and composition were measured for 8 h. Renal blood flow and glomerular filtration rate were determined by radionuclide techniques. Blood was withdrawn for the measurement of hormones before and 3 h after dosing.. All doses of candoxatrilat increased urinary volume (e.g., [mean +/- SEM] 263 +/- 53 to 490 +/- 82 ml for saline solution and the 200-mg dose, respectively, p < 0.01) and sodium content (14 +/- 4 to 37 +/- 11 mmol, p < 0.001) in the 1st 4 h after dosing. Plasma atrial natriuretic peptide increased (140 +/- 26 to 279 +/- 37 pg/ml, p < 0.01), whereas aldosterone decreased (178 +/- 41 to 125 +/- 35 pg/ml, p < 0.01), and renin activity was unchanged (10 +/- 2 to 12 +/- 3 ng/ml per h).. Candoxatrilat given acutely causes diuresis, even in patients with moderately severe heart failure.

Topics: Aged; Aldosterone; Atrial Natriuretic Factor; Cross-Over Studies; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Double-Blind Method; Drug Administration Schedule; Electrolytes; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Neprilysin; Renal Circulation; Sodium; Urine; Vasoactive Intestinal Peptide

Hemodynamic tolerance has been observed within several hours of continuous infusion of nitroglycerin (NTG). We examined the hemodynamic parameters as well as femoral arterial and venous cyclic guanosine monophosphate (cGMP) concentrations during intravenous infusion of NTG or nicorandil, a nitrate and potassium channel opener, in patients with congestive heart failure. Doses of NTG or nicorandil were titrated to achieve a > or = 25% reduction in pulmonary capillary wedge pressure (PCWP) within 1 hour, and the infusion was maintained at a constant rate for 24 hours. The reduction in PCWP and mean arterial blood pressure was identical after a 1-hour infusion of either NTG or nicorandil. In the NTG group, PCWP and mean blood pressure were not significantly different from the baseline value at 12 hours, but in the nicorandil group PCWP and mean blood pressure remained significantly lower than the preinfusion value for 24 hours. The cGMP production with NTG (assessed by the difference between the plasma arterial and venous cGMP level) paralleled the changes in PCWP, suggesting that the plasma arteriovenous cGMP difference is a biochemical indicator of nitrate tolerance. Although the sustained decrease in PCWP was observed in the nicorandil group, cGMP production with nicorandil was also attenuated at 24 hours of continuous infusion. These findings suggest that the absence of the hemodynamic tolerance of nicorandil, a nitrate and potassium channel opener, is likely due to its action as a potassium channel opener, and not to its nitrate activity.

Topics: Adult; Aged; Analysis of Variance; Blood Pressure; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Least-Squares Analysis; Male; Middle Aged; Niacinamide; Nicorandil; Nitroglycerin; Pulmonary Wedge Pressure; Regression Analysis; Vasodilator Agents

Urodilatin [ANP-95-126] is a new natriuretic peptide of renal origin not subjected to tolerance in experimental congestive heart failure (CHF). To evaluate its therapeutic potentials in CHF, we investigated the efficacy of a prolonged infusion of urodilatin (15 ng/kg/min for 10 hours) in 12 patients with CHF (New York Heart Association functional classes II and III) in a randomized, double-blind, placebo-controlled study. Urodilatin elevated plasma cyclic guanosine monophosphate (cGMP) concentrations and increased urinary cGMP excretion. Systolic blood pressure (121 +/- 9 mm Hg to 111 +/- 7 mm Hg) and central venous pressure (7.4 +/- 3.3 mm Hg to 5.2 +/- 3.4 mm Hg) decreased significantly, and diastolic blood pressure and heart rate remained unchanged. Urine flow (0.7 +/- 0.6 ml/min to 1.5 +/- .6 ml/min) and urinary sodium excretion (48 +/- 16 mumol/min to 180 +/- 97 mumol/min) were significantly increased. Plasma norepinephrine, renin, aldosterone, and vasopressin were unaltered. The substance was well tolerated. Thus prolonged infusion of urodilatin lowers preload and increases diuresis and natriuresis without neurohumoral activation or adverse side effects, demonstrating a profile of effects that may be beneficial in patients with CHF.

Topics: Aged; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Diuretics; Double-Blind Method; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Peptide Fragments; Renin; Time Factors

This study evaluated the relation between plasma cyclic guanosine monophosphate (cGMP) and hemodynamic and neurohormonal parameters in patients with chronic congestive heart failure and assessed the effect of organic nitrate on plasma cGMP levels. Plasma cGMP was fourfold higher in 18 patients with congestive heart failure compared with 15 control subjects (16.7 +/- 9.7 versus 4.0 +/- 1.0 pmol/ml; p < 0.0001) but did not correlate with plasma levels of catecholamines, renin, atrial natriuretic peptide, or with baseline hemodynamic values. The administration of a hemodynamically effective dose of oral isosorbide dinitrate (40 mg) resulted in a transient reduction in plasma cGMP from 16.7 +/- 9.7 pmol/ml at baseline to 13.0 +/- 6.6 pmol/ml at 1 hour (p < 0.05). This change was associated with small and statistically insignificant changes in neurohormonal values and had no relation to any of the hemodynamic changes. We concluded that (1) elevated plasma cGMP in congestive heart failure does not correlate with other neurohormonal or hemodynamic parameters and may be an independent parameter of heart failure, (2) in contrast to previously documented nitrate-mediated increases in intracellular cGMP, nitrate therapy results in a reduction in plasma cGMP, and (3) changes in plasma cGMP cannot serve as a surrogate measurement of changes in intracellular cGMP.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Middle Aged; Neurotransmitter Agents

Urodilatin (ANF(95-126)) is an analogue of the atrial natriuretic factor (ANF(99-126)), which has been isolated from human urine. Recently we have shown in healthy volunteers, that intravenous bolus injections of synthetic urodilatin produce more pronounced reductions of pulmonary arterial pressure than ANF(99-126). To compare haemodynamic and renal effects of synthetic urodilatin with those of ANF(99-126) in congestive heart failure (CHF), 12 patients (66.3 +/- 1.4 years) received either two high dose intravenous bolus injections of 4 micrograms kg-1 bw Urodilatin (URO) at a 30 min interval (n = 6) or the same doses of ANF(99-126) (n = 6). Prior to i.v. URO, no URO immunoreactivity was found in human plasma (specific RIA, no crossreactivity to ANF). Similar to ANF, the increase in diuresis (1.4 +/- 0.7 to 3.7 +/- 1.6 ml min-1) and natriuresis (169 +/- 114 to 430 +/- 197 mumol min-1) was moderate after URO in CHF. During the 90 min study period, mean plasma cyclic GMP levels increased much more after URO (by 53.4 +/- 15.1 nM) than after ANF (by 13.1 +/- 3.0 nM; P = 0.04). In contrast to ANF, i.v. bolus injections of URO produced sustained haemodynamic effects in CHF lasting up to 90 min: The average (0-90 min) reduction of systemic vascular resistance was more pronounced after URO (-578 +/- 148) than after ANF (-204 +/- 65 dyn*s*cm-5, P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Amino Acid Sequence; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Diuretics; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Kidney; Male; Middle Aged; Molecular Sequence Data; Peptide Fragments

Sinorphan is a powerful inhibitor of enkephalinases or endopeptidases 24-11, enzymes implicated in the degradation of the atrial natriuretic factor (ANF). In healthy volunteers, it increases plasma concentrations of endogenic ANF and increases diuresis and natriuresis. In order to study the tolerance and biological effects of pharmacological increase of plasma concentrations of endogenic ANF in severe congestive cardiac failure, 12 patients (in functional Classes III or IV of the NYHA classification) were given a single oral dose of 10, 20 or 40 mg of Sinorphan. Sinorphan was clinically well tolerated. The diastolic blood pressure decreased slightly (- 10 +/- 9 mmHg) but significantly (p less than 0.05). Systolic blood pressure and heart rate were unchanged. Despite spontaneously high plasma ANF concentrations (on average 15 times higher than normal subjects), Sinorphan induced an additional increase of 80 to 100% of plasma ANF concentration compared to the initial values (p less than 0.01) with no dose-dependent response for the dosages used. The inhibition of plasma endopeptidase activity attained 47% at the 30th minute. Urinary cyclic GMP excretion increased by 30% at the second hour (p less than 0.05). In addition, a statistically non significant tendency to increase diuresis and natriuresis was observed. These results show that Sinorphan increases plasma ANF concentrations by inhibition of its degradation in severe congestive cardiac failure and that this increase seems to be associated with potentially beneficial biological changes. The concept of endopeptidase inhibition should constitute a new therapeutic approach in cardiac failure, a situation in which the ANF seems to exert a favourable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Cyclic GMP; Diuresis; Female; Heart Failure; Humans; Male; Middle Aged; Natriuresis; Neprilysin; Thiorphan

We examined the mechanisms involved in the cardiovascular and renal response to prolonged infusion of atrial natriuretic factor (ANF) in patients with chronic heart failure. ANF infusion was titrated to produce a 30% decrease in pulmonary capillary wedge pressure or a 20% increase in cardiac output, and this dose (average, 75 +/- 4 ng/kg/min) was then administered for 20 hours. The short-term response to ANF included significant reductions in central filling pressures, increases in cardiac output, modest increases in diuresis and glomerular filtration rates, significant reduction in plasma aldosterone levels, and a 3.6-fold increase in plasma cyclic GMP levels. During prolonged infusion, plasma cGMP levels and cardiac output gradually returned to baseline. Similarly, the initially increased diuretic effects were completely abolished during prolonged ANF infusion, although plasma alpha-hANF levels remained consistently elevated above baseline values (control, 198 +/- 38; titration, 2,760 +/- 596; 20 hours, 3,499 +/- 659 pg/ml). Four hours after beginning the ANF infusion, marked increases in hematocrit levels were noted (42.5 +/- 1.0% versus 45.3 +/- 1.4%, control and infusion, respectively, p less than 0.05); during this time, no change in total plasma protein concentration occurred, indicating extravascular shift of fluid and plasma proteins. No evidence was noted for activation of vasoconstrictor hormones during prolonged ANF infusion, although mean arterial pressure was significantly reduced throughout the infusion period. Plasma pro-ANF (31-67) levels, determined as a marker for endogenous ANF secretion, were significantly suppressed as were the reductions of central filling pressures. After ANF discontinuation, heart rate and pulmonary capillary wedge pressure increased significantly above baseline values without evidence for sympathetic stimulation. We conclude that 1) prolonged infusion of ANF causes only transient increases in plasma cGMP levels but a sustained reduction of the cardiac release of ANF and that 2) the beneficial hemodynamic effects of ANF, that is, unloading of the ventricles, may be associated with or, in part, may be secondary to a shift of plasma constituents into the extravascular space. The latter may limit the therapeutic potential of ANF for long-term treatment.

Topics: Atrial Natriuretic Factor; Cardiac Output; Cyclic GMP; Diuresis; Female; Heart Failure; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Pulmonary Wedge Pressure; Renin-Angiotensin System; Time Factors

In eight patients (63 +/- 8 years) with dilated cardiomyopathy, the acute effects of positive inotropic stimulation with dopexamine hydrochloride, a beta-2-agonistic and DA1-dopaminergic catecholamine, on the plasma levels of ANP and cGMP were tested. A four-point dose-response curve was prepared for dopexamine from 1 microgram/kg/min to 4 micrograms/kg/min. Each infusion stage lasted 15 min; ANP and cGMP were taken from the mixed venous blood. Hemodynamic parameters were determined by a Swan-Ganz catheter; cardiac output was determined by thermodilution. ANP dropped by 40% from 348 +/- 124 pg/ml to 208 +/- 70 pg/ml (p less than or equal to 0.01), while cGMP dropped by 25% from 4.8 +/- 1.6 pmol to 3.6 +/- 1.3 pmol/ml at the time of maximum hemodynamic effect after 1 h. Linear regression analyses revealed a significant relationship (p less than or equal to 0.01) between ANP as the independent variable and cGMP as the dependent variable. The hemodynamic determinants of the ANP concentration proved to be--independently of each other--the pulmonary capillary wedge pressure (p less than or equal to 0.01) and the mean right atrial pressure (p less than or equal to 0.01). The results show that chronically elevated ANP and cGMP levels can be strikingly reduced within a short time, whereby ANP and cGMP show similar kinetics. The results suggest a use of ANP and cGMP as humoral parameters in the therapy control of chronic heart failure.

Topics: Adrenergic beta-Agonists; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Clinical Trials as Topic; Cyclic GMP; Dopamine; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged

Ibopamine is a novel oral dopamine analogue with positive inotropy and diuretic effects. In a double-blind, randomized study, the drug was investigated in 10 patients (mean age 49 +/- 10 years, six male, four female) with mild heart failure (NYHA classes II: six patients, III: four patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide, and of 200 mg ibopamine plus 40 mg furosemide were compared in each patient at 3-day-intervals. One h after application, systolic and diastolic blood pressure increased from 119 +/- 11 to 124 +/- 8, and from 75 +/- 4 to 80 +/- 6 mm Hg (p less than 0.01) in the ibopamine group, while changes in both other groups and changes of the heart rate were insignificant. During 2 h after drug ingestion urinary flow was raised from 124 +/- 81 to 227 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the application of furosemide (with or without ibopamine) resulted in several fold increases of urinary flow. After ibopamine, the 2-h-creatinine-clearance rose from 123 +/- 73 to 130 +/- 85 ml/min (not significant). Sodium excretion remained unchanged by ibopamine, potassium excretion was increased from 2.9 +/- 1.7 to 4.0 +/- 3.3 mmol/h (p less than 0.05), while effects of furosemide were several fold of those of ibopamine. Atrial natriuretic factor concentrations in plasma increased significantly after ibopamine and after ibopamine plus furosemide (p less than 0.01), but remained constant after furosemide alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Coronary Disease; Cyclic GMP; Deoxyepinephrine; Diuretics; Dopamine; Electrolytes; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Natriuresis; Urodynamics

The natriuretic peptides (NPs) are potent natriuretic/diuretic and vasodilatory factors, and augmentation of their levels or signaling via inhibition of the enzymes neprilysin (NEP) and phosphodiesterase 9 (PDE9), respectively, has beneficial actions in heart failure (HF).. The authors investigated dual enhancement of NP bioactivity by combining PDE9 inhibition and NEP inhibition in HF using an ovine model.. Eight sheep with pacing-induced HF received on 4 separate days intravenous PDE9 inhibition (PF-04749982), NEP inhibition (SCH-32615), PDE9 inhibition + NEP inhibition (PI+NI), and vehicle control treatment.. Compared with the control treatment, NEP inhibition significantly increased plasma NP concentrations with a corresponding rise in second messenger cyclic guanosine monophosphate (cGMP), whereas PDE9 inhibition increased circulating cGMP with a negligible effect on NP levels. Combined PI+NI elevated plasma NPs to an extent comparable to that seen with NEP inhibition alone but further increased cGMP, resulting in a rise in the cGMP-to-NP ratio. All active treatments reduced mean arterial pressure, left atrial pressure, pulmonary arterial pressure, and peripheral resistance, with combined PI+NI further reducing mean arterial pressure and left atrial pressure relative to either inhibitor separately. Active treatments increased urine volume and sodium, potassium and creatinine excretion, and creatinine clearance, in association with rises in urine cGMP levels. PI+NI induced a significantly greater natriuresis and increase in urinary cGMP relative to either inhibitor singly.. The present study demonstrates for the first time that combined PI+NI has additional beneficial hemodynamic and renal effects when compared with either PDE9 inhibition or NEP inhibition alone. The superior efficacy of this 2-pronged augmentation of NP bioactivity supports PI+NI as a potential therapeutic strategy for HF.

Topics: Animals; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Diuretics; Heart Failure; Humans; Natriuretic Peptides; Neprilysin; Phosphoric Diester Hydrolases; Sheep; Vasodilator Agents

Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.

Topics: Animals; Cardio-Renal Syndrome; Cyclic GMP; Fistula; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Nitric Oxide; Rats; Rats, Transgenic; Soluble Guanylyl Cyclase

Topics: Cyclic GMP; Guanosine Monophosphate; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Pyrimidines; Stroke Volume; Ventricular Dysfunction, Left

To determine whether Shunxin decoction improves diastolic function in rats with heart failure with preserved ejection fraction (HFpEF) by regulating the cyclic guanosine monophosphate-dependent protein kinase (cGMP-PKG) signaling pathway.. Except for control group 8 and sham surgery group 8, the remaining 32 male Sprague-Dawlay rats were developed into HFpEF rat models using the abdominal aorta constriction method. These rats in the HFpEF model were randomly divided into the model group, the Shunxin high-dose group, the Shunxin low-dose group, and the Qiliqiangxin capsule group. The three groups received high-dose Shunxin decoction, low-dose Shunxin decoction, and Qiliqiangxin capsule by gavage, respectively, for 14 d. After the intervention, the diastolic function of each rat was evaluated by testing E/A, heart index, hematoxylin-eosin staining, Masson, myocardial ultrastructure, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) software was used to predict targets for which Shunxin decoction acts on the cGMP-PKG pathway. Natriuretic peptide receptor A (NPRA) and guanylate cyclase (GC) were detected by immunohistochemistry, and eNOS, phosphodiesterase 5A (PDE5A), and cGMP-dependent protein kinase 1(PKG I) were determined by Western blotting.. Compared to the model group, the thickness of the interventricular septum at the end of diastole (IVSd) and the thickness of the posterior wall at the end of diastole (PWd) of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group were all significantly reduced ( < 0.01). Furthermore, Shunxin decoction high-dose group E/A value was decreased ( < 0.01). Compared to the model group, the expression of NPRA and GC increased in the Shunxin decoction low-dose group and the Qiliqiangxin capsule group ( < 0.01). Compared to the model group, the expressions of eNOS and PKG I increased ( < 0.05) in the Shunxin decoction high-dose group. The expression of PDE5A expression decreased in the myocardium of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group compared to the model group ( < 0.01).. Shunxin decoction can improve diastolic function in rats with HFpEF. It increases the expression of NPRA, GC, and eNOS in the myocardial cell cGMP-PKG signaling pathway, upregulates cGMP expression, decreases PDE5A expression to reduce the cGMP degradation. Thus, the cGMP continually stimulates PKG I, reversing myocardial hypertrophy and improving myocardial compliance in HFpEF rats.

Topics: Animals; Aorta, Abdominal; Constriction; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diastole; Guanosine Monophosphate; Heart Failure; Male; Rats; Signal Transduction; Stroke Volume

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic GMP; Heart Failure; High-Throughput Screening Assays; Mice

cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo.. Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored.. MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo.. MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity.. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Humans; Mice; Natriuretic Peptides; Vasodilator Agents

Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF.. We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF.. These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Cyclic GMP; Disease Models, Animal; Diuresis; Diuretics; Endothelin-1; Female; Heart Failure; Hemodynamics; Kidney; Natriuresis; Natriuretic Peptide, Brain; Renin; Sheep, Domestic; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.. CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (. The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Aorta; Carrier Proteins; Collagen; Constriction, Pathologic; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Fibrosis; Heart; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Lung; Male; Mice; Organ Size; Phosphodiesterase Inhibitors; Phosphorylation; Pulmonary Edema; Stroke Volume; Ventricular Remodeling

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Connectin; Cyclic GMP; Diastole; Disease Models, Animal; Drug Combinations; Electrocardiography; Female; Fibrosis; Glycated Hemoglobin; Heart Failure; Muscle, Skeletal; Muscular Atrophy; Natriuretic Peptide, Brain; Peptide Fragments; Phosphorylation; Rats, Mutant Strains; Valsartan; Ventricular Function, Left

[Figure: see text].

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Failure; Mice; Mice, Transgenic; Myocardium; Neprilysin; Ventricular Remodeling

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (

Topics: Angiotensin I; Animals; Biological Availability; Biomarkers; Blood Pressure; Cardiomyopathy, Dilated; Cyclic GMP; Diet, Sodium-Restricted; Edema; Heart Failure; Kidney; Male; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Phosphoric Diester Hydrolases; Pleural Effusion; Renin-Angiotensin System; Survival Analysis; Systole

When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

Topics: Cyclic GMP; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Nitric Oxide; Soluble Guanylyl Cyclase

Background Cyclic guanosine monophosphate (cGMP) is a second messenger regulated through natriuretic peptide and nitric oxide pathways. Stimulation of cGMP signaling is a potential therapeutic strategy for heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HFpEF, any HF, ASCVD, and coronary heart disease (CHD). Methods and Results We conducted a case-cohort analysis nested in the ARIC (Atherosclerosis Risk in Communities) study. Plasma cGMP was measured in 875 participants at visit 4 (1996-1998), with oversampling of incident HFpEF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HFpEF, HF, ASCVD (CHD+stroke), and CHD. The mean (SD) age was 62.4 (5.6) years and median (interquartile interval) cGMP was 3.4 pmol/mL (2.4-4.6). During a median follow-up of 9.9 years, there were 283 incident cases of HFpEF, 329 any HF, 151 ASCVD, and 125 CHD. In models adjusted for CVD risk factors, the hazard ratios (95% CI) associated with the highest cGMP tertile compared with lowest for HFpEF, HF, ASCVD, and CHD were 1.88 (1.17-3.02), 2.18 (1.18-4.06), 2.84 (1.44-5.60), and 2.43 (1.19-5.00), respectively. In models further adjusted for N-terminal-proB-type natriuretic peptide, associations were attenuated for HFpEF and HF but remained statistically significant for ASCVD (2.56 [1.26-5.20]) and CHD (2.25 [1.07-4.71]). Conclusions Contrary to our hypothesis, higher cGMP levels were associated with incident CVD in a community-based cohort. The associations of cGMP with HF or HFpEF may be explained by N-terminal-proB-type natriuretic peptide, but not for ASCVD and CHD.

Topics: Aged; Atherosclerosis; Biomarkers; Case-Control Studies; Coronary Disease; Cyclic GMP; Female; Heart Disease Risk Factors; Heart Failure; Humans; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prospective Studies; United States

This study aimed to evaluate whether the heart is the target organ of endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with heart failure (HF) with reduced ejection fraction (HFrEF).We measured the plasma levels of cyclic guanosine monophosphate (cGMP), which is a second messenger of ANP and BNP, in the aortic root (AO) and coronary sinus (CS) in 237 patients with HFrEF. Plasma levels of cGMP were significantly higher in the CS than those in the AO in 237 patients with HFrEF (10.0 ± 4.5 versus 10.5 ± 4.3 pmoL/mL, P < 0.0001) and were significantly higher in the CS than those in the AO (8.0 ± 3.6 versus 8.9 ± 3.8 pmoL/mL, P < 0.0001) in mild HF patients (New York Heart Association (NYHA) II, n = 114), but there was no difference in plasma cGMP between the AO and the CS (11.9 ± 4.4 versus 11.9 ± 4.3 pmoL/mL, NS) in severe HF patients (NYHA III-IV, n = 123). In mild HF patients, log (ANP + BNP) in the AO was an independent predictor of (CS-AO) cGMP among hemodynamics and nitrate therapy. There was a significant correlation between log [(CS-AO) ANP + (CS-AO) BNP] and (CS-AO) cGMP (r = 0.455, P < 0.0001) in mild HF patients.These findings indicate that cGMP is produced from the failing heart and that the heart is the target organ of endogenous ANP and BNP in patients with HFrEF. In severe HF patients, cGMP production may be attenuated because of the downregulation of biological receptors and/or increased cGMP degradation in the failing heart.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Catheterization; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Stroke Volume

Topics: Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Pyrimidines; Stroke Volume

Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B-KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B-KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload.

Topics: Animals; Cyclic GMP; Heart Failure; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Myocytes, Cardiac; Natriuretic Agents; Natriuretic Peptide, C-Type; Phosphorylation; Protein Kinases; Receptors, Atrial Natriuretic Factor

Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model.. HFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined.. Blood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment.. 9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.

Topics: Animals; Aorta; Benzhydryl Compounds; Biomarkers; Blood Pressure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cytokines; Disease Models, Animal; Female; Fibrosis; Glucosides; Heart Failure; Hypertension; Inflammation Mediators; Lipids; Nitric Oxide; Norepinephrine; Sodium-Glucose Transporter 2 Inhibitors; Sus scrofa; Sympathetic Nervous System; Ventricular Function, Left; Ventricular Remodeling

This study investigated the differential regulation of circulating atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in patients with acute decompensated heart failure (ADHF) and tested the hypothesis that a relative deficiency of ANP exists in a subgroup of patients with ADHF.. The endocrine heart releases the cardiac hormones ANP and BNP, which play a key role in cardiovascular (CV), renal, and metabolic homeostasis. In heart failure (HF), both plasma ANP and BNP are increased as a compensatory homeostatic response to myocardial overload.. ANP and BNP concentrations were measured in a small group of patients with ADHF (n = 112). To support this study's goal, a total of 129 healthy subjects were prospectively recruited to establish contemporary normal values for ANP and BNP. Plasma 3',5'cyclic guanosine monophosphate (cGMP), ejection fraction (EF), and body mass index (BMI) were measured in these subjects.. In cases of ADHF, 74% of patients showed elevated ANP and BNP. Importantly, 26% of patients were characterized as having normal ANP (21% of this subgroup had normal ANP and elevated BNP). Cyclic GMP was lowest in the ADHF group with normal levels of ANP (p < 0.001), whereas BMI and EF were inversely related to ANP levels (p = 0.003).. Among a subgroup of patients hospitalized with ADHF, the presence of an ANP deficiency is consistent with a differential regulation of ANP and BNP and suggests the existence of a potentially compromised compensatory cardiac endocrine response. These findings have implications for the pathophysiology, diagnostics, and therapeutics of human HF.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Body Mass Index; Case-Control Studies; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Phenotype; Stroke Volume

Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675 mg/day) vs. placebo, sacubitril (360 mg/day), valsartan (900 mg/day), and benazepril (5 mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n = 18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675 mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675 mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675 mg administration was similar to that observed with valsartan 900 mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.

Topics: Aldosterone; Aminobutyrates; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Cross-Over Studies; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Drug Combinations; Female; Heart Failure; Humans; Male; Natriuretic Peptides; Renin-Angiotensin System; Sodium, Dietary; Tetrazoles; Valsartan

Topics: Acetylcholine; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Endothelium; Gene Expression Regulation; Heart Failure; Hemodynamics; Kidney; Male; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; Vasodilation

Topics: Cardiovascular System; Cyclic GMP; Enzyme Activators; Heart Failure; Humans; Soluble Guanylyl Cyclase

Topics: Animals; Cells, Cultured; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Guanylate Cyclase; Heart Failure; Male; Mice; Nitric Oxide; Phosphodiesterase Inhibitors; Signal Transduction

We have previously shown that the natriuretic peptide receptor B (NPR-B) agonist C-type natriuretic peptide (CNP) enhances cyclic adenosine 3´,5´-monophosphate (cAMP)-mediated signaling in failing hearts, through cyclic guanosine 3´,5´-monophosphate (cGMP)-mediated phosphodiesterase (PDE) 3 inhibition. As several signaling pathways are importantly changed in failing hearts, it could not be taken for granted that this crosstalk would be the same in non-failing hearts. Thus, we wanted to clarify to which extent this effect of CNP occurred also in non-failing hearts. Inotropic and lusitropic responses were measured in muscle strips and cGMP levels, localized cAMP levels, cAMP-PDE activity and mRNA levels were analyzed in isolated cardiomyocytes from left ventricles of non-failing and failing rat hearts. CNP increased cGMP and enhanced β

Topics: Animals; Cell Survival; Cyclic AMP; Cyclic GMP; Heart Failure; Male; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Phosphodiesterase 3 Inhibitors; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction

Heart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long-term preventive application of the phosphodiesterase-5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy-associated HFpEF.. Zucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure-volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro-oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro-oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro-oxidative stress, myocardial hypertrophy and fibrotic remodelling.. We report that vardenafil successfully prevented the development of diabetes mellitus-associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

Topics: Animals; Apoptosis; Cardiomegaly; Cyclic GMP; Diabetes Mellitus, Type 2; Echocardiography; Fibrosis; Heart; Heart Failure; Myocardium; Myocytes, Cardiac; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Rats; Rats, Zucker; Stroke Volume; Vardenafil Dihydrochloride

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Heart Failure; Humans; Phosphoric Diester Hydrolases; Up-Regulation

We examine the hypothesis that cyclic guanosine monophosphate (cGMP) levels are elevated in recipients of continuous-flow left ventricular assist devices (CF-LVADs) and that elevated cGMP levels are associated with a risk of gastrointestinal (GI) bleeding events.. The levels of cGMP, nitric oxide, platelet activation markers, platelet-derived growth factors (PDGF) AB/BB and AA, and the inflammatory mediator C-reactive protein (CRP) were examined in 19 CF-LVAD recipients, 21 patients who had heart failure, and 19 healthy control-group participants.. The median level of cGMP was significantly higher in CF-LVAD recipients, compared with healthy participants (6.6 vs 2.1 pmol/mL, u = 62.5; P = .001; r = -0.55). Median cGMP levels in the heart failure group (12.5 pmol/L) were higher, compared with both CF-LVAD recipients (u = 75.0; P = .001; r = -0.53) and healthy participants (u = 4.0; P < .001; r = -0.83). Compared with the healthy group, median CRP levels were significantly higher in CF-LVAD recipients (2.9 vs 8.0 mg/L; u = 58.0; P < .001; r = -0.63) and heart failure patients (2.9 vs 7.0 mg/L; u = 59.0; P < .001; r = -0.65). In the subgroup of patients supported with the HeartMate II (Thoratec Corporation, Pleasanton, Calif), pulsatility index was significantly negatively correlated with cGMP levels (r = -0.73; P < .05), indicating that low pulsatility index is associated with higher cGMP levels. High cGMP levels were significantly associated with GI bleeding events, but not with bleeding events in general.. The primary finding of this study is that GI bleeding in CF-LVAD recipients is associated with significantly elevated cGMP levels, despite high levels of CRP, which interfere with cGMP production. Further studies are required to determine whether elevated cGMP levels can be used as a clinical marker for increased risk of GI bleeding in CF-LVAD recipients.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Cyclic GMP; Female; Gastrointestinal Hemorrhage; Heart Failure; Heart-Assist Devices; Humans; Inflammation Mediators; Male; Middle Aged; Platelet Activation; Prosthesis Design; Pulsatile Flow; Risk Assessment; Risk Factors; Treatment Outcome; Up-Regulation; Ventricular Function, Left

Topics: Cyclic GMP; Female; Gastrointestinal Hemorrhage; Heart Failure; Heart-Assist Devices; Humans; Male; Ventricular Function, Left

Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG Iα attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG Iα disulfide formation. To investigate the role of PKG Iα disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG Iα knock-in (KI) mice. Echocardiography showed that doxorubicin treatment caused loss of myocardial tissue and depressed left ventricular function in WT mice. Doxorubicin also reduced pro-survival signaling and increased apoptosis in WT hearts. In contrast, KI mice were markedly resistant to the dysfunction induced by doxorubicin in WTs. In follow-on experiments the influence of the PDE5 inhibitor tadalafil on the development of doxorubicin-induced cardiomyopathy in WT and KI mice was investigated. In WT mice, co-administration of tadalafil with doxorubicin reduced PKG Iα oxidation caused by doxorubicin and also protected against cardiac injury and loss of function. KI mice were again innately resistant to doxorubicin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associated protein kinase (ROCK) in WTs. These pro-apoptotic events were absent in KI mice and were attenuated in WTs co-administered tadalafil. PKG Iα disulfide formation triggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.

Topics: Animals; Cardiomegaly; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic Nucleotide Phosphodiesterases, Type 5; Disulfides; Doxorubicin; Heart Failure; Mice; Mice, Mutant Strains; Oxidation-Reduction; Phosphodiesterase 5 Inhibitors; rho-Associated Kinases; Second Messenger Systems; Tadalafil

Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF).. Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45±3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure-volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 μg/kg/min) or SNP (0.3 μg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP.. SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54±5.84% to 36.59±5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49±6.35% to 50.30±7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75).. Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Heart Failure; Humans; Infusions, Intravenous; Myocardial Contraction; Myocardial Infarction; Myocardium; Nitric Oxide Donors; Nitroprusside; Oxygen Consumption; Stroke Volume; Vasodilator Agents; Ventricular Dysfunction, Left

Cardiac hypertrophy is an abnormal enlargement of heart muscle. It frequently results in congestive heart failure, which is a leading cause of human death. Previous studies demonstrated that the nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway can inhibit cardiac hypertrophy and thus improve cardiac function. However, the underlying mechanisms are not fully understood. Here, based on the human embryonic stem cell-derived cardiomyocyte (hESC-CM) model system, we showed that Orai1, the pore-forming subunit of store-operated Ca(2+) entry (SOCE), is the downstream effector of PKG. Treatment of hESC-CMs with an α-adrenoceptor agonist phenylephrine (PE) caused a marked hypertrophy, which was accompanied by an upregulation of Orai1. Moreover, suppression of Orai1 expression/activity using Orai1-siRNAs or a dominant-negative construct Orai1(G98A) inhibited the hypertrophy, suggesting that Orai1-mediated SOCE is indispensable for the PE-induced hypertrophy of hESC-CMs. In addition, the hypertrophy was inhibited by NO and cGMP via activating PKG. Importantly, substitution of Ala for Ser(34) in Orai1 abolished the antihypertrophic effects of NO, cGMP, and PKG. Furthermore, PKG could directly phosphorylate Orai1 at Ser(34) and thus prevent Orai1-mediated SOCE. Together, we conclude that NO, cGMP, and PKG inhibit the hypertrophy of hESC-CMs via PKG-mediated phosphorylation on Orai1-Ser-34. These results provide novel mechanistic insights into the action of cGMP-PKG-related antihypertrophic agents, such as NO donors and sildenafil.

Topics: Calcium; Calcium Channels; Cardiomegaly; Cell Differentiation; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Gene Expression Regulation; Heart Failure; Human Embryonic Stem Cells; Humans; Myocytes, Cardiac; Nitric Oxide; ORAI1 Protein; Phenylephrine; Phosphorylation; Signal Transduction

Pharmacological activation of cGMP-dependent protein kinase G I (PKGI) has emerged as a therapeutic strategy for humans with heart failure. However, PKG-activating drugs have been limited by hypotension arising from PKG-induced vasodilation. PKGIα antiremodeling substrates specific to the myocardium might provide targets to circumvent this limitation, but currently remain poorly understood.. We performed a screen for myocardial proteins interacting with the PKGIα leucine zipper (LZ)-binding domain to identify myocardial-specific PKGI antiremodeling substrates. Our screen identified cardiac myosin-binding protein-C (cMyBP-C), a cardiac myocyte-specific protein, which has been demonstrated to inhibit cardiac remodeling in the phosphorylated state, and when mutated leads to hypertrophic cardiomyopathy in humans. GST pulldowns and precipitations with cGMP-conjugated beads confirmed the PKGIα-cMyBP-C interaction in myocardial lysates. In vitro studies demonstrated that purified PKGIα phosphorylates the cMyBP-C M-domain at Ser-273, Ser-282, and Ser-302. cGMP induced cMyBP-C phosphorylation at these residues in COS cells transfected with PKGIα, but not in cells transfected with LZ mutant PKGIα, containing mutations to disrupt LZ substrate binding. In mice subjected to left ventricular pressure overload, PKGI activation with sildenafil increased cMyBP-C phosphorylation at Ser-273 compared with untreated mice. cGMP also induced cMyBP-C phosphorylation in isolated cardiac myocytes.. Taken together, these data support that PKGIα and cMyBP-C interact in the heart and that cMyBP-C is an anti remodeling PKGIα kinase substrate. This study provides the first identification of a myocardial-specific PKGIα LZ-dependent antiremodeling substrate and supports further exploration of PKGIα myocardial LZ substrates as potential therapeutic targets for heart failure.

Topics: Animals; Carrier Proteins; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Heart Failure; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Phosphorylation; Rats; Rats, Sprague-Dawley

Recently, we showed C-type natriuretic peptide (CNP)-induced negative inotropic (NIR) and positive lusitropic response (LR) in failing rat heart. We wanted to study whether, and if so, how phosphodiesterases (PDEs) regulate CNP-induced cyclic 3',5'-guanosine monophosphate (cGMP) elevation and functional responses. Inotropic and lusitropic responses were measured in left ventricular muscle strips and cyclic nucleotide levels, PDE activity and phospholamban (PLB) and troponin I (TnI) phosphorylation were measured in ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. CNP-mediated increase in global cGMP was mainly regulated by PDE2, as reflected by a marked amplification of the cGMP increase during PDE2 inhibition and by a high PDE2 activity in cardiomyocytes. PDE3 inhibition, on the other hand, caused no significant cGMP increase by CNP. The functional consequences did not correspond to the changes of cGMP. PDE3 inhibition increased the potency of the CNP-induced NIR and LR, while PDE2 inhibition desensitized the CNP-induced NIR, but not LR. A role for PDE2 on the maximal LR and PDE5 on the maximal NIR to CNP was revealed in the presence of PDE3 inhibition. CNP increased PLB phosphorylation about 25- to 30-fold and tended to increase TnI phosphorylation about twofold. As a whole, CNP-induced functional responses were only modestly regulated by PDEs compared to the cAMP-mediated functional responses to β1-adrenoceptor stimulation, which are highly regulated by PDEs. There is a mismatch between the CNP-induced cGMP increase and functional responses. Global cGMP levels are mainly regulated by PDE2 after CNP stimulation, whereas the functional responses are modestly regulated by both PDE2 and PDE3, indicating cGMP compartmentation by PDEs affecting CNP-induced responses in failing hearts.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Heart Failure; In Vitro Techniques; Male; Myocardial Contraction; Natriuretic Peptide, C-Type; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Rats; Rats, Wistar; Signal Transduction

Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.. Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.. These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.

Topics: Aged; Animals; Biological Availability; Cyclic GMP; Cytoprotection; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Middle Aged; Nitric Oxide; Signal Transduction; Sodium Nitrite; Stroke Volume; Ventricular Dysfunction, Left

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

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

Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

Topics: Animals; Cardiotonic Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Estradiol; Estrogens; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Guanylate Cyclase; Heart Diseases; Heart Failure; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Ovariectomy; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Receptors, Atrial Natriuretic Factor; Sex Characteristics; Sildenafil Citrate; Sulfones; Treatment Outcome

Nitric oxide activation of soluble guanylyl cyclase (sGC) blunts the cardiac stress response, including cardiomyocyte hypertrophy. In the concentric hypertrophied heart, oxidation and re-localization of myocardial sGC diminish cyclase activity, thus aggravating depressed nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling in the pressure-overloaded failing heart. Here, we hypothesized that volume-overload differentially disrupts myocardial sGC activity during early compensated and late decompensated stages of eccentric hypertrophy. To this end, we studied the expression, redox state, subcellular localization, and activity of sGC in the left ventricle of dogs subjected to chordal rupture-induced mitral regurgitation (MR). Unoperated dogs were used as Controls. Animals were studied at 4weeks and 12months post chordal rupture, corresponding with early (4wkMR) and late stages (12moMR) of eccentric hypertrophy. We found that the sGC heterodimer subunits relocalized away from caveolae-enriched lipid raft microdomains at different stages; sGCβ1 at 4wkMR, followed by sGCα1 at 12moMR. Moreover, expression of both sGC subunits fell at 12moMR. Using the heme-dependent NO donor DEA/NO and NO-/heme-independent sGC activator BAY 60-2770, we determined the redox state and inducible activity of sGC in the myocardium, within caveolae and non-lipid raft microdomains. sGC was oxidized in non-lipid raft microdomains at 4wkMR and 12moMR. While overall DEA/NO-responsiveness remained intact in MR hearts, DEA/NO responsiveness of sGC in non-lipid raft microdomains was depressed at 12moMR. Caveolae-localization protected sGC against oxidation. Further studies revealed that these modifications of sGC were also reflected in caveolae-localized cGMP-dependent protein kinase (PKG) and MAPK signaling. In MR hearts, PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) disappeared from caveolae whereas caveolae-localization of phosphorylated ERK5 increased. These findings show that differential oxidation, re-localization, and expression of sGC subunits distinguish eccentric from concentric hypertrophy as well as compensated from decompensated heart failure.

Topics: Animals; Cardiomegaly; Cell Adhesion Molecules; Cyclic GMP; Dogs; Female; Guanylate Cyclase; Heart Failure; Male; Membrane Microdomains; Microfilament Proteins; Mitral Valve Insufficiency; Muscle Proteins; Myocardium; Nitric Oxide; Oxidation-Reduction; Phosphoproteins; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Time Factors

We investigated if soluble guanylate cyclase stimulation either alone or in combination with phosphodiesterase-5 (PDE5) inhibition could prevent pressure overload-induced right ventricular (RV) hypertrophy and failure.. The soluble guanylate cyclase stimulator BAY 41-2272 (BAY, 10 mg · kg⁻¹ · d⁻¹) either alone or in combination (BAY + SIL) with a PDE5 inhibitor sildenafil (SIL, 100 mg · kg⁻¹ · d⁻¹) was examined for prevention of RV hypertrophy and failure in Wistar rats (n = 73) operated by pulmonary trunk banding.. All treatments failed to inhibit the development of RV hypertrophy and failure. In the BAY and BAY + SIL groups, there was an increased mortality. Mean arterial blood pressure was lowered and cardiac output increased in the BAY + SIL group. Systolic RV pressure was increased in the BAY and BAY + SIL groups possibly because of an inotropic response and/or increased venous return.. Stimulation of soluble guanylate cyclase by BAY 41-2272 alone or in combination with sildenafil failed to prevent the development of RV hypertrophy and failure in rats subjected to pulmonary trunk banding. An increased mortality was observed in animals treated by BAY 41-2272 alone and in combination with sildenafil.

Topics: Animals; Blood Pressure; Cardiac Output; Cyclic GMP; Disease Models, Animal; Disease Progression; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Survival Analysis

Myocardial C-type natriuretic peptide (CNP) levels are increased in heart failure. CNP can induce negative inotropic (NIR) and positive lusitropic responses (LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP-induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca(2+) ATPase2 (SERCA2) activity is essential for these responses.. Contractility, cGMP levels, Ca(2+) transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction.. CNP increased cGMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban (PLB) Ser(16) and troponin I (TnI) Ser(23/24) phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/cGMP analogue (Rp-8-Br-Pet-cGMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca(2+) transient and increased SERCA2 activity in cardiomyocytes. The CNP-elicited NIR and LR were not affected by the L-type Ca(2+) channel activator BAY-K8644, but were abolished in the presence of isoprenaline (induces maximal activation of cAMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte-specific inactivation of the SERCA2 gene.. We conclude that CNP-induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium-Binding Proteins; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart Failure; Isoproterenol; Male; Mice; Mice, Knockout; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Phosphorylation; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thapsigargin; Thionucleotides; Troponin I

cAMP and cGMP signalling pathways are common targets in the pharmacological treatment of heart failure, and often drugs that modulate the level of these second messengers are simultaneously administered to patients. cGMP can potentially affect cAMP levels by modulating the activity of PDEs (phosphodiesterases), the enzymes that degrade cyclic nucleotides. This biochemical cross-talk provides the means for drugs that increase cGMP to concomitantly affect cAMP signals. Recent studies using FRET (fluorescence resonance energy transfer) reporters and real-time imaging show that, in cardiac myocytes, the interplay between cGMP and cAMP has different outcomes depending on the specific location where the cross-modulation occurs. cGMP can either increase or decrease the cAMP response to catecholamines, based on the cyclase that generates it and on the PDEs associated with each subcellular compartment. cGMP-mediated modulation of cAMP signals has functional relevance as it affects protein phosphorylation downstream of protein kinase A and myocyte contractility. The physical separation of positive and negative modulation of cAMP levels by cGMP offers the previously unrecognized possibility to selectively modulate local cAMP signals to improve the efficacy of therapy.

Topics: Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Heart; Heart Failure; Humans; Isoenzymes; Myocardium; Myocytes, Cardiac; Second Messenger Systems

Phosphodiesterases (PDEs) are key enzymes controlling cAMP and cGMP levels and spatial distribution within cardiomyocytes. Despite the clinical importance of several classes of PDE inhibitor there has not been a complete characterization of the PDE profile within the human cardiomyocyte, and no attempt to assess which species might best be used to model this for drug evaluation in heart disease.. Ventricular cardiomyocytes were isolated from failing human hearts of patients with various etiologies of disease, and from rat and guinea pig hearts. Expression of PDE isoforms was determined using RT-PCR. cAMP- and cGMP-PDE hydrolytic activity was determined by scintillation proximity assay, before and after treatment with PDE inhibitors for PDEs 1, 2, 3, 4, 5 and 7. Functional effects of cAMP PDEi were determined on the contraction of single human, rat and guinea pig cardiomyocytes.. The presence and activity of PDE5 were confirmed in ventricular cardiomyocytes from failing and hypertrophied human heart, as well as PDE3, with ventricle-specific results for PDE4 and a surprisingly large contribution from PDE1 for hydrolysis of both cAMP and cGMP. The total PDE activity of human cardiomyocytes, and the profile of inhibition by PDE1, 3, 4, and 5 inhibitors, was modelled well in guinea pig but not rat cardiomyocytes.. Our results provide the first full characterisation of human cardiomyocyte PDE isoforms, and suggest that guinea pig myocytes provide a better model than rat for PDE levels and activity.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Female; Guinea Pigs; Heart Failure; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Contraction; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F(passive)) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F(passive) and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF).. Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(passive) was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(passive) in HFPEF was corrected by in vitro PKG administration.. Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F(passive) and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.

Topics: Aortic Valve Stenosis; Biopsy; Cohort Studies; Comorbidity; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Obesity; Oxidative Stress; Stroke Volume; Tyrosine

In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide- (specifically from nitric oxide synthase 3) but not natriuretic peptide (NP)-stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Because nitric oxide signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling.. Mice with cardiac myocyte inducible PDE5 overexpression (P5(+)) were crossed to those lacking nitric oxide synthase 3 (N3(-)), and each model, the double cross, and controls were subjected to transaortic constriction. P5(+) mice developed worse dysfunction and hypertrophy and enhanced NP stimulation, whereas N3(-) mice were protected. However, P5(+)/N3(-) mice behaved similarly to P5(+) mice despite the lack of nitric oxide synthase 3-coupled cGMP generation, with protein kinase G activity suppressed in both models. PDE5 inhibition did not alter atrial natriuretic peptide-stimulated cGMP in the resting heart but augmented it in the transaortic constriction heart. This functional retargeting was associated with PDE5 translocation from sarcomeres to a dispersed distribution. P5(+) hearts exhibited higher oxidative stress, whereas P5(+)/N3(-) hearts had low levels (likely owing to the absence of nitric oxide synthase 3 uncoupling). This highlights the importance of myocyte protein kinase G activity as a protection for pathological remodeling.. These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for natriuretic peptide-derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely affects the pathophysiological consequence and the therapeutic impact of PDE5 modulation in heart disease.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Heart Failure; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Ventricular Remodeling

Recombinant human brain natriuretic peptide (rhBNP) is an important peptide-based therapeutic drug indicated for the treatment of acute heart failure. Accurate determination of the potency of therapeutic rhBNP is crucial for the safety and efficacy of the drug. The current bioassay involves use of rabbit aortic strips, with experiments being complicated and time-consuming and markedly variable in results. Animal-less methods with better precision and accuracy should be explored. We have therefore developed an alternative cell-based assay, which relies on the ability of BNP to induce cGMP production in HEK293 cells expressing BNP receptor guanylyl cyclase-A.. An alternative assay based on the measurement of BNP-induced cGMP production was developed. Specifically, the bioassay employs cells engineered to express BNP receptor guanylyl cyclase-A (GCA). Upon rhBNP stimulation, the levels of the second messager cGMP in these cells drastically increased and subsequently secreted into culture supernatants. The quantity of cGMP, which corresponds to the rhBNP activity, was determined using a competitive ELISA developed by us. Compared with the traditional assay, the novel cell-based assay demonstrated better reproducibility and precision.. The optimized cell-based assay is much simpler, more rapid and precise compared with the traditional assay using animal tissues. To our knowledge, this is the first report on a novel and viable alternative assay for rhBNP potency analysis.

Topics: Biological Assay; Cyclic GMP; Gene Expression; Heart Failure; HEK293 Cells; Humans; Natriuretic Peptide, Brain; Recombinant Proteins

Elevations in the plasma concentrations of natriuretic peptides correlate with increased severity of myxomatous mitral valve disease (MMVD) in dogs. This study correlates the severity of MMVD with the plasma concentrations of the biomarkers N-terminal fragment of the pro-brain-natriuretic peptide (NT-proBNP) and its second messenger, cyclic guanosine monophosphate (cGMP). Furthermore, the L-arginine:asymmetric dimethylarginine (ADMA) ratio was measured as an index of nitric oxide availability. The study included 75 dogs sub-divided into five groups based on severity of MMVD as assessed by clinical examination and echocardiography. Plasma NT-proBNP and cGMP concentrations increased with increasing valve dysfunction and were significantly elevated in dogs with heart failure. The cGMP:NT-proBNP ratio decreased significantly in dogs with heart failure, suggesting the development of natriuretic peptide resistance. Although the l-arginine:ADMA ratio decreased with increasingly severe MMVD, this was largely due to the older age of the dogs with heart failure.

Topics: Age Factors; Animals; Arginine; Biomarkers; Cyclic GMP; Dog Diseases; Dogs; Echocardiography; Female; Heart Failure; Heart Valve Diseases; Male; Mitral Valve; Mitral Valve Insufficiency; Natriuretic Peptide, Brain; Peptide Fragments

By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides suggests that this compensatory system is limited.. Levels of circulating corin (the pro-ANP-converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n=14) had severe heart failure (New York Heart Association class III-IV) with a median ejection fraction of 18% and median brain natriuretic peptide levels of 1940 pg/mL. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal control subjects (180 versus 1368 pg/mL, P<0.01). In contrast, in patients with heart failure, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 versus 7.5 ng/mL, P<0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in patients with heart failure (P<0.01), suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cyclic guanosine monophosphate were elevated in patients with heart failure (150.0 versus 7.6 pmol/mL, P<0.01), and plasma cyclic guanosine monophosphate levels positively correlated with the fractional amount of cleaved pro-ANP (r(s)=0.59, P<0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact.. Taken together, these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Cyclic GMP; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Humans; Male; Middle Aged; Serine Endopeptidases; Severity of Illness Index; Stroke Volume; Ventricular Function; Young Adult

Topics: Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Down-Regulation; Heart Failure; Humans; Natriuretic Peptide, Brain; Prognosis; Serine Endopeptidases; Severity of Illness Index; Stroke Volume; Ventricular Function

Heart failure is associated with deficient endothelial nitric oxide (NO) production as well as increased oxidative stress and accelerated NO degradation. The aim of this study was to evaluate platelet NO biosynthesis and superoxide anion (O(2)(-)) production in patients with heart failure.. In platelets from patients with heart failure due to idiopathic dilated cardiomyopathy (n= 16) and healthy control subjects (n= 23), NO synthase (NOS) activity was evaluated by L-[(3)H]-arginine to l-[(3)H]-citrulline conversion, cGMP was determined by radioimmunoassay, vasodilator-stimulated phosphoprotein (VASP: total and serine-239-phosphorylated) was assessed by western blotting, and O(2)(-) production and O(2)(-) scavenging capacity were measured by pholasin-enhanced chemiluminescence. In platelets from patients with heart failure, basal NOS activity was higher than in those from controls; furthermore, whereas platelet NOS activity increased as expected in response to albuterol or collagen in controls, no increase occurred in platelets from heart failure subjects. Despite this, basal intraplatelet NO-attributable cGMP was lower in heart failure than in control subjects, as was serine-239 phosphorylation of VASP, suggesting a decrease in bioactive NO. Platelets from heart failure subjects exhibited higher basal and collagen-stimulated O(2)(-) production and impaired O(2)(-) scavenging capacity, resulting in higher oxidative stress, consistent with the observed decrease in bioactive NO.. In heart failure, despite activation of NOS, platelets produce less bioactive NO, probably as a result of NO scavenging due to increased O(2)(-) production. This functional defect in the platelet l-arginine/NO/guanylyl cyclase pathway could contribute to the platelet activation observed in heart failure.

Topics: Adult; Blood Platelets; Cell Adhesion Molecules; Cyclic GMP; Female; Heart Failure; Humans; Male; Microfilament Proteins; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Phosphoproteins; Phosphorylation; Signal Transduction; Superoxides

We hypothesized that cardiac myocyte-specific overexpression of caveolin-3 (Cav-3), a muscle-specific caveolin, would alter natriuretic peptide signaling and attenuate cardiac hypertrophy.. Natriuretic peptides modulate cardiac hypertrophy and are potential therapeutic options for patients with heart failure. Caveolae, microdomains in the plasma membrane that contain caveolin proteins and natriuretic peptide receptors, have been implicated in cardiac hypertrophy and natriuretic peptide localization.. We generated transgenic mice with cardiac myocyte-specific overexpression of caveolin-3 (Cav-3 OE) and also used an adenoviral construct to increase Cav-3 in cardiac myocytes.. The Cav-3 OE mice subjected to transverse aortic constriction had increased survival, reduced cardiac hypertrophy, and maintenance of cardiac function compared with control mice. In left ventricle at baseline, messenger ribonucleic acid for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were increased 7- and 3-fold, respectively, in Cav-3 OE mice compared with control subjects and were accompanied by increased protein expression for ANP and BNP. In addition, ventricles from Cav-3 OE mice had greater cyclic guanosine monophosphate levels, less nuclear factor of activated T-cell nuclear translocation, and more nuclear Akt phosphorylation than ventricles from control subjects. Cardiac myocytes incubated with Cav-3 adenovirus showed increased expression of Cav-3, ANP, and Akt phosphorylation. Incubation with methyl-β-cyclodextrin, which disrupts caveolae, or with wortmannin, a PI3K inhibitor, blocked the increase in ANP expression.. These results imply that cardiac myocyte-specific Cav-3 OE is a novel strategy to enhance natriuretic peptide expression, attenuate hypertrophy, and possibly exploit the therapeutic benefits of natriuretic peptides in cardiac hypertrophy and heart failure.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Caveolae; Caveolin 3; Cyclic GMP; Heart Failure; Immunoenzyme Techniques; In Vitro Techniques; Mice; Mice, Knockout; Mice, Transgenic; Myocytes, Cardiac; Natriuretic Peptide, Brain; NFATC Transcription Factors; RNA, Messenger

In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Cell Separation; Cells, Cultured; Cyclic GMP; Diuresis; Glomerular Filtration Rate; Glucocorticoids; Heart Failure; Hormone Antagonists; Kidney; Kidney Medulla; Kidney Tubules, Collecting; Male; Mifepristone; Natriuresis; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Sodium; Stroke Volume; Up-Regulation; Urodynamics

Our goal was to examine the role of B-type natriuretic peptide (BNP) in lipolysis regulation in heart failure (HF) patients.. Enhanced adipose tissue lipolysis can contribute to myocardial lipid overload, insulin resistance, and cachexia in advanced HF. Natriuretic peptides were recently recognized to stimulate lipolysis in healthy subjects.. Ten nondiabetic HF patients (New York Heart Association functional class III, 50% nonischemic etiology) and 13 healthy subjects (control subjects) of similar age, sex, and body composition underwent a microdialysis study of subcutaneous abdominal adipose tissue. Four microdialysis probes were simultaneously perfused with 0.1 μM BNP(1-32,) 10 μM BNP(1-32), 10 μM norepinephrine (NE) or Ringer's solution. Outgoing dialysate glycerol concentration (DGC) was measured as an index of lipolysis.. Spontaneous lipolysis was higher in HF patients compared with control subjects (DGC: 189 ± 37 μmol/l vs. 152 ± 35 μmol/l, p < 0.01). Response to NE was similar (p = 0.35) in HF patients and control subjects (DGC increase of 1.7 ± 0.2-fold vs. 1.7 ± 0.4-fold). BNP(1-32) 10 μM markedly increased lipolysis in both HF patients and control subjects (DGC increase of 2.8 ± 0.5-fold vs. 3.2 ± 0.3-fold), whereas the response to 0.1 μM BNP(1-32) was more pronounced in HF patients (p = 0.02). In HF patients, spontaneous lipolysis positively correlated with insulin resistance and the response to BNP(1-32) negatively correlated with adiposity.. BNP(1-32) exerts strong lipolytic effects in humans. Despite marked elevation of plasma immunoreactive BNP, the responsiveness of adipose tissue to BNP(1-32) is not attenuated in HF, possibly reflecting a deficiency of endogenous bioactive BNP. Lipolytic effects of BNP can contribute to excessive fatty acid mobilization in advanced HF.

Topics: Case-Control Studies; Cyclic GMP; Extracellular Fluid; Heart Failure; Humans; Lipolysis; Male; Microdialysis; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Regional Blood Flow; Subcutaneous Fat, Abdominal

Activation of 5-HT(4) receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT(4)-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT(4)-mediated inotropic response. However, CNP increased the 5-HT(4)-mediated inotropic response as well as the β(1)-adrenoceptor (β(1)-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by L-NAME and ODQ, respectively, attenuated the 5-HT(4)-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT(4) response, Sin-1 inhibited whereas L-NAME and ODQ enhanced the β(1)-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT(4)-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β(1)-AR and 5-HT(4) receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different G(s)-coupled receptors.

Topics: Animals; Cyclic GMP; Disease Models, Animal; GTP-Binding Protein alpha Subunits, Gs; Guanylate Cyclase; Heart Failure; Male; Myocardial Contraction; Myocardial Infarction; Natriuretic Peptide, C-Type; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Receptors, Atrial Natriuretic Factor; Receptors, Cytoplasmic and Nuclear; Receptors, Serotonin, 5-HT4; Soluble Guanylyl Cyclase

Whereas natriuretic peptides increase cGMP levels with beneficial cardiovascular effects through protein kinase G, we found an unexpected cardio-excitatory effect of C-type natriuretic peptide (CNP) through natriuretic peptide receptor B (NPR-B) stimulation in failing cardiac muscle and explored the mechanism.. Heart failure was induced in male Wistar rats by coronary artery ligation. Contraction studies were performed in left ventricular muscle strips. Cyclic nucleotides were measured by radio- and enzyme immunoassay. Apoptosis was determined in isolated cardiomyocytes by Annexin-V/propidium iodide staining and phosphorylation of phospholamban (PLB) and troponin I was measured by western blotting. Stimulation of NPR-B enhanced beta1-adrenoceptor (beta1-AR)-evoked contractile responses through cGMP-mediated inhibition of phosphodiesterase 3 (PDE3). CNP enhanced beta1-AR-mediated increase of cAMP levels to the same extent as the selective PDE3 inhibitor cilostamide and increased beta1-AR-stimulated protein kinase A activity, as demonstrated by increased PLB and troponin I phosphorylation. CNP promoted cardiomyocyte apoptosis similar to inhibition of PDE3 by cilostamide, indicative of adverse effects of NPR-B signalling in failing hearts.. An NPR-B-cGMP-PDE3 inhibitory pathway enhances beta(1)-AR-mediated responses and may in the long term be detrimental to the failing heart through mechanisms similar to those operating during treatment with PDE3 inhibitors or during chronic beta-adrenergic stimulation.

Topics: Animals; Apoptosis; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Heart Failure; Male; Myocardial Contraction; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Quinolones; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Signal Transduction

Brain natriuretic peptide (BNP) increases in proportion to the extent of right ventricular dysfunction in pulmonary hypertension and after heart transplantation. No data are available after lung transplantation. Clinical, biological, respiratory, echocardiographic characteristics and circulating BNP and its second messenger cyclic guanosine monophosphate (cGMP) were determined in thirty matched subjects (10 lung-, 10 heart-transplant recipients (Ltx, Htx) and 10 healthy controls). Eventual correlations between these parameters were investigated. Heart rate and pulmonary arterial blood pressure were slightly increased after transplantation. Creatinine clearance was decreased. Mean of forced expiratory volume in 1 s was 76.6 +/- 5.3% and vital capacity was 85.3 +/- 6.4% of the predicted values in Ltx. BNP was similarly increased in Ltx and Htx, as compared with control values (54.1 +/- 14.2 and 45.6 +/- 9.2 vs. 6.2 +/- 1.8 pg/ml, respectively). Significant relationships were observed between plasma BNP and cGMP values (r = 0.62; P < 0.05 and r = 0.75; P < 0.01, in Ltx and Htx) and between BNP and right ventricular fractional shortening and tricuspid E/Ea ratio in Ltx (r = -0.75 and r = 0.93; P < 0.01, respectively). BNP is increased after lung transplantation, like after heart transplantation. The relationships observed suggest that the cardiac hormone might counterbalance possible deleterious effects of lung-transplantation on right functioning of patient's heart.

Topics: Adult; Blood Pressure; Cyclic GMP; Female; Heart Failure; Heart Transplantation; Humans; Lung Transplantation; Male; Middle Aged; Natriuretic Peptide, Brain; Ventricular Function, Right

Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and intracellular guanosine 3',5'-cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC-A-overexpressing cells have indicated that GC-A is extensively phosphorylated, and that ANP-induced homologous desensitization of GC-A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC-A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP-provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC-A was diminished. However, intriguingly, the phosphorylation of GC-A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site-directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC-A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC-A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC-A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC-A responsiveness to ANP may have important pathophysiological implications.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Cardiomegaly; Catalytic Domain; Cell Line; Cyclic GMP; Guanylate Cyclase; Heart Failure; Humans; Kidney; Natriuretic Peptide, Brain; Oligopeptides; Peptides; Phosphopeptides; Phosphorylation; Rats; Receptors, Atrial Natriuretic Factor; Second Messenger Systems

Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A.

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Cyclic GMP; Disease Models, Animal; Female; Guanylate Cyclase; Heart Failure; LIM Domain Proteins; Mice; Mice, Knockout; Mice, Transgenic; Muscle Proteins; Myocardial Contraction; Natriuretic Peptide, Brain; NFATC Transcription Factors; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Time Factors; Up-Regulation

Attenuation of the effects of natriuretic peptides has been demonstrated in animal models but studies in humans are scarce, particularly concerning renal attenuation. We investigated the attenuation of B-type natriuretic peptide (BNP) in chronic advanced heart failure (HF).. We included 62 outpatients with HF and severe left ventricular systolic dysfunction. Cases had at least one hospital admission or emergency department visit for acute HF in the previous year and were in NYHA class III/IV despite optimized therapy. The individual age- and sex-matched controls were symptomatically controlled (NYHA I and II). We collected 24 h urine and a blood sample from all patients. Plasma BNP and plasma (pcGMP) and urine cyclic guanosine monophosphate (ucGMP) were measured. Patients were followed for 3 months for hospital admission or all-cause death. ucGMP to plasma BNP (ucGMP/BNP) ratio was attenuated in cases vs. controls [median (IQR): 8354 (4293-16,456) vs. 12,693 (6896-22,851)]. There were no differences in pcGMP to BNP (pcGMP/BNP) ratio or urine cGMP excretion. Patients with worse outcome had lower pcGMP/BNP [260 (86-344) vs. 381 (244-728) in patients without adverse outcome events] and lower ucGMP/BNP [4146 (2207-9363) vs. 10,922 (7495-19,971)].. Renal NP's second messenger production is attenuated in advanced HF. Patients with worse outcome have lower ucGMP/BNP and pcGMP/BNP ratios.

Topics: Aged; Chronic Disease; Creatinine; Cyclic GMP; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Second Messenger Systems; Ventricular Dysfunction, Left

Phosphodiesterase-5 (PDE5) inhibitors, which induce relaxation of smooth muscle with some selectivity for the pulmonary vasculature, are used in the treatment of pulmonary hypertension. In some patients, the use of PDE5 inhibitors does not result in the desired magnitude of pulmonary vasodilation. The use of additional vasodilators to further reduce pulmonary vascular resistance is often accompanied by unacceptable reductions in systemic arterial pressure.. In 3 patients with heart failure, pulmonary hypertension and low systemic arterial pressures treated with sildenafil, systemic nitrates were added to reduce pulmonary hypertension further. Hemodynamic measurements were made before and after addition of nitrates. Addition of systemic nitrates to sildenafil led to a reduction in mean pulmonary arterial pressure of 11 mm Hg, from 37 mm Hg to 26 mm Hg (P = .06), whereas mean systemic arterial pressure decreased by only 4 mm Hg, from 77 mm Hg to 73 mm Hg (P = .53). The ratio of pulmonary vascular resistance to systemic vascular resistance was reduced by 45% (P = .1). Treatment with sildenafil and nitrates was continued for two to eight months, with no episodes of marked systemic hypotension, syncope, or lightheadedness.. These results suggest that addition of systemic nitrates to sildenafil results in a potentiation of vasodilation that is relatively selective for the pulmonary vasculature, and that this combination may be safe and effective in the treatment of pulmonary hypertension in patients with low systemic arterial pressures.

Topics: Cyclic GMP; Drug Therapy, Combination; Heart Failure; Humans; Hypertension, Pulmonary; Isosorbide Dinitrate; Male; Middle Aged; Nitro Compounds; Nitroglycerin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

B-type natriuretic peptide (BNP) is an established first-line therapy for acute decompensated heart failure (HF), but its efficacy in preventing left ventricular (LV) remodeling after myocardial injury is unknown. The goal of this study was to evaluate the effects of BNP therapy on remodeling after ischemic injury in an awake canine model. Dogs were chronically instrumented for hemodynamics. Ischemia was created by daily coronary embolization (Embo; 3.1 x 10(4) beads/day) for 3 wk; 60 min after the first embolization, BNP (100 ng x kg(-1) x min(-1); n = 6) or saline (control; n = 6) was continuously infused via a left atrial catheter for 3 wk. Hemodynamics and echocardiography were performed in an awake state at baseline, 3 wk after Embo + BNP infusion, and 4 wk after stopping Embo + BNP infusion. End-systolic elastance (E(es)) and LV change in pressure over time (dP/dt) were preserved throughout Embo + BNP therapy versus control therapy (E(es): 3.76 +/- 1.01 vs. 1.41 +/- 0.16 mmHg/ml; LV dP/dt: 2,417 +/- 96 vs. 2,068 +/- 95 mmHg/s; both P < 0.05 vs. control). LV end-diastolic dimension was significantly smaller in BNP-treated dogs compared with control dogs (4.29 +/- 0.10 vs. 4.77 +/- 0.17 cm), and ejection fraction was maintained in treated dogs vs. control dogs (53 +/- 1% vs. 46 +/- 2%) (both P < 0.05 vs. control). Cyclooxygenase (COX)-2 expression in terminal LV tissue was significantly reduced after BNP therapy. Treatment with continuous infusion of BNP preserved LV geometry, improved systolic function, and prevented the progression of systolic HF after persistent ischemic injury.

Topics: Animals; Cyclic GMP; Cyclooxygenase 2; Disease Models, Animal; Dogs; Echocardiography; Embolism; Factor VIII; Female; Fibrosis; Heart Failure; Infusion Pumps; Macrophages; Male; Myocardial Ischemia; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Stroke Volume; Ventricular Pressure; Ventricular Remodeling

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Capillaries; Cell Adhesion Molecules; Cell Size; Coronary Vessels; Cyclic GMP; Fibrosis; Heart Failure; Male; Microfilament Proteins; Myocarditis; Myocardium; Neovascularization, Physiologic; Phosphoproteins; Phosphorylation; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Proteins; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Our aim was to design, synthesize and test in vivo and in vitro a new chimeric peptide that would combine the beneficial properties of 2 distinct natriuretic peptides with a biological profile that goes beyond native peptides.. Studies have established the beneficial vascular and antiproliferative properties of C-type natriuretic peptide (CNP). While lacking renal actions, CNP is less hypotensive than the cardiac peptides atrial natriuretic peptide and B-type natriuretic peptide but unloads the heart due to venodilation. Dendroaspis natriuretic peptide is a potent natriuretic and diuretic peptide that is markedly hypotensive and functions via a separate guanylyl cyclase receptor compared with CNP.. Here we engineered a novel chimeric peptide CD-NP that represents the fusion of the 22-amino acid peptide CNP together with the 15-amino acid linear C-terminus of Dendroaspis natriuretic peptide. We also determined in vitro in cardiac fibroblasts cyclic guanosine monophosphate-activating and antiproliferative properties of CD-NP.. Our studies demonstrate in vivo that CD-NP is natriuretic and diuretic, glomerular filtration rate enhancing, cardiac unloading, and renin inhibiting. CD-NP also demonstrates less hypotensive properties when compared with B-type natriuretic peptide. In addition, CD-NP in vitro activates cyclic guanosine monophosphate and inhibits cardiac fibroblast proliferation.. The current findings advance an innovative design strategy in natriuretic peptide drug discovery and development to create therapeutic peptides with favorable properties that may be preferable to those associated with native natriuretic peptides.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cell Proliferation; Chimera; Cyclic GMP; Diuretics; Dogs; Drug Design; Elapid Venoms; Fibroblasts; Glomerular Filtration Rate; Heart; Heart Failure; Hemodynamics; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Kidney; Myocardium; Natriuretic Peptide, C-Type; Peptides; Renin

Adiponectin, which is an adipocyte-specific cytokine that has a beneficial effect in cardiovascular disease, may be downregulated by oxidative stress in patients with chronic heart failure (CHF). Plasma levels of both adiponectin and biomarkers of oxidative stress are increased and have a prognostic impact on CHF patients.. The plasma adiponectin level was measured in 116 patients with CHF (left ventricular ejection fraction <45%) who underwent cardiac catheterization, and these findings were compared with the atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) levels, hemodynamic parameters and plasma oxidized low-density lipoprotein (oxLDL) level as a marker of oxidative stress. There was no correlation between the plasma adiponectin level and hemodynamic parameters, but there was a positive correlation with the cardiac natriuretic peptides [ANP (r(s)=0.464, p<0.0001) or BNP (r(s)=0.489, p<0.0001)]. There was a significant negative correlation between plasma adiponectin level and oxLDL (r=-0.245, p=0.0079). In the stepwise multivariate analysis, a high level of natriuretic peptide (log BNP) (p=0.0098), and a low level of oxLDL (p=0.0105) were independent predictors of a high adiponectin level in CHF patients.. The plasma adiponectin level is regulated not only by cardiac natriuretic peptides but also by oxidative stress in patients with CHF.

Topics: Adiponectin; Aged; Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Down-Regulation; Female; Heart Failure; Hemodynamics; Humans; Lipoproteins, LDL; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prognosis

Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF.. In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 microg.kg body weight.min) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.. In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation.. If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.

Topics: Administration, Inhalation; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Failure; Hypertension, Pulmonary; Male; Milrinone; Phosphodiesterase Inhibitors; Pulmonary Edema; Rats; Rats, Sprague-Dawley

In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.

Topics: Acetylcholine; Animals; Bradykinin; Coronary Circulation; Coronary Vessels; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Dogs; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Heart Failure; Male; Myocardial Contraction; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroglycerin; Phosphoproteins; Phosphorylation; Recovery of Function; RNA, Messenger; Signal Transduction; Vasodilation; Vasodilator Agents; Ventricular Function, Left

The Na-Ca exchanger (NCX) is a critical calcium efflux pathway in excitable cells, but little is known regarding its autonomic regulation.. We investigated beta-adrenergic receptor and muscarinic receptor regulation of the cardiac NCX in control and heart failure (HF) conditions in atrially paced pigs. NCX current in myocytes from control swine hearts was significantly increased by isoproterenol, and this response was reversed by concurrent muscarinic receptor stimulation with the addition of carbachol, demonstrating "accentuated antagonism." Okadaic acid eliminated the inhibitory effect of carbachol on isoproterenol-stimulated NCX current, indicating that muscarinic receptor regulation operates via protein phosphatase-induced dephosphorylation. However, in myocytes from atrially paced tachycardia-induced HF pigs, the NCX current was significantly larger at baseline but less responsive to isoproterenol compared with controls, whereas carbachol failed to inhibit isoproterenol-stimulated NCX current, and 8-Br-cGMP did not restore muscarinic responsiveness. Protein phosphatase type 1 dialysis significantly reduced NCX current in failing but not control cells, consistent with NCX hyperphosphorylation in HF. Protein phosphatase type 1 levels associated with NCX were significantly depressed in HF pigs compared with control, and total phosphatase activity associated with NCX was significantly decreased.. We conclude that the NCX is autonomically modulated, but HF reduces the level and activity of associated phosphatases; defective dephosphorylation then "locks" the exchanger in a highly active state.

Topics: Adrenergic beta-Agonists; Animals; Carbachol; Cardiac Pacing, Artificial; Cell Separation; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Drug Antagonism; Female; Heart Failure; Isoproterenol; Male; Muscarinic Agonists; Myocytes, Cardiac; Niflumic Acid; Patch-Clamp Techniques; Phosphoprotein Phosphatases; Phosphorylation; Receptors, Adrenergic, beta; Receptors, Muscarinic; Sodium-Calcium Exchanger; Swine; Tachycardia

One of the clinical characteristics associated with septic shock is heart failure. Several lines of evidence indicate that functional consequences of heart failure in septic shock are linked to the activated NO-cyclic guanosine monophosphate (NO-cGMP) pathway. We have previously shown that the high-affinity cGMP export transporter, multidrug resistance protein 5 (MRP5), is expressed in the heart, which modulates intracellular concentrations and, hence, the effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to the development of heart failure. We therefore investigated MRP5 expression in the heart using two established murine models of septic shock (intraperitoneal LPS injection and surgical implantation of a stent into the ascending colon, resulting in a multibacterial peritonitis [CASP, colon ascendens stent peritonitis] in C57BL/6N mice, respectively; n = 38). Cardiac MRP5 was assessed by quantitative polymerase chain reaction and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle, and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared with controls both in the LPS (31.9 +/- 16.8 x 10(-4) vs. 54.1 +/- 14.8 x 10(-4), P = 0.025) and CASP model (18.3 +/- 9.4 x 10(-4) vs. 42.8 +/- 12.1 x 10(-4), P = 0.009; MRP5/glyceraldehyde 3-phosphate dehydrogenase copy numbers, respectively). In parallel, IL-6 plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL1) with 5 ng/mL IL-6 resulted in decreased expression of MRP5 (54% of control), as did incubation of the cells with serum from septic mice (LPS serum, 22% of control; CASP serum, 11% of control). In conclusion, cardiac expression of the cGMP export transporter MRP5 is decreased in two murine models of septic shock, most likely by a transcriptional mechanism. Reduced cGMP export as a consequence of decreased MRP5 expression can attenuate heart failure in sepsis.

Topics: Animals; Cells, Cultured; Colon; Cyclic GMP; Disease Models, Animal; Endothelium; Female; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; Heart Failure; Interleukin-6; Lipopolysaccharides; Mice; Multidrug Resistance-Associated Proteins; Myocardium; Myocytes, Cardiac; Myocytes, Smooth Muscle; Nitric Oxide; Peritonitis; Polymerase Chain Reaction; RNA, Messenger; Shock, Septic; Stents

Formation of cardiogenic pulmonary edema in acute left heart failure is traditionally attributed to increased fluid filtration from pulmonary capillaries and subsequent alveolar flooding. Here, we demonstrate that hydrostatic edema formation at moderately elevated vascular pressures is predominantly caused by an inhibition of alveolar fluid reabsorption, which is mediated by endothelial-derived nitric oxide (NO). In isolated rat lungs, we quantified fluid fluxes into and out of the alveolar space and endothelial NO production by a two-compartmental double-indicator dilution technique and in situ fluorescence imaging, respectively. Elevation of hydrostatic pressure induced Ca(2+)-dependent endothelial NO production and caused a net fluid shift into the alveolar space, which was predominantly attributable to impaired fluid reabsorption. Inhibition of NO production or soluble guanylate cyclase reconstituted alveolar fluid reabsorption, whereas fluid clearance was blocked by exogenous NO donors or cGMP analogs. In isolated mouse lungs, hydrostatic edema formation was attenuated by NO synthase inhibition. Similarly, edema formation was decreased in isolated mouse lungs of endothelial NO synthase-deficient mice. Chronic heart failure results in endothelial dysfunction and preservation of alveolar fluid reabsorption. These findings identify impaired alveolar fluid clearance as an important mechanism in the pathogenesis of hydrostatic lung edema. This effect is mediated by endothelial-derived NO acting as an intercompartmental signaling molecule at the alveolo-capillary barrier.

Topics: Absorption; Animals; Capillaries; Cyclic GMP; Endothelium, Vascular; Extravascular Lung Water; Guanylate Cyclase; Heart Failure; Hydrostatic Pressure; In Vitro Techniques; Indicator Dilution Techniques; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Sprague-Dawley

Worsening renal function in the setting of human acute heart failure (AHF) predicts poor outcomes, such as rehospitalization and increased mortality. Understanding potential renoprotective mechanisms is warranted. The guanylate cyclase (GC) enzymes and their second messenger cGMP are the target of two important circulating neurohumoral systems with renoprotective properties. Specifically, natriuretic peptides (NP) released from the heart with AHF target particulate GC in the kidney, while the nitric oxide (NO) system is an activator of renal soluble GC. We hypothesized that both systems are essential to preserve renal excretory and hemodynamic function in AHF but with distinct roles. We investigated these roles in three groups of anesthetized dogs (6 each) with AHF induced by rapid ventricular pacing. After a baseline AHF clearance, each group received intrarenal vehicle (control), N(G)-monomethyl-l-arginine (l-NMMA), a competitive NO inhibitor (50 microg.kg(-1).min(-1)) or a specific NP receptor antagonist, HS-142-1 (0.5 mg/kg). We observed that intrarenal l-NMMA decreased renal blood flow (RBF) without significant decreases in glomerular filtration rate (GFR), urinary sodium excretion (UNaV), or urinary cGMP. In contrast, HS-142-1 resulted in a decrease in UNaV and cGMP excretion together with a reduction in GFR and an increase in distal fractional tubular sodium reabsorption. We conclude that in AHF, the NP system plays a role in maintaining sodium excretion and GFR, while the function of NO is in the maintenance of RBF. These studies have both physiological and therapeutic implications warranting further research into cardiorenal interactions in this syndrome of AHF.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Guanylate Cyclase; Heart Failure; Kidney; Male; omega-N-Methylarginine; Polysaccharides

BNP is a cardiac peptide with vasodilating, lusitropic and natriuretic properties mediated by the second messenger cGMP. We have previously shown that chronic subcutaneous (SQ) administration of BNP in experimental CHF resulted in improved haemodynamics and unloading of the heart. However, it is unknown if this will lead to the development of tolerance to exogenous BNP.. The current study extends our previous study and compares the cardiorenal effects of acute administration of SQ BNP (5 microg/kg) in a group of dogs (n = 5) with rapid ventricular pacing induced CHF (180 bpm for 10 days) to a separate group of CHF dogs (n = 6), who received chronic SQ BNP (5 microg/kg) three times a day for 10 days.. Acute administration of SQ BNP resulted in similar increases in both plasma cGMP (35+/-5 vs. 29+/-2 pmol/ml) and urinary cGMP excretion (UcGMPV) (6000+/-1000 vs. 4000+/-600 pmol/min) in both the Chronic SQ BNP treated and the Untreated CHF groups (P > 0.05). These were associated with decreased cardiac filling pressures and increased urine flow, which were also similar in both groups.. In experimental CHF, chronic SQ BNP administration did not result in the development of tolerance as demonstrated by increases in both plasma cGMP and UcGMPV following acute administration of SQ BNP. This may have important clinical implications, suggesting that chronic BNP administration does not lead to the development of tolerance to acute BNP administration.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Dogs; Drug Administration Schedule; Glomerular Filtration Rate; Heart Failure; Injections, Subcutaneous; Kidney; Male; Natriuretic Peptide, Brain; Pulmonary Wedge Pressure

In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis.. We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP.. Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Calcineurin; Calcium Signaling; Calcium-Transporting ATPases; Cardiomyopathy, Dilated; Cohort Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Induction; Female; Guanylate Cyclase; Heart Failure; Heart-Assist Devices; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; NFATC Transcription Factors; Receptors, Atrial Natriuretic Factor; Recombinant Fusion Proteins; RNA, Messenger; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stress, Mechanical

Congestive heart failure (CHF) is characterized by abnormal vasoconstriction and an impairment in nitric oxide (NO)-mediated vasodilatation. We have previously demonstrated that the decrease in sensitivity to NO lies at least partially at the level of the smooth muscle and is due to a reduction in the relative expression of the leucine zipper positive (LZ(+)) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. We hypothesized that since the attenuated vasodilatory response to NO in CHF has been shown to be secondary to an increased activity of the renin-angiotensin system, angiotensin converting enzyme (ACE) inhibition could affect MYPT1 isoform expression. To test this hypothesis, a rat myocardial infarction (MI) model of CHF was used; following left coronary artery ligation, rats were divided into control and captopril-treated groups. A third group of rats was given prazosin for 4 weeks. In the untreated control group, left ventricular function (LVF) was reduced at 2 weeks post-MI and remained at this level. Captopril treatment attenuated the fall in LVF. In the control aorta and iliac artery, the expression of the LZ(+) MYPT1 isoform fell 44-52% between 2 and 4 weeks post-MI, whereas in animals treated with captopril, MYPT1 isoform expression did not change. A decrease in the sensitivity to cGMP-mediated smooth muscle relaxation occurred coincident with the decrease in LZ(+) MYPT1 expression. The change in LZ(+) MYPT1 expression was not due to the decrease in afterload, as prazosin therapy produced an improvement in LVF but did not increase the relative expression of LZ(+) MYPT1 isoform. These data suggest that ACE inhibition, unique from pure afterload reduction, prevents MYPT1 isoform switching, which would preserve normal flow, or NO-mediated vasodilatation.

Topics: Animals; Antihypertensive Agents; Captopril; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Heart Failure; Male; Myosin-Light-Chain Phosphatase; Myosins; Nitric Oxide; Protein Isoforms; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Heart Failure; Kidney; Male; Natriuretic Peptide, Brain; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Heart failure (HF) cell or siderophages are pulmonary macrophages that phagonicytize erythrocytes leaked from the congested capillaries due to HF. Degradation of erythrocytes and hemoglobin increases concentrations of heme in the lung. We hypothesized that the HF-induced increase in the concentration of heme up-regulates the expression and enzymatic activity of heme oxygenase (HO)-1 in the lung.. Using the aortocaval (AC) fistula model of HF, we examined the following parameters 8-10 weeks after the creation of the fistula: morphological changes in the lung by Prussian blue iron and immunohistochemical staining, HO-1 protein expression and activity in the rat lungs, and concentrations of nitrite/nitrate (NO(x)(-)) and cyclic guanosine 3',5'-monophospate (cGMP) of the lung homogenates.. Iron-stained siderophages were observed only in the lungs of rats with AC fistula. Protein level and enzyme activity of HO-1 were significantly enhanced in the lung of HF rats. NO(x)(-) concentrations of the two groups were similar, but cGMP was elevated in the lung of AC fistula rats (0.34+/-0.06 vs. 0.89+/-0.20 pmol/mg protein, P=0.025). Staining of serial sections of the lung tissues demonstrated induction of HO-1 co-localized to iron-stained siderophages.. HF causes increased pulmonary HO-1 expression and activity, which emanates largely from siderophages. Up-regulation of HO-1 may have pulmonary protective in HF.

Topics: Animals; Blotting, Western; Cyclic GMP; Heart Failure; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Lung; Models, Animal; Myocardium; Nitrates; p38 Mitogen-Activated Protein Kinases; Proteins; Rats; Rats, Sprague-Dawley; Time Factors

A hallmark of overt congestive heart failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP) are of myocardial origin, whereas urodilatin (Uro) is thought to be derived from kidney. All three peptides are agonists to the natriuretic peptide-A receptor. Our objective was to compare the cardiorenal and humoral actions of ANP, BNP, and Uro in experimental overt CHF. We determined cardiorenal and humoral actions of 90 min of intravenous equimolar infusion of ANP, BNP, and Uro (2 and 10 pmol.kg-1.min-1) in three separate groups of anesthetized dogs with rapid ventricular pacing-induced overt CHF (240 beats/min for 10 days). BNP resulted in increases in urinary sodium excretion (U(Na)V) (2.2+/-0.7 to 164+/-76 microeq/min, P<0.05) and glomerular filtration rate (GFR) (27+/-4 to 52+/-11 ml/min, P<0.05) that were greater than those with Uro (P<0.05), whereas ANP did not result in increases in U(Na)V or GFR. Increases in plasma cGMP (25+/-2 to 38+/-2 pmol/ml, P<0.05) and urinary cGMP excretion with BNP (1,618+/-151 to 6,124+/-995 pmol/min, P<0.05) were similar to those with Uro; however, there was no change with ANP. Cardiac filling pressures were reduced in all three groups. These studies also support the conclusion that in experimental overt CHF, renal resistance to natriuretic peptides in increasing rank order is BNP

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Heart Failure; Hemodynamics; Kidney; Male; Natriuretic Peptide, Brain; Peptide Fragments

Contribution of the natriuretic peptide system to the development of heart failure (HF) in vivo was examined using mice lacking or having decreased natriuretic peptide receptor-A (NPRA), a guanylyl cyclase-linked receptor.. Volume-overloaded HF was produced by aortocaval fistula in mice with wild-type (+/+), heterozygous (+/-), and homozygous null mutants (-/-) of the NPRA gene. Severity of HF was assessed 4 weeks after operation on the basis of organ weight, hemodynamics, echocardiographic indices, urinary variables, neurohumoral factors, and myocardial gene expression.. There were no significant differences in lung weight, kidney weight, left ventricular end-diastolic pressure (LVEDP), left ventricular systolic function, or urinary variables among the three sham-operated groups; however, sham-operated (-/-) mice had higher blood pressure and individual cardiac chamber weights than did (+/+) mice. In contrast, (-/-) mice with aortocaval fistula had higher LVEDP, left and right ventricular weights, lung weight, and left ventricular dimension, as well as lower fractional shortening and urinary sodium and cyclic guanosine monophosphate (cGMP) excretion than did (+/+) mice with aortocaval fistula. In addition, ventricular mRNA expression of natriuretic peptides and beta-myosin heavy chain increased markedly only in (-/-) mice. Plasma atrial natriuretic peptide, renin, and aldosterone, but not cGMP, showed greater responses to aortocaval fistula in (-/-) mice than in (+/+) mice. Both sham-operated and aortocaval fistula NPRA (+/-) mice almost consistently showed a phenotype intermediate between those of NPRA (-/-) and NPRA (+/+) mice.. These results provide genetic evidence that NPRA signaling protects against HF induced by volume overload in mice.

Topics: Aldosterone; Angiotensin I; Animals; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Disease Susceptibility; Guanylate Cyclase; Heart Failure; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; Protein Isoforms; Receptors, Atrial Natriuretic Factor; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

Neutral endopeptidase (NEP) degrades atrial natriuretic peptide (ANP) that via cyclic guanosine monophosphate (cGMP) is natriuretic and aldosterone-inhibiting. We hypothesized that chronic oral NEP inhibition (NEPI), initiated in early experimental congestive heart failure (CHF), would delay onset of decreases in sodium excretion during the progression of CHF and, in the severe phase, suppress aldosterone activation and reduce the magnitude of sodium retention. We also hypothesized that chronic NEPI during progressive CHF (PCHF) would improve the natriuretic response to acute volume expansion.. In a novel canine model that progresses over 38 days from early to moderate and finally severe CHF, we defined the actions of chronic NEPI (candoxatril, 10 mg/kg, orally, twice a day) upon cardiorenal and neurohumoral function as well as the clinical well being of treated and untreated dogs in CHF.. From baseline through the moderate phase of CHF, NEPI maintained sodium excretion. In contrast, in moderate CHF, sodium excretion was reduced compared to the early phase in the controls. In severe CHF, sodium excretion was higher with NEPI compared to control. Chronic NEPI also resulted in lower plasma aldosterone as compared to controls. In severe CHF, the natriuretic response to acute saline volume expansion was enhanced with oral NEPI as compared to control.. This study supports the conclusion that chronic oral NEPI delays the onset of reduction in sodium excretion during the transition from early to severe CHF in this model of PCHF. This therapeutic strategy also improved the natriuretic response to acute volume expansion in severe CHF while enhancing ANP and suppressing aldosterone activation. Thus, these studies demonstrated a selective renal and adrenal action of chronic NEPI in heart failure indicating a therapeutic potential.

Topics: Administration, Oral; Aldosterone; Animals; Atrial Natriuretic Factor; Cyclic GMP; Disease Models, Animal; Dogs; Heart; Heart Failure; Indans; Kidney; Male; Mineralocorticoid Receptor Antagonists; Natriuresis; Neprilysin; Propionates; Protease Inhibitors

To evaluate the effects of different doses of N(G)-nitro-L-arginine methyl ester (L-NAME) on hemodynamics, cyclic guanosine monophosphate (cGMP) production and the level of beta-adrenergic receptors (beta-ARs) mRNA in a heart failure rat model after BRL-37344 (beta(3)-ARs agonist) injection. Meanwhile, to investigate the influence of beta(3)-ARs and L-NAME on signal transduction in failing heart.. The rats were randomly divided into six groups, control group (group I), Iso (isoproterenol) group (group II), Iso + BRL group (group III), Iso + BRL + low dose of L-NAME group (5 mg/kg, group IV), Iso + BRL + moderate dose of L-NAME group (50 mg/kg, group V), Iso + BRL + high dose of L-NAME group (100 mg/kg, group VI). The hemodynamics [left ventricular end systolic pressure (LVESP), +/- dp/dt, left ventricular end diastolic pressure (LVEDP)], cardiac cGMP and the levels of beta(1)-, beta(2)-, and beta(3)-ARs mRNA were measured.. (1) LVESP, +/- dp/dt values in group II were significantly lower, and LVEDP was significantly higher than that in group I (except -dp/dt P < 0.05, the rest were P < 0.01). Comparing with group II, group III had lower -dp/dt value and LVESP, higher LVEDP (P < 0.05). The level of +dp/dt had a trend to be lower but lacked statistical significance between two groups. The value of +/- dp/dt got higher and LVEDP got lower along with higher dose of L-NAME, but a large dose of L-NAME had more deteriorated cardiac functions. (2) The cardiac cGMP in group I, II and III had a higher tendency (P < 0.01). The tendency of cardiac cGMP in group IV, V and VI was inversed with the dose of L-NAME. After a large dose of L-NAME was applied, cGMP returned to the same level as Group I. (3) Among groups I, II and III, the level of beta(1)-AR mRNA was the highest in group I and the lowest in group III (P < 0.01). The levels of beta(2)-AR mRNA were also tended to be lower among three groups but with no significance. While the level of beta(3)-AR mRNA was the highest in group III. The levels of beta-AR mRNA were all the same in group VI, V and VI.. The negative inotropic effect of beta(3)-ARs stimulation was mediated by activation of the NOS pathway. L-NAME blocked beta(3)-ARs agonist negative chronotropic effect on failing heart partly and improved hemodynamics, but a large dose of L-NAME had more deteriorated cardiac functions.

Topics: Adrenergic Agonists; Animals; Cyclic GMP; Heart Failure; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; RNA, Messenger

Topics: Animals; Carotid Body; Chemoreceptor Cells; Cyclic GMP; Gene Transfer, Horizontal; Heart Failure; Nerve Tissue Proteins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Rabbits

Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10(-7), 10(-6), and 10(-5) M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE(2)) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE(3) inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (R(max)) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (R(max): control dogs, 95.3 +/- 17.3; hypertrophy dogs, 88.2 +/- 5.5; failure dogs, 53.2 +/- 6.4 mum/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10(-6) M) and milrinone (10(-6) M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (R(max) for control dogs: cGMP, -46%; +EHNA, -21%; +milrinone, -19%; for hypertrophy dogs: cGMP, -40%; +EHNA, -13%; +milrinone, -20%; for failure dogs: cGMP, -40%; +EHNA, -29%; +milrinone, -32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.

Topics: Adenine; Animals; Body Weight; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Dogs; Drug Interactions; Enzyme Inhibitors; Heart Failure; Hypertrophy, Left Ventricular; Milrinone; Myocardial Contraction; Myocytes, Cardiac; Organ Size; Signal Transduction

Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects.. Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%+/-1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001).. In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Topics: Adult; Aged; Aged, 80 and over; Arteries; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Heart Failure; Humans; Injections, Intra-Arterial; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Peptide Fragments; Tetrahydroisoquinolines; Vascular Resistance; Vasodilation; Veins

The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF.. CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg x kg(-1) x h(-1)). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg x kg(-1) x h(-1)) and low-dose (2 pmol x kg(-1) x min(-1)) BNP followed by 45-minute coinfusion of Fs (1 mg x kg(-1) x h(-1)) and high-dose (10 pmol x kg(-1) x min(-1)) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35+/-3 to 56+/-4*) (* indicates P<0.05 versus baseline) (P<0.0001 between groups). Plasma aldosterone increased with Fs (41+/-10 to 100+/-11* ng/dL) but was attenuated in the Fs+BNP group (44+/-11 to 54+/-9 ng/dL low-dose and to 47+/-7 ng/dL high-dose) (P=0.0007 between groups).. Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.

Topics: Animals; Cardiac Output; Cardiac Pacing, Artificial; Cyclic GMP; Diuresis; Diuretics; Dogs; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Furosemide; Glomerular Filtration Rate; Heart Failure; Mineralocorticoid Receptor Antagonists; Natriuresis; Natriuretic Peptide, Brain; Norepinephrine; Renal Circulation; Renin-Angiotensin System

In 15 patients with chronic heart failure of ischemic origin who were not previously treated with angiotensin-converting enzyme inhibitors, platelets exhibited hyperaggregability and impaired responsiveness to the antiaggregatory and cyclic guanosine monophosphate-stimulatory effects of nitric oxide donor sodium nitroprusside compared with normal subjects; this was paralleled by increased blood levels of superoxide radicals. Treatment with perindopril for 4 days significantly improved platelet responses to sodium nitroprusside; there was also a trend toward a decrease in superoxide radical levels.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Perindopril; Platelet Aggregation; Platelet Function Tests; Superoxides; Time Factors; Ventricular Dysfunction, Left

Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide (NO)-mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3' exon produces leucine zipper positive and negative (LZ+/-) MYPT1 isoforms. Expression of a LZ+ MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ+/- MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ+/- MYPT1 isoforms were determined. In control animals, the expression of the LZ+ MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30+/-5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ+ MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ+ MYPT1 isoform and the sensitivity to 8-Br-cGMP-mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ+ MYPT1 isoform.

Topics: Alternative Splicing; Animals; Blotting, Western; Calcium; Carrier Proteins; Coronary Vessels; Cyclic GMP; Dose-Response Relationship, Drug; Heart Failure; Ligation; Muscle, Smooth, Vascular; Myocardial Infarction; Nitric Oxide; Phosphoprotein Phosphatases; Phosphorylation; Protein Isoforms; Protein Phosphatase 1; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ultrasonography; Vasodilation

In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dogs; Drug Administration Schedule; Drug Evaluation, Preclinical; Heart Failure; Heart Rate; Heart Ventricles; Hypertension, Pulmonary; Injections, Intravenous; Isoquinolines; Japan; Lung; Myocardial Contraction; Natriuretic Peptides; Norepinephrine; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Polysaccharides; Pyridines; Receptors, Atrial Natriuretic Factor; Time Factors; Vascular Resistance

B-type natriuretic peptide (BNP) has been in clinical use for the treatment of decompensated congestive heart failure. However, BNP has a very short half-life in circulation, which limits its application to acute CHF and requires continuous i.v. infusion. To provide superior pharmacological benefits of BNP to other stages of chronic congestive heart failure and to eliminate problems associated with drug delivery via continuous i.v. infusion, we have designed and evaluated AlbuBNP, a long-acting form of BNP by recombinant fusion to human serum albumin for use in chronic congestive heart failure, post-acute follow-up, and postmyocardial infarction.. Human BNP (1-32) was seamlessly fused to mature human serum albumin at N-terminus to create AlbuBNP. The bioactivities of AlbuBNP were evaluated by natriuretic peptide receptor-A mediated cGMP activation assay, hemodynamic responses, and plasma cGMP elevation. The pharmacokinetic properties were determined after single i.v. or s.c. bolus injection in C57/BL6 mice.. AlbuBNP had approxiamtely the same maximal bioactivity as BNP to activate cGMP in the in vitro NPRA/cGMP assay. The EC50s were 28.4+/-1.2 and 0.46+/-1.1 nM for AlbuBNP and BNP, respectively. In spontaneously hypertensive rats, AlbuBNP lowered both systolic and diastolic blood pressure, having sustainable mean arterial pressure reduction for more than 2 days. Six nmol/kg AlbuBNP i.v. bolus in mice increased plasma cGMP level 5.6-fold over the baseline. The elimination half-life in mice was dramatically increased from 3 min for BNP to 12-19 h for AlbuBNP.. AlbuBNP is bioactive and has desired pharmacokinetic properties for long-term use. It has the potential to be further developed as a new therapeutic option for chronic, acute, and post-acute CHF to alleviate symptoms, improve clinical status, and slow the disease progression by sustained drug exposure via infrequent simple subcutaneous injections.

Topics: Amino Acid Sequence; Animals; Area Under Curve; Blood Pressure; Cyclic GMP; Gene Expression; Heart Failure; Humans; Immunochemistry; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Recombinant Fusion Proteins; Serum Albumin

In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure.. As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeleton-associated muscle LIM protein (MLP) in endothelin-1 (ET-1)-stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (-49%, P<0.01) and protein (-52%, P<0.01) abundance in ET-1-treated cardiomyocytes via cGMP-dependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1beta and IFN-gamma downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (-52%, P<0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes.. NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.

Topics: Animals; Cell Size; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Cytokines; Cytoskeletal Proteins; Down-Regulation; Endothelin-1; Gene Expression Regulation; Heart Failure; Humans; LIM Domain Proteins; Muscle Proteins; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oligonucleotides, Antisense; Peroxynitrous Acid; Rats; Rats, Sprague-Dawley; Sarcomeres; Superoxides

We hypothesized that decreases in expression and/or activity of cAMP-specific phosphodiesterases (PDE) contribute to protective adaptations observed in lung after heart failure. In this study, we compared PDE activity in lung parenchyma isolated from control dogs and those paced to heart failure by assaying cyclic nucleotide hydrolysis in fractions of homogenate supernatant eluted from DEAE-Trisacryl columns. Cyclic nucleotide hydrolysis due to PDE3, PDE4, and PDE5 isoforms was predominant in both control and paced groups. The ratio of PDE3 activity to total cAMP PDE activity was decreased in the paced group compared with control (P < 0.05), whereas PDE4 or PDE5 activity ratios were not different between the two groups. With the use of RT-PCR, message expression for PDE3A or PDE3B did not differ between the two groups. Cilostamide, a selective PDE3 inhibitor, and forskolin, a nonspecific agonist for adenylyl cyclase, both inhibited thapsigargin-induced increases in endothelial permeability in control lung. We conclude that PDE3 activity, but not mRNA expression, is reduced in lung from dogs paced to heart failure, a change that could contribute to heart failure-induced attenuation of the lung endothelial permeability response to injury.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Capillaries; Capillary Permeability; Colforsin; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Dogs; Heart Failure; Hydrolysis; Lung; Pacemaker, Artificial; Phosphodiesterase Inhibitors; Pulmonary Circulation; Quinolones; Reverse Transcriptase Polymerase Chain Reaction

Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO(-) cardiotropic action. Thus, HNO/NO(-) has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.

Topics: Animals; Calcitonin Gene-Related Peptide; Cyclic GMP; Dogs; Heart Failure; Myocardial Contraction; Nitrogen Oxides; Receptors, Adrenergic, beta; Signal Transduction

Chronic congestive heart failure (CHF) is a complex clinical syndrome characterized by marked neurohormonal activation which may lead to further decompensation of the circulatory system. This study was undertaken to establish the role of certain hormones in pathogenesis of congestive heart failure. Plasma levels of brain natriuretic peptide (BNP), cyclic 3'5'-guanosine monophosphate (c-GMP), endothelin 1 (ET-1), and noradrenaline (NA) were examined in patients in patients with CHF and with decompensation of circulatory system. The survey was made in 92 patients with CHF, among them there were 42 females aged 50-76 years (mean 66 years) and 50 males aged 53-76 years (mean 68 years). All patients were divided into 3 groups according to NYHA classification. On admission blood samples were taken from all patients to determine plasma levels of BNP, c-GMP, ET-1, and NA. Then patients received captopril and furosemide. Next blood samples were taken between 5 and 7 day of the treatment, after entire remission symptoms of decompensation. Plasma levels of BNP, c-GMP, ET-1, and NA were estimated with radioimmunoassay. Our study showed that plasma levels of ET-1, BNP, c-GMP, and NA were increased in patients with CHF. 5-7 days of the treatment with ACE inhibitor and diuretic caused significant decrease of ET-1, BNP, and c-GMP levels, but did not influence NA plasma levels. Determination of ET-1, BNP, c-GMP, and NA plasma levels may be a noninvasive method useful in estimation of degree of CHF and efficacy of the treatment.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Case-Control Studies; Cyclic GMP; Diuretics; Dose-Response Relationship, Drug; Endothelin-1; Female; Furosemide; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Radioimmunoassay; Time Factors

Topics: Adrenergic beta-Agonists; Animals; Cyclic GMP; Depression, Chemical; Heart Failure; Humans; Mice; Mice, Transgenic; Models, Animal; Myocardial Contraction; Myocardium; Nitric Oxide; Receptors, Adrenergic, beta-3

Cyclic GMP (cGMP) serves as an intracellular second messenger of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and nitric oxide (NO) and its peripheral blood concentration is an index of its biological activity. It has been reported that the plasma concentration of cGMP is correlated with the concentrations of ANP and BNP and is related to the prognosis of chronic heart failure patients, but the relation with NO has not been studied. Therefore, we investigated the roles of ANP, BNP, and NO in relation to cGMP in the blood during worsening and improvement of chronic heart failure. The subjects were 25 patients who were hospitalized in our hospital for acute worsening of chronic heart failure. Plasma concentrations of NO, norepinephrine (NE), ANP, BNP, and cGMP were measured on acute worsening (admission) and improvement (discharge) of heart failure. The cGMP concentration on worsening showed a positive correlation with the NO concentration (r = (0.57, P < 0.01), but no correlations with ANP or BNP were observed. The cGMP concentration on improvement showed no correlation with the NO concentration, but a positive correlation with ANP (r = 0.69, P < 0.001) and BNP (r = 0.67, P < 0.001). No correlation was observed between the NO and NE concentrations. We also studied serious cases of NYHA IV and mild cases of NYHA II to III. The cGMP concentration in the serious group showed a positive correlation with the NO concentration but no correlations with ANP or BNP concentrations on worsening. However, in the mild group, the cGMP concentration during worsening showed positive correlations with both the NO and BNP concentrations. On improvement, the cGMP concentration showed no correlation with the NO concentration but positive correlations with both the ANP and BNP concentrations in both the severe and mild groups. The results suggest the possibility that cGMP is produced mainly by NO during worsening, and by ANP and BNP rather than NO during improvement of chronic heart failure.

Topics: Aged; Analysis of Variance; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Nitric Oxide; Norepinephrine; Tropanes

Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1 mg/kg per day, n=5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270 beats/min). Vehicle dogs were given a placebo (n=5) and normal dogs (n=5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r=-0.802 and P<0.001 respectively). Our results indicate that chronic PDE5 inhibition ameliorates the antagonistic relationship between renal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Depression, Chemical; Dogs; Endothelin-1; Endothelins; Glomerular Filtration Rate; Heart Failure; Isoquinolines; Kidney; Models, Animal; Phosphodiesterase Inhibitors; Protein Precursors; Pyridines; RNA, Messenger; Sodium; Urine

The enzyme neutral endopeptidase (NEP; EC 3.4.24.11) cleaves several vasoactive peptides such as the atrial natriuretic peptide (ANP). ANP is a hormone of cardiac origin with diuretic and natriuretic actions. Despite elevated circulating levels of ANP, congestive heart failure (CHF) is characterized by progressive sodium and water retention. In order to elucidate the loss of natriuretic and diuretic properties of ANP in CHF we analyzed activity, protein concentrations, mRNA and immunostaining of NEP in kidneys of different models of severe CHF in the rat.CHF was induced by either aortocaval shunt, aortic banding or myocardial infarction in the rat. All models were defined by increased left ventricular end-diastolic pressure and decreased contractility. The diminished effectiveness of ANP was reflected by reduced cGMP/ANP ratio in animals with shunt or infarction. Renal NEP activity was increased in rats with aortocaval shunt (203 +/- 7%, p < 0.001), aortic banding (184 +/- 11%, p < 0.001) and infarction (149 +/- 10%, p < 0.005). Western blot analysis revealed a significant increase in renal NEP protein content in two models of CHF (shunt: 214 +/- 57%, p < 0.05; infarction: 310 +/- 53 %, p < 0.01). The elevated protein expression was paralleled by a threefold increase in renal NEP-mRNA level in the infarction model. The increased renal NEP protein expression and activity may lead to enhanced degradation of ANP and may contribute to the decreased renal response to ANP in heart failure. Thus, the capacity to counteract sodium and water retention, would be diminished. The increased renal NEP activity may therefore be a hitherto unknown factor in the progression of CHF.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Cyclic GMP; DNA Primers; Heart Failure; Hemodynamics; Kidney; Male; Neprilysin; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger

Growth hormone (GH) application is a new strategy in the treatment of heart failure. However, clinical and experimental investigations have shown contradictory effects of GH on cardiac performance. We tested the hypothesis that GH could improve cardiac and renal function in volume overload-induced heart failure. The effect of 4 weeks of GH treatment (2 mg/kg daily) was investigated in Wistar rats with aortocaval shunt. GH application did not influence left ventricular contractility and end-diastolic pressure in rats with aortocaval shunt. In contrast, GH treatment normalized impaired diuresis (vehicle 10.8+/-0.6 mL/d, GH 15.8+/-0.7 mL/d; P<0.05) and sodium excretion (vehicle 1.5+/-0.1 mmol/d, GH 2.2+/-0.1 mmol/d; P<0.001) in shunt-operated rats, with a similar increase of fractional sodium excretion. The urinary excretion of cGMP, the second messenger of atrial natriuretic peptide and NO, was higher in animals with shunts than in sham-operated animals and was further increased by GH (vehicle 293+/-38 nmol/d, GH 463+/-57 nmol/d; P<0.01). Although the atrial natriuretic peptide plasma levels were unchanged after GH, the excretion of NO metabolites (nitrate/nitrite) was elevated (vehicle 2020+/-264 nmol/d, GH 2993+/-375 nmol/d; P<0.05) in parallel with increased renal mRNA levels of inducible NO synthase 2. The changes of renal function after GH and the increased excretion of NO metabolites and cGMP were abolished by simultaneous treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. GH treatment did not influence cardiac function in rats with aortocaval shunts. However, GH improved renal function by increasing diuresis and sodium excretion. The responsible mechanism might be the enhanced activity of the renal NO system.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Enzyme Inhibitors; Growth Hormone; Heart; Heart Failure; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Wistar; Recombinant Proteins; RNA, Messenger; Ventricular Dysfunction, Left

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.

Topics: Adrenomedullin; Angiotensin II; Animals; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Dipeptides; Drug Synergism; Female; Heart Failure; Hemodynamics; Kidney; Natriuretic Peptide, Brain; Neprilysin; Peptides; Protease Inhibitors; Renin; Sheep; Vasodilator Agents

Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure.. We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D.. Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.

Topics: Adrenomedullin; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Diuretics; Dogs; Drug Therapy, Combination; Glomerular Filtration Rate; Heart Failure; Heart Function Tests; Hemodynamics; Kidney Function Tests; Male; Neprilysin; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Pulmonary Wedge Pressure; Pyridines; Renin; Thiazepines; Treatment Outcome

A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF.. We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 micromol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 microg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 microg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone.. This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Injections, Subcutaneous; Kidney; Male; Natriuretic Peptide, Brain; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Sodium; Thiazepines

We identified abnormalities in the vascular beta-adrenergic receptor (beta-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured beta-AR-mediated hemodynamics, vascular reactivity, and the vascular beta-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/dt). LV dP/dt responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats (P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats (P < 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in beta-AR signaling (P < 0.05): decreases in beta-AR density (aorta: 58.7 +/- 6.0 vs. 35.7 +/- 1.9 fmol/mg membrane protein; carotid: 29.6 +/- 5.6 vs. 18.0 +/- 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 +/- 39 vs. 259 +/- 26 in the aorta and 115 +/- 30 vs. 202 +/- 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 +/- 0.10 vs. 0.31 +/- 0.06 pmol/mg protein and 2.3 +/- 0.3 vs. 1.2 +/- 0.1 pmol/mg protein, n = 5) with no change in Galpha(s) or Galpha(i )in the aorta. Thus in heart failure there are abnormalities in the vascular beta-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.

Topics: 1-Methyl-3-isobutylxanthine; Adrenergic beta-Agonists; Animals; Aorta; Aurora Kinases; Blood Pressure; Carotid Arteries; Colforsin; Coronary Vessels; Cyclic AMP; Cyclic GMP; GTP-Binding Proteins; Heart Failure; In Vitro Techniques; Isoproterenol; Ligation; Muscle, Smooth, Vascular; Myocardial Infarction; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Signal Transduction; Ventricular Pressure

Dendroaspis natriuretic peptide (DNP), a recently discovered peptide, shares structural similarity to the other known natriuretic peptides, ANP, BNP, and CNP. Studies have reported that DNP is present in human and canine plasma and atrial myocardium and increased in plasma of humans with congestive heart failure (CHF). In addition, synthetic DNP is markedly natriuretic and diuretic and is a potent activator of cGMP in normal animals. To date, the ability of synthetic DNP to improve cardiorenal function in experimental CHF is unknown. Synthetic DNP was administered intravenously at 10 and 50 ng. kg(-1). min(-1) in dogs (n=7) with severe CHF induced by rapid ventricular pacing for 10 days at 245 bpm. In addition, we determined endogenous DNP in normal (n=4) and failing (n=4) canine atrial and ventricular myocardium. We report that administration of synthetic DNP in experimental severe CHF has beneficial cardiovascular, renal, and humoral properties. First, DNP in CHF decreased cardiac filling pressures, specifically right atrial pressure and pulmonary capillary wedge pressure. Second, DNP increased glomerular filtration rate in association with natriuresis and diuresis despite a reduction in mean arterial pressure. Third, DNP increased plasma and urinary cGMP and suppressed plasma renin activity. Fourth and finally, we report that DNP immunoreactivity is present in canine atrial and ventricular myocardium and increased in CHF. These studies report the acute intravenous actions of synthetic DNP in experimental severe CHF and suggest that on the basis of its beneficial properties, DNP may have potential as a new intravenous agent for the treatment of decompensated CHF.

Topics: Analysis of Variance; Animals; Blood Pressure; Cardiovascular Agents; Cyclic GMP; Dogs; Elapid Venoms; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Intercellular Signaling Peptides and Proteins; Kidney Tubules; Male; Myocardium; Peptides; Pulmonary Wedge Pressure; Radioimmunoassay; Renin

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

Topics: Adrenergic beta-Agonists; Animals; Cyclic GMP; Diastole; Dobutamine; Dogs; Drug Synergism; Heart; Heart Failure; Hemodynamics; Male; Myocardial Contraction; Natriuretic Peptide, Brain; Nitric Oxide; Reference Values; Second Messenger Systems; Systole; Ventricular Function, Left

Mild heart failure is characterized by increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11, which degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, urinary ANP excretion, and glomerular filtration rate (P<0.05 for OMA versus ACE inhibition). Plasma renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dogs; Fosinopril; Glomerular Filtration Rate; Heart Failure; Male; Neprilysin; Polysaccharides; Protease Inhibitors; Pyridines; Receptors, Atrial Natriuretic Factor; Sodium; Thiazepines

Downregulation of the L-type Ca(2+) current (I(Ca)) is an important determinant of the electrical remodeling of diseased atria. Using a rat model of heart failure (HF) due to ischemic cardiopathy, we studied I(Ca) in isolated left atrial myocytes with the whole-cell patch-clamp technique and biochemical assays. I(Ca) density was markedly reduced (1.7+/-0.1 pA/pF) compared with sham-operated rats (S) (4.1+/-0.2 pA/pF), but its gating properties were unchanged. Calcium channel alpha(1C)-subunit quantities were not significantly different between S and HF. The beta-adrenergic agonist isoproterenol (1 micromol/L) had far greater stimulatory effects on I(Ca) in HF than in S (2.5- versus 1-fold), thereby suppressing the difference in current density. Dialyzing cells with 100 micromol/L cAMP or pretreating them with the phosphatase inhibitor okadaic acid also increased I(Ca) and suppressed the difference in density between S and HF. Intracellular cAMP content was reduced more in HF than in S. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine had a greater effect on I(Ca) in HF than in S (76.0+/-11.2% versus 15.8+/-21.2%), whereas the inhibitory effect of atrial natriuretic peptide on I(Ca) was more important in S than in HF (54.1+/-4.8% versus 24.3+/-8.8%). Cyclic GMP extruded from HF myocytes was enhanced compared with S (55.8+/-8.0 versus 6.2+/-4.0 pmol. mL(-1)). Thus, I(Ca) downregulation in atrial myocytes from rats with heart failure is caused by changes in basal cAMP-dependent regulation of the current and is associated with increased response to catecholamines.

Topics: 1-Methyl-3-isobutylxanthine; Adrenergic beta-Agonists; Animals; Atrial Natriuretic Factor; Calcium; Calcium Channels, L-Type; Catecholamines; Cell Separation; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Heart Atria; Heart Failure; Male; Myocardial Infarction; Myocardium; Okadaic Acid; Patch-Clamp Techniques; Phosphoprotein Phosphatases; Rats; Rats, Wistar; Signal Transduction

Topics: Adrenergic beta-Agonists; Animals; Blood Pressure; Cyclic AMP; Cyclic GMP; Dobutamine; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart Failure; Humans; Isoenzymes; Myocardial Contraction; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Substance P; Ventricular Function, Left

To evaluate the effect of age and body weight on several neurohumoral variables that are commonly altered in heart failure in Cavalier King Charles Spaniels.. 17 healthy privately owned Cavalier King Charles Spaniels, 10 males and 7 females, ranging in age from 0.4 to 9.7 years, and ranging in body weight from 6.6 to 12.2 kg.. The clinical condition of the dogs was evaluated by physical examination, thoracic radiography, and echocardiography. Plasma nitrate and nitrite (P-NN), N-terminal atrial natriuretic and brain natriuretic peptides (NT-ANP and BNP, respectively), endothelin (ET-1), urine cyclic guanosine monophosphate (U-cGMP), and urine nitrate and nitrite (U-NN) concentrations were analyzed.. Plasma concentrations of NT-ANP and P-NN increased significantly with age, but plasma NT-ANP and P-NN also correlated significantly, irrespective of age. A modest increase of left atrial size did not explain the increase of NT-ANP and P-NN with age. Concentration of ET-1 correlated positively with heart rate; heart rate did not change with age. Weight had a negative impact on NT-ANP, P-NN, and U-cGMP concentrations and left atrial relative size.. Age-matched controls are essential for evaluation of NT-ANP and P-NN concentrations and left atrial size. Weight may alter reference values of plasma NT-ANP, P-NN, and urine cGMP concentrations. Natriuretic peptides can be used as further evidence that heart failure exists. The increased plasma concentrations of NT-ANP (but not BNP) and P-NN with aging reflect neurohumoral physiologic changes that must be distinguished from pathologic changes in patients with heart failure.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Body Weight; Cardiac Output; Creatinine; Cyclic GMP; Dogs; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Failure; Heart Rate; Male; Natriuretic Peptide, Brain; Neurotransmitter Agents; Nitrites; Radiography, Thoracic; Regression Analysis

beta-adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR) during beta-adrenergic stimulation.. Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca(2+) spark frequency (CaSpF, reflecting resting RyR openings) and Ca(2+) transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 micromol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca(2+) transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca(2+) load).. iNOS/NO depresses beta-adrenergic-stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits beta-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

Topics: Animals; Calcium; Colforsin; Cyclic GMP; Enzyme Inhibitors; Guanidines; Guanylate Cyclase; Heart Failure; Heart Ventricles; Humans; Lipopolysaccharides; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxadiazoles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Sarcoplasmic Reticulum

Neurohumoral factors play important role in the pathogenesis of congestive heart failure (CHF) and digoxin (dig) is one of the most frequently used drugs in this condition. The aim of this study was to assess the effects of dig on atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their "second messenger" cyclic 3',5'-guanosine monophosphate (cGMP).. The study group consisted of 25 patients (pts) aged 25-81 with CHF (NYHA II/III), 13 women and 12 men. Control group consisted of 10 healthy volunteers, 2 women and 8 men. The blood samples for evaluation of ANP, BNP and cGMP plasma level was taken at baseline conditions and 3 hours (h) after intravenous injection of 0.25 mg of dig. From the next day 0.25 mg dig was administrated orally for 6 days and plasma levels of ANP, BNP and cGMP were assessed on the 3rd and 6th day of treatment. Medium serum dig concentration on the 6th day was 0.98 ng/mL.. The baseline ANP, BNP and cGMP plasma level was significantly higher in pts with CHD than in control group (ANP 144.4 vs 98.8 pg/ml p < 0.001; BNP 130.0 vs 97.2 pg/ml p < 0.001; cGMP 1.44 vs 0.86 pg/ml p < 0.001). In pts with CHF there was a significant increase ANP, BNP and cGMP plasma level 3 h after dig intravenous injection (ANP 205.2 vs 144.4 pg/ml p < 0.01; BNP 227.1 vs 130.0 pg/ml p < 0.01; cGMP 1.84 vs 1.44 pg/ml p < 0.01). The ANP and BNP plasma level after 3 days of oral dig was still significantly increased (ANP 171.1 vs 144.4 pg/ml p < 0.05; BNP 223.7 vs 130.0 pg/ml p < 0.01). ANP, BNP and cGMP plasma level was higher in pts with CHF also after 6 days of oral dig, but the difference was statistically significant. After 6 days of digoxin treatment there was a significant increase of ejection fraction (p < 0.005), with reduction of end-diastolic diameter of left ventricle (p < 0.05) and diameter of left atrium (p < 0.01). ANP at baseline correlated positively with baseline cGMP (r = 0.702 p < 0.05). On the 6th day BNP correlated positively with cGMP (r = 0.628 p < 0.05). 3 h after dig intravenous injection ANP correlated positively with BNP (r = 0.881 p < 0.05), but on the 3rd day of oral dig ANP correlated negatively with BNP (r = -0.536 p < 0.05). On the 6th day of oral dig end-diastolic diameter of left ventricle correlated negatively with BNP (r = -0.483 p < 0.05) and cGMP (r = -0.824 p < 0.05).. 1. In pts with CHF a single intravenous digoxin injection increases ANP, BNP and cGMP plasma level. 2. Oral digoxin administration supports this beneficial neurohumoral effect and improves hemodynamic parameters of left ventricle as well as reduces left atrium diameter.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiotonic Agents; Case-Control Studies; Cyclic GMP; Digoxin; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Time Factors; Treatment Outcome

Uroguanylin is a small-molecular-weight peptide that activates membrane-bound receptor-guanylate cyclases in the intestine, kidney, and other epithelia. Uroguanylin has been shown to participate in the regulation of salt and water homeostasis in mammals via cGMP-mediated processes, bearing a distinct similarity to the action of the atriopeptins, which play a defined role in natriuresis and act as prognostic indicators of severe congestive heart failure (CHF). The objectives of this study were to measure the urinary levels of uroguanylin and the circulating plasma levels of atrial natriuretic peptide (ANP) in healthy individuals (n = 53) and patients with CHF (n = 16). Urinary excretion of uroguanylin was assessed by a cGMP accumulation bioassay employing human T84 intestinal cells. In individuals without CHF, the concentration of uroguanylin bioactivity was 1.31 +/- 0.27 nmol cGMP/ml urine and 1.73 +/- 0.25 micromol cGMP/24-h urine collection. The urinary bioactivity of uroguanylin in males (1.74 +/- 0.55 nmol cGMP/ml urine; n = 27) tended to be higher than the excretion levels in females (0.94 +/- 0.16 nmol cGMP/ml urine; n = 26) over a 24-h period but did not achieve statistical significance. Both male and female groups showed 24-h temporal diurnal variations with the highest uroguanylin levels observed between the hours of 8:00 AM and 2:00 PM. The circulating level of ANP was 12.1 +/- 1.6 pg/ml plasma and did not significantly vary with respect to male/female population or diurnal variation. In patients with CHF, the concentration of plasma ANP and urinary uroguanylin bioactivity increased substantially (7.5-fold and 70-fold, respectively, both P

Topics: Adult; Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Cell Line; Circadian Rhythm; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptides; Peptides; Reference Values; Sex Characteristics

To evaluate short-term hemodynamic effects of ecadotril in a model of congestive heart failure in dogs.. 6 conscious adult male dogs.. Instruments were placed in dogs to measure left ventricular, aortic, and atrial blood pressures. Heart failure was induced by repeated coronary embolization with latex microspheres. Four times, and in random order, dogs were given vehicle or active drug (3, 10, or 30 mg/kg of body weight) orally. Hemodynamic variables, urine flow, and urinary electrolyte excretion were measured before and 30, 90, and 150 minutes, and 10 and 21 hours after drug administration.. Changes in urine flow, heart rate, mean arterial pressure, or peak positive and negative rate of change in ventricular pressure were not apparent. Urinary sodium excretion significantly increased in response to the low and high doses of ecadotril but not in response to the 10 mg/kg dose. Left ventricular end diastolic pressure (LVEDP) consistently decreased in dose- and time-dependent manner. Maximal group-averaged reductions in LVEDP were 5.2, 8.1, and 10 mm Hg for the low, middle, and high doses, respectively. The magnitude of the decrease in LVEDP was not related to cumulative change in urine flow.. Orally administered ecadotril reduced left ventricular filling pressures in these dogs by a mechanism that does not require a substantial diuretic effect. Ecadotril may be effective for alleviating clinical signs in dogs with left-sided heart failure and may be particularly beneficial for use in dogs that are refractory to traditional diuretic therapy.

Topics: Animals; Cyclic GMP; Dog Diseases; Dogs; Electrocardiography; Heart Failure; Hemodynamics; Male; Microspheres; Potassium; Protease Inhibitors; Random Allocation; Sodium; Thiorphan

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenylyl Cyclases; Adrenergic beta-Agonists; Analysis of Variance; Animals; Aortic Valve Stenosis; Cardiac Pacing, Artificial; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dogs; Down-Regulation; Heart Failure; Hypertrophy, Left Ventricular; Isoproterenol; Myocardium; Oxygen Consumption; Protein Binding; Receptors, Adrenergic, beta-1; Signal Transduction

Fragments derived from the prohormone of alpha-human atrial natriuretic peptide (alpha-ANP) in patients with cardiac failure are more closely related to the disease state than intact alpha-ANP.. Specific immunoassays have been developed to detect proANP 1-30, proANP 31-67, and proANP 1-98. Plasma concentrations of these fragments were determined in 122 hemodialysis patients with and without cardiac dysfunction, with and without hypertension, as well as with and without dialysis-associated hypotensive episodes either before or after a regularly scheduled hemodialysis session. The effects of different dialyzer membranes were also evaluated. The results of these assays along with other markers of volume regulation such as alpha-ANP and cyclic 3',5' guanosine monophosphate (cGMP) were compared with those of healthy controls.. Predialytic and postdialytic plasma concentrations of the proANP fragments were markedly higher in uremic patients than in controls (98-fold for proANP 1-98, 56-fold for proANP 31-67, and 35-fold for proANP 1-30). All proANP fragments, alpha-ANP, and cGMP decreased during hemodialysis. A strong linear correlation was found between predialytic and postdialytic plasma levels. There was no correlation, however, with the amount of fluid removed during hemodialysis. Patients with altered left ventricular hemodynamics displayed significantly higher plasma concentrations of all proANP fragments and alpha-ANP, but not cGMP, than patients with normal cardiac function. Hemodialysis patients with moderate or severe hypertension had higher concentrations of proANP fragments, alpha-ANP, and cGMP than patients with normal blood pressure or patients with only mild hypertension. There was no significant difference in circulating levels of proANP peptides, alpha-ANP, and cGMP between patients with and without frequent dialysis-associated hypotensive episodes. Cellulose-triacetate dialyzers reduced plasma levels of proANP 1-30, proANP 31-67, and proANP 1-98 significantly more than polysulfone dialyzers, but alpha-ANP and cGMP levels were not different.. Circulating alpha-ANP and proANP fragments are influenced by a variety of factors such as end-stage renal disease, hemodialysis treatment, dialyzer membrane material, cardiac dysfunction, and hypertension. Therefore, these are not useful markers to accurately estimate volume status in hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cyclic GMP; Female; Heart Failure; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Peptide Fragments; Protein Precursors; Renal Dialysis

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (P<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P<0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P<0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (P<0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiovascular Agents; Cross-Over Studies; Cyclic GMP; Disease Models, Animal; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Injections, Intravenous; Kidney; Natriuretic Peptide, Brain; Pyridines; Renin; Sheep; Sodium; Thiazepines

To determine changes in plasma brain natriuretic peptide (BNP) after direct current cardioversion (DC) and to evaluate the relationship between plasma atrial natriuretic peptide (ANP) and BNP and the recurrence of atrial fibrillation (AF) after DC in patients with mild congestive heart failure (CHF), plasma ANP and BNP were measured before and after DC in 71 patients with mild CHF and then followed. In 65 patients with successful DC, both ANP and BNP decreased 15 min after DC. Cox stepwise multivariate analysis among 14 variables such as age, history of AF, echocardiographic parameters, medication and ANP and BNP revealed that only low ANP (p=0.005) and high BNP before DC (p=0.0002) were independent predictors of recurrent AF. A ratio of ANP to BNP less than 0.44 was a significant risk factor for AF recurrence by Kaplan-Meier analysis (p=0.02). BNP began to decrease immediately after successful DC. High BNP and relatively low ANP compared with BNP were independent risk factors of AF recurrence in patients with mild CHF.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Electric Countershock; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Recurrence

The effect of a continuous infusion of human brain natriuretic peptide, 2 pmol.min-1.kg-1, during 60 min was studied in nine patients with congestive heart failure and in 10 healthy control subjects. Brain natriuretic peptide increased from 1.6 to 101 pmol/l in control subjects and from 25 to 173 pmol/l in congestive heart failure during infusion. Urinary sodium excretion increased significantly in both congestive heart failure (60%) and control subjects (71%), but the absolute increase was significantly lower in congestive heart failure (27 micromol/min) than in control subjects (190 micromol/min). Urinary flow rate did not change. The lithium clearance technique was used to evaluate the segmental tubular function; the distal fractional reabsorption of sodium decreased significantly less in congestive heart failure (DFRNa: -0.8%) than in control subjects (DFRNa: -3.7%). Baseline values for glomerular filtration rate and renal plasma flow were reduced in congestive heart failure, but brain natriuretic peptide induced no significant changes between congestive heart failure and control subjects. Brain natriuretic peptide induced the same absolute increase in secondary messenger cGMP in plasma and urine in both patients and healthy subjects. It is concluded that the natriuretic response to brain natriuretic peptide infusion was impaired in patients with congestive heart failure compared with healthy subjects, and it is likely that the impaired natriuretic response was caused by a reduced responsiveness in the distal part of the nephron.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Cyclic GMP; Female; Glomerular Filtration Rate; Heart Failure; Hematocrit; Humans; Kidney Tubules; Lithium; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Potassium; Renal Plasma Flow; Renin; Statistics, Nonparametric; Urination

To determine the relations of plasma levels of brain natriuretic peptide (BNP), atrial natriuretic factor (ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate (cGMP; the cardiac peptide second messenger), and plasma catecholamines to left ventricular function and to prognosis in patients admitted with acute myocardial infarction.. Plasma hormones and ventricular function (radionuclide ventriculography) were measured 1-4 days after myocardial infarction in 220 patients admitted to a single coronary care unit. Radionuclide scanning was repeated 3-5 months after infarction. Clinical events were recorded over a mean period of 14 months.. Both early and late left ventricular ejection fraction (LVEF) were most closely related to plasma BNP (r = -0.60, n = 220, p < 0.001; and r = -0.53, n = 192, p < 0.001, respectively), followed by ANF, N-ANF, cGMP, and the plasma catecholamines. Early plasma BNP concentrations less than twofold the upper limit of normal (20 pmol/l) had 100% negative predictive value for LVEF < 40% at 3-5 months after infarction. In multivariate analysis incorporating all the neurohormonal factors, only BNP remained independently predictive of LVEF < 40% (p < 0.005). Survival analysis by median levels of candidate predictors identified BNP as the most powerful discriminator for death (p < 0.0001). No early deaths (within 4 months) occurred in patients with plasma BNP concentrations below the group median (27 pmol/l), and over follow up only three of 26 deaths occurred in this subgroup. Of all episodes of left ventricular failure, 85% occurred in patients with plasma BNP above the median (p < 0.001). In multivariate analyses, BNP alone gave additional predictive information beyond sex, age, clinical history, LVEF, and plasma noradrenaline for both subsequent onset of LVF and death.. Plasma BNP measured within 1-4 days of acute myocardial infarction is a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and superior to ANF, N-ANF, cGMP, and plasma catecholamines.

Topics: Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Epinephrine; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Norepinephrine; Predictive Value of Tests; Prospective Studies; Protein Precursors; Radionuclide Imaging; Ventricular Dysfunction, Left

The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2+/-1.1 microl/min versus 27.5+/-3.1 microl/min with vehicle, P < 0.001) and in HS-142-1-treated shunted rats (8.1+/-1.3 microl/min versus 19.9+/-2.3 microl/min with vehicle, P < 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6+/-0.3 ml/min versus 2.1+/-0.4 ml/min with vehicle, P < 0.05) and after an acute volume load (1.2+/-0.4 ml/min versus 2.6+/-0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure.

Topics: Analysis of Variance; Angiotensin II; Animals; Atrial Natriuretic Factor; Cyclic GMP; Disease Models, Animal; Glomerular Filtration Rate; Heart Failure; Kidney Function Tests; Male; Polysaccharides; Rats; Rats, Wistar; Reference Values; Renal Circulation; Statistics, Nonparametric; Urodynamics

Heart failure is characterized by increased vascular resistance and water retention. Adrenomedullin is a peptide hormone with vasodilating and diuretic properties whose efficacy in heart failure has not been well established. We used an aortocaval shunt model of moderate heart failure in rats and infused increasing doses of adrenomedullin, both as bolus injections and 20-min infusions. In controls, a clear dose-dependent 4.8+/-1.0 to 13.6+/-2.3 mm Hg decrease in arterial blood pressure was observed after injection of 1 microg to 30 microg of adrenomedullin. In rats with aortocaval shunt, the hypotensive responses were significantly diminished. The urine flow rate, which was diminished at baseline in rats with aortocaval shunt, was increased and normalized by adrenomedullin administration. The glomerular filtration rate increased after infusion of adrenomedullin (0.5 microg/kg min(-1)) from 2.37+/-0.25 to 3.47+/-0.43 ml/min (P<0.01) in controls and from 1.79+/-0.33 to 2.58+/-0.49 (P<0.05) in rats with aortocaval shunt. Similarly, renal blood flow was significantly increased by adrenomedullin in both groups. Our results indicate a beneficial effect of adrenomedullin on renal function in rats with aortocaval shunt. These data suggest that adrenomedullin might be of potential therapeutic value in heart failure, without inordinately decreasing blood pressure.

Topics: Adrenomedullin; Animals; Arteriovenous Shunt, Surgical; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Diuresis; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Male; Natriuresis; Peptides; Rats; Rats, Wistar; Renal Circulation

Natriuretic peptide (NP) receptor has been postulated to be downregulated under a high concentration of atrial NP (ANP) in congestive heart failure (CHF), but limited information is available on how the vascular functional responsiveness to NPs is altered in coronary circulation during CHF. We assessed the relaxant effects of ANP, brain NP (BNP), and other vasodilators in isolated coronary arteries obtained from dogs with and without severe CHF induced by rapid right ventricular pacing. In CHF dogs, plasma ANP and cGMP concentrations were elevated compared with control dogs. In CHF arteries the relaxant effects of ANP and BNP (10(-8) and 10(-7) mol/l) were suppressed compared with control arteries. Nitroglycerin, nitric oxide, 8-bromo-cGMP, and beraprost sodium produced similar concentration-response curves in both arteries. The addition of 10(-7) mol/l ANP increased the level of tissue cGMP in control arteries, but not in CHF arteries. We conclude that there was a specific reduction in the relaxant effects of ANP and BNP in isolated coronary arteries in severe CHF dogs, which suggests the possibility of the downregulation of NP receptors coupled to guanylate cyclase.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Vessels; Cyclic GMP; Dinoprost; Dogs; Heart Failure; Hemodynamics; Humans; In Vitro Techniques; Natriuretic Peptide, Brain; Potassium Chloride; Reference Values; Vasodilator Agents

Dendroaspis natriuretic peptide (DNP), recently isolated from the venom of the green Mamba snake Dendroaspis angusticeps, is a 38 amino acid peptide containing a 17 amino acid disulfide ring structure similar to that of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). DNP-like immunoreactivity (DNP-LI) was reported to be present in human plasma and atrial myocardium and to be elevated in human congestive heart failure. Although previously named DNP, it remains unknown if DNP is natriuretic or if is it present in canine plasma, urine, and atrial myocardium.. Studies were performed in vivo in anesthetized dogs (N = 6) using intravenous infusion of synthetic DNP at 10 and 50 ng/kg/min. Employing a sensitive and specific radioimmunoassay for DNP, the presence of DNP-like peptide was assessed in the canine plasma and urine before, during, and following the administration of exogenous synthetic DNP. Additionally, we performed immunohistochemical studies using the indirect immunoperoxidase method with polyclonal DNP antiserum in normal atrial myocardium (N = 10). Atrial concentrations of DNP-LI were also assessed.. We report that DNP is markedly natriuretic and diuretic, which, like ANP and BNP, is associated with the increase in urinary and plasma cGMP. DNP-like peptide is also detected in canine plasma, urine, and atrial myocardium.. These studies establish that DNP is a potent natriuretic and diuretic peptide with tubular actions linked to cGMP and that DNP may play a physiological role in the regulation of sodium excretion.

Topics: Amino Acid Sequence; Animals; Blood Pressure; Cyclic GMP; Dogs; Elapid Venoms; Heart Atria; Heart Failure; Humans; Intercellular Signaling Peptides and Proteins; Kidney; Male; Molecular Sequence Data; Myocardium; Peptides; Sodium; Urine

In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system.. We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function.. ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response.. Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Diuresis; Heart Failure; Male; Myocardium; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Statistics, Nonparametric; Tetrazoles; Valine; Valsartan

We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive effects on coronary hemodynamics and on cardiac remodeling in post-myocardial infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for 6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their combination, after which coronary hemodynamics (basal and at maximal vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were investigated. Neither trandolapril nor losartan (both in nonantihypertensive doses) nor their combination (which significantly decreased blood pressure) proved to be effective at improving MI-induced impairments of basal coronary hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis development. In contrast, both trandolapril and losartan significantly improved the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and -39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively] and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in their combination, tended to exert additive effects on these three parameters (-49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended to exert additive effects on systemic hemodynamics and cardiac hypertrophy in post-MI heart failure rats, no such effect was found for coronary hemodynamics, probably in relation to the lack of prevention of cardiac fibrosis. We conclude that an early (6 weeks) drug-induced improvement in coronary hemodynamics does not contribute to the long-term survival prolongation observed in this experimental model after either ACEI or AT1-.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Coronary Circulation; Cyclic GMP; Heart Failure; Hemodynamics; Indoles; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

We examined for the first time the specific roles of angiotensin II and the natriuretic peptides during inhibition of angiotensin-converting enzyme (captopril, 25 mg bolus + 6 mg/3 h infusion) and endopeptidase 24.11 (SCH32615, 5 mg/kg bolus + 3 mg/kg/3 h infusion), both separately and in combination, in eight sheep with pacing-induced heart failure. Plasma atrial and brain natriuretic peptide levels were similarly increased by SCH32615 and to a lesser extent during combined inhibition but decreased with captopril. Captopril and combined inhibition induced identical increases in plasma renin activity and reductions in angiotensin II, whereas neither was changed by SCH32615 alone. Mean arterial pressure and peripheral resistance decreased during SCH32615 and further still during captopril and combined treatment. Left atrial pressure was reduced to a similar extent by SCH32615 and captopril alone and reduced further by combined inhibition. Cardiac output increased during all treatments. Urine volume and sodium excretion were significantly increased during SCH32615 and combined inhibition. Creatinine clearance increased during SCH32615, decreased during captopril, and was maintained during combined treatment. In conclusion, compared with captopril alone, cotreatment with an endopeptidase 24.11 inhibitor further improved filling pressures and induced a diuresis and natriuresis with preservation of renal glomerular filtration.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Failure; Hemodynamics; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Sheep; Time Factors; Ventricular Function

Topics: Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Cyclic GMP; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelins; Heart Failure; Polysaccharides; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Tetrazoles; Water-Electrolyte Balance

The influence of the atrial natriuretic factor (ANF) on heart-cell communication was investigated in cell pairs isolated from the ventricle of cardiomyopathic hamsters (BIO TO-2; 11 months old), and the results were compared with controls (F1B) of same age. The results indicated that ANF (10(-8) M) added to the bath caused a decline in junctional conductance (gj) of 48 +/- 2% (n = 15) within 90 s. The effect of ANF was suppressed by HS-142-1, a specific antagonist of guanylyl cyclase ANF receptor. Moreover, the decline in gj elicited by ANF was related to the synthesis of cyclic guanosine monophosphate (cGMP). Indeed, dibutyryl-cGMP (10(-4) M) decreased gj by 80 +/- 3.5% (n = 15) within 90 s, and zaprinast, a selective inhibitor of cGMP phosphodiesterase, enhanced the effect of ANF on gj. The possible relationship between ischemia, ANF release, and impairment of cell coupling is discussed.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Bucladesine; Cardiomyopathies; Cell Communication; Cricetinae; Cyclic GMP; Electrophysiology; Gap Junctions; Heart Failure; Heart Ventricles; Male; Mesocricetus; Phosphodiesterase Inhibitors; Purinones; Receptors, Atrial Natriuretic Factor

Controversy persists regarding the acute responsiveness of atrial (ANP) and brain (BNP) natriuretic peptides in pathophysiological conditions such as acute heart failure (AHF). This study was designed to test the hypothesis that AHF is characterized by selective activation of ANP, but not BNP. We also hypothesized that BNP replacement in AHF would reduce cardiac filling pressures, increase sodium excretion, and inhibit circulating renin. Two groups of anesthetized dogs underwent rapid left ventricular pacing to induce AHF. Group 1 (n = 7) served as control and group 2 (n = 7) received canine BNP (10 ng x kg(-1) x min(-1)). Cardiorenal parameters, circulating natriuretic peptides, 3',5'-cyclic guanosine monophosphate (cGMP), and plasma renin activity (PRA) were determined at baseline and during AHF in both groups. AHF was characterized by reductions in cardiac output (2.3 +/- 0.2 vs. 3.7 +/- 0.3 l/min, P < 0.05), pulmonary capillary wedge pressure (PCWP; 11.7 +/- 0.8 vs. 5.1 +/- 0.3 mmHg, P < 0.05), and selective activation of ANP (250 +/- 51 vs. 39 +/- 13 pg/ml, P < 0.05), with no increase in circulating BNP (49 +/- 15 vs. 60 +/- 16 pg/ml, P = not significant). Compared with control, exogenous supplemental BNP in AHF resulted in marked increases in circulating cGMP (65 +/- 6 vs. 18 +/- 5 pg/ml, P < 0.05), with reductions in PCWP (9.1 +/- 0.9 vs. 12.9 +/- 1.1 mmHg, P < 0.05) and increased urinary sodium excretion (120 +/- 36.8 vs. 24 +/- 6.3 microeq/min, P < 0.05) via reductions in distal tubular sodium reabsorption (94.3 +/- 1.8 vs. 98.0 +/- 0.4%, P < 0.05). Exogenous BNP prevented the increase in PRA that occurred in the control group. We conclude that AHF is characterized by a failure to increase circulating BNP underscoring differential physiological and pathophysiological roles for ANP and BNP in states of immediate cardiac overload. These studies also support a potential role for BNP in the therapeutics of AHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cyclic GMP; Dogs; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pulmonary Wedge Pressure; Radioimmunoassay; Reference Values; Renal Circulation; Renin; Vascular Resistance

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Enzyme Inhibitors; Heart Failure; Hypertension; Macaca fascicularis; Neprilysin; Pyridines; Rats; Renin; Sodium; Thiazepines

To evaluate the effects of endogenous angiotensin II (ANG II) on the development of congestive heart failure (CHF), we examined cardiorenal and hormonal factors after chronic administration of the ANG II type 1 receptor antagonist TCV-116 in dogs with CHF induced by rapid right ventricular pacing. After 8 days of pacing, TCV-116 administration [1 (group 1) or 3 mg.kg-1.day-1 (group 2)] was started and continued until the 22nd day. TCV-116 was found to have protected the deterioration of cardiorenal functions and the activation of neurohormonal factors. Although there was no significant difference in the pulmonary capillary wedge pressure or plasma atrial natriuretic peptide (ANP) level between the TCV-116-treated groups (354 +/- 85 and 364 +/- 29 pg/ml for groups 1 and 2, respectively) and the vehicle group (385 +/- 20 pg/ml), the plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels, a second messenger of ANP, were twofold higher in TCV-116-treated groups (49.4 +/- 10.2 and 50.6 +/- 7.7 pmol/ml for groups 1 and 2, respectively) than in the vehicle group (24 +/- 4.0 pmol/ml), with a high correlation between the plasma ANP and cGMP levels (r = 0.90; P < 0.05). These findings indicate that endogenous ANG II has important roles in hemodynamics and renal functions during the development of CHF, which may be due, in part, to a reduction in endogenous ANP activity, suggesting the usefulness of an ANG II-receptor antagonist against the development of CHF.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Cyclic GMP; Dogs; Female; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Kidney; Male; Norepinephrine; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles; Time Factors; Vascular Resistance

To examine whether preoperative heart failure and cardiac surgery influence nitric oxide production and atrial natriuretic peptide (ANP) biological activity in infants and whether nitric oxide and ANP participate in the control of postoperative pulmonary vascular tone.. Prospective, clinical study.. Tertiary pediatric cardiac intensive care unit in a referral cardiosurgical center.. Nineteen infants (median age 4 months) undergoing cardiac surgery: 13 infants with ventricular or atrioventricular septal defect associated with heart failure and pulmonary hypertension (group 1); and six infants with tetralogy of Fallot, without heart failure (group 2).. Blood samples obtained from indwelling catheters or bypass circuit outlets.. Nitrite and nitrate blood concentrations (as a marker for nitric oxide synthesis) and the molar ratio of cyclic guanosine 3',5'-monophosphate (cGMP) to ANP (as a marker for ANP biological activity) were determined before, during, and up to 24 hrs after cardiopulmonary bypass (CPB). In group 1 patients, these biological parameters were related to postoperative pulmonary arterial pressure. Preoperative nitrite and nitrate concentrations were higher in group 1 patients than in group 2 patients (p < .02), and this difference persisted during CPB. Nitrite and nitrate concentrations 24 hrs postoperatively were lower than preoperative values in group 1 patients (p < .05) and were unchanged in group 2 patients. An inverse correlation was observed postoperatively between nitrite and nitrate concentrations and systolic pulmonary arterial pressure (r2 = 0.4, p < .05). Group 1 patients had a lower preoperative cGMP/ANP ratio than group 2 patients (p < .05), despite higher ANP levels (p < .005). The cGMP/ANP ratio decreased during CPB in both groups (p < .0001), and in group 2 patients, cGMP and ANP values remained below preoperative values < or = 24 hrs postoperatively. A correlation was observed between ANP levels and systolic pulmonary arterial pressure 2 and 4 hrs postoperatively (r2 = .4, p < .05, respectively), but no correlation was observed between ANP biological activity and postoperative pulmonary arterial pressure.. Infants with heart failure and pulmonary hypertension have increased nitric oxide synthesis and decreased ANP biological activity; both phenomena may be involved in the pathophysiology of this clinical condition. CPB has no detectable effect on nitric oxide production but does decrease ANP biological activity. In patients with preoperative heart failure and pulmonary hypertension, endogenous nitric oxide appears to play a role in the control of postoperative pulmonary vascular tone.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiopulmonary Bypass; Cyclic GMP; Heart Failure; Heart Septal Defects; Humans; Hypertension, Pulmonary; Infant; Nitrates; Nitric Oxide; Nitrites; Prospective Studies; Pulmonary Circulation; Tetralogy of Fallot

Accumulating evidence suggests that urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because urodilatin excretion, considerably increases with increasing nutritive sodium intake (p<0.004), the CHF patients (15 NYHA I/II, 8 NYHA III/IV) were kept on a 165 mmol/day sodium diet and 6 healthy volunteers on a identical nutritive sodium intake level were selected as proper controls. Although urodilatin excretion significantly increased (p<0.027) with increasing severity of CHF and was therefore significantly higher in mild CHF (40.7 +/- 2.5 fmol/min) and severe CHF (54.7 +/- 6.6 fmol/min) than in healthy controls (3.2 +/- 4.2 fmol/min), both groups of CHF patients retained sodium and had significantly lower sodium excretion rates (NYHA I/II 79.0 +/- 6.9 micromol/min, NYHA III/IV 97.9 +/- 12.7 micromol/min) than the healthy controls (139 +/- 3.4 micromol/min). Our data suggest that renal urodilatin synthesis, may not be involved in the etiology of sodium retention in CHF, but may rather be stimulated to counteract antinatriuresis during CHF.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Child; Child, Preschool; Cyclic GMP; Diuretics; Female; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Sodium; Sodium, Dietary

Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.. Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.. Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Volume; Chronic Disease; Collagen; Consciousness; Coronary Vessels; Cyclic GMP; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Heart Ventricles; Male; Myocardial Infarction; Myocardium; Norepinephrine; Pressure; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Survival Analysis; Ventricular Function, Left

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4-23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4-23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4-23). Combined administration of SCH-32615 and C-ANP-(4-23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.

Topics: Aldosterone; Animals; Atrial Function, Left; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dipeptides; Diuresis; Endopeptidases; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Natriuresis; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protease Inhibitors; Receptors, Atrial Natriuretic Factor; Sheep; Time Factors; Vascular Resistance

Ventricular concentrations of atrial, brain (BNP) and C-type natriuretic peptide are enhanced in congestive heart failure (CHF). Natriuretic peptide receptors are present on ventricular myocytes and stimulate guanosine 3',5'-cyclic monophosphate (cGMP) production. cGMP has been demonstrated to affect myocyte function in vitro. Thus we hypothesized that the intracardiac natriuretic peptide system may modulate myocardial and coronary function in CHF. To test this hypothesis, the effects of an intracoronary infusion of the natriuretic peptide receptor antagonist HS-142-1 on ventricular and coronary function were examined in anesthetized dogs with chronic CHF. To determine whether receptor stimulation had contrasting effects to those of receptor blockade, intracoronary BNP was infused in anesthetized normal and CHF dogs. Low-dose HS-142-1 delayed and slowed left ventricular (LV) relaxation and decreased coronary blood flow without changes in LV pressures. Higher doses further impaired LV relaxation without further decreases in coronary blood flow. In normal and CHF dogs, exogenous BNP produced the opposite effect with a quicker onset and faster rate of LV relaxation without effects on LV pressures or coronary blood flow. The endogenous natriuretic peptide system has an autocrine-paracrine role to modulate LV and coronary vascular function in CHF.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Cardiac Output; Cardiomyopathies; Coronary Circulation; Coronary Vessels; Cyclic GMP; Dogs; Heart Failure; Heart Rate; Hemodynamics; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Polysaccharides; Propanolamines; Receptors, Atrial Natriuretic Factor; Tachycardia; Vascular Resistance; Ventricular Function, Left

We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7-quinazolinyl)-3-methyl-4-oxobutyric acid (-)-menthyl ester (6) was separated into both diastereoisomers, and each was converted to optically pure 1 (> 99% ee) in an enantioselective manner. In order to determine the absolute configuration of the isomers, an alternative synthesis of optically active 1 was employed. The precursor of (-)-1 ((+)-9) was obtained by enantioselective synthesis from (R)-D-alanine. Consequently, we concluded that the absolute configuration of (-)-1 at the 5-position of the pyridazinone ring was R. The cardiotonic effects and inhibitory activities to PDE III and V of racemic 1 and (-)-1 were more potent than those of (+)-1. These compounds also demonstrated greater vasorelaxant effects in guinea pig aorta. In contrast, (+)-1 showed only weak cardiotonic and vasodilating effects, although the compound displayed potent Ca(2+)-sensitizing activity. Racemic and (-)-1 attracted our interest for the treatment of congestive heart failure.

Topics: Animals; Aorta; Calcium; Cardiotonic Agents; Cattle; Dogs; Guinea Pigs; Heart Failure; In Vitro Techniques; Male; Molecular Conformation; Molecular Structure; Myocardial Contraction; Nucleotides, Cyclic; Phosphodiesterase Inhibitors; Quinazolines; Stereoisomerism; Trifluoperazine; Vasodilator Agents; Ventricular Pressure

Topics: Animals; Cyclic GMP; Diabetic Neuropathies; Dinoprostone; Heart Failure; Humans; Hypertension; Receptors, Angiotensin; Renin-Angiotensin System

In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/- 28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80 min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure-induced cardiac hypertrophy independent of hemodynamic effects.

Topics: Alanine; Angiotensin II; Animals; Aorta, Abdominal; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Enzyme Inhibitors; Heart Failure; Hemodynamics; Male; Natriuresis; Neprilysin; Rats; Rats, Wistar; Renin; Vena Cava, Inferior

Recently, a significant activity of inducible nitric oxide synthase (iNOS) has been reported in biopsies from failing hearts due to idiopathic dilated cardiomyopathy (IDC). Thus, a potential pathophysiological role of iNOS in IDC has been stated. In order to investigate, whether iNOS expression is of pathophysiological relevance in human heart failure, we measured iNOS protein expression and cGMP content in left ventricular myocardium from non-failing and failing human hearts. Immunoblot analysis revealed iNOS protein expression in four out of six failing hearts from septic patients, whereas no iNOS-protein expression was detected in either non-failing human hearts (n = 6) or failing hearts due to IDC (n = 9), ischemic heart disease (IHD, n = 7), Becker muscular dystrophy (BMD, n = 2) and mitoxantrone-induced toxic cardiomyopathy TCM, n = 1). cGMP content was increased by 130% in septic hearts, whereas there was no cGMP increase in hearts with IDC. IHD and BMD compared to non-failing hearts. We conclude, that the induction of iNOS may play a role in contractile dysfunction observed in septic shock, but is unlikely to be of major pathophysiological importance in end-stage heart failure due to IDC, IHD, BMD and TCM.

Topics: Animals; Cardiomyopathies; Cardiomyopathy, Dilated; Cell Line; Cyclic GMP; Gene Expression; Heart Failure; Heart Ventricles; Humans; Isoenzymes; Macrophages; Mice; Mitoxantrone; Muscular Dystrophies; Myocardial Ischemia; Myocardium; Nitric Oxide Synthase; Reference Values; Sepsis

Atrial and brain natriuretic peptides exert renal and cardiovascular actions through binding to the natriuretic peptide-A receptor, while C-type natriuretic peptide mediates actions that occur through binding to the natriuretic peptide-B receptor, with subsequent generation of cyclic guanosine monophosphate. This study determined responses of circulating atrial natriuretic peptides in experimental acute heart failure and addressed the hypothesis that elevated circulating atrial natriuretic peptides serve a homeostatic role in regulating sodium excretion and that this action is localized to the glomerulus and distal nephron, sites rich in natriuretic peptide-A receptors.. Studies were performed in the absence and presence of HS-142-1, an inhibitor of the natriuretic peptide receptors. Two groups of anesthetized dogs underwent induction of acute heart failure by rapid ventricular pacing, as characterized by decreases in cardiac output and increases in filling pressures with associated elevation of endogenous atrial natriuretic peptides secondary to increases in atrial stretch. In group 1 (n = 5, vehicle intrarenal bolus), despite acute heart failure-mediated decreases in cardiac output, sodium excretion was preserved with maintenance of the glomerular filtration rate and distal fractional sodium reabsorption. In group 2 (n = 5), in response to the natriuretic peptide receptor antagonist, HS-142-1 (0.5 mg/kg intrarenal bolus), sodium excretion (17.0 +/- 4.4 to 5.9 +/- 3.2 microEq/min; P < .05) and glomerular filtration rate decreased (33.0 +/- 3.6 to 21.0 +/- 3.9 mL/min; P < .05) and distal fractional sodium reabsorption increased (98.0 +/- 0.63 to 99.3 +/- 0.25%; P < .05), in association with a decrease in plasma cyclic guanosine monophosphate (13.0 +/- 3.5 to 6.6 +/- 2.9 pmol/mL; P < .05) and renal cyclic guanosine monophosphate generation (1,216 +/- 421 to 466 +/- 208 pmol/min; P < .05).. This study supports a functionally significant role for the endogenous natriuretic peptide system in preserving sodium homeostasis and glomerular filtration rate in acute heart failure.

Topics: Acute Disease; Analysis of Variance; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Glomerular Filtration Rate; Guanylate Cyclase; Heart Failure; Hemodynamics; Kidney; Male; Polysaccharides; Receptors, Atrial Natriuretic Factor; Sodium

The hemodynamic, hormonal, and metabolic effects of chronic neutral endopeptidase (NEP) 24.11 inhibition and furosemide were compared in the pacing model of ovine heart failure (HF). Intravenous SCH 39370 induced a dose-related inhibition of NEP activity during 4-days treatment, in association with a transient increase in plasma atrial natriuretic peptide (ANP) and, at the higher dose, an increased mean level of plasma cyclic guanosine monophosphate. There was a significant and persistent decrease in left atrial pressure, a brief increase in cardiac output (CO), and a tendency for arterial pressure to be reduced. Significant dose-related diuresis and natriuresis were also observed. Furosemide induced a similar hemodynamic response, associated with greater diuresis and natriuresis. Both agents significantly reduced plasma aldosterone levels. Coinfusion of captopril on day 4 of treatment resulted in similar responses in both the SCH 39370- and furosemide pretreated groups. Chronic NEP inhibition significantly alters circulatory and renal function and appears to be as effective as furosemide in reducing cardiac preload in this model of congestive HF.

Topics: Animals; Atrial Natriuretic Factor; Captopril; Cyclic GMP; Dipeptides; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Heart Failure; Hemodynamics; Neprilysin; Sheep

The natriuretic peptide (NP) and nitric oxide (NO) systems are activated in congestive heart failure (CHF), resulting in increased synthesis of cGMP, which serves as a second messenger for both humoral systems. These two regulatory systems play functional roles in the preservation of glomerular filtration rate (GFR) and sodium excretion in both acute and chronic CHF. A progressive decline in glomerular responsiveness to atrial natriuretic peptide (ANP) characterizes the terminal stage of chronic CHF despite elevation of plasma ANP. Phosphodiesterase isozymes (PDEs) are integral factors in determining cellular content and accumulation of cGMP, and up-regulation of PDE activity could participate in the glomerular resistance to ANP in severe CHF. To date, characterization of possible alteration of glomerular PDE isozyme activities in CHF is unknown, as is the in vitro glomerular response to the nitric oxide-soluble guanylyl cyclase pathway. We, therefore, first determined cGMP generation in response to particulate and soluble guanylyl cyclase activation by ANP and sodium nitroprusside (SNP) in isolated glomeruli from normal (N = 6) and CHF dogs (N = 5) in which CHF was induced by rapid ventricular pacing for 18 to 28 days. Secondly, we explored the presence of major PDE isozymes in glomeruli isolated from the control and CHF dogs. When ANP or SNP (10(-10) to 10(-4) M) were incubated with the suspension of isolated glomeruli, cGMP accumulation was lower by -72 to -96% with ANP and -42 to -77% with SNP in all glomerular medias obtained from CHF compared to controls. PDE hydrolyzing activity of both cAMP and cGMP were higher in the glomerular homogenates obtained from the kidneys of the CHF group (N = 5) compared to those of the control group (N = 5). We conclude that in severe chronic experimental CHF, glomerular cGMP accumulation decreases in response to both ANP and SNP, and CHF is characterized by enhanced cGMP- and cGMP-PDE activities that may participate in glomerular maladaptation to this cardiovascular syndrome.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Heart Failure; Hemodynamics; Hormones; In Vitro Techniques; Isoenzymes; Kidney; Kidney Glomerulus; Male; Nitroprusside; Stimulation, Chemical; Vasodilator Agents

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; 8-Bromo Cyclic Adenosine Monophosphate; Amrinone; Cells, Cultured; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Interleukin-1; Interleukin-6; Kinetics; Leukocytes, Mononuclear; Lipopolysaccharides; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pyrazines; Pyridazines; Quinazolines; Quinolines; Tumor Necrosis Factor-alpha

The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg-1 min-1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50 bpm). Urodilatin was discontinued and symptoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.

Topics: Atrial Natriuretic Factor; Blood Pressure; Bradycardia; Cardiac Output; Cyclic GMP; Heart Failure; Heart Rate; Hematocrit; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments

We investigated whether atrial natriuretic peptide (ANP) contributed to the regulation of renin release during the development of experimental heart failure in dogs. Significant increases of plasma ANP and plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels were observed in dogs with mild heart failure induced by 6 days of rapid ventricular pacing. However, plasma renin activity (PRA) was not elevated, despite the significant decreases in renal plasma flow and mean arterial pressure. An inverse correlation between PRA and the ratio of plasma cGMP to ANP (rs = -0.59, P < 0.05) was found in dogs subjected to 9 days of rapid pacing. In dogs with advanced heart failure induced by 15-24 days of rapid pacing, the plasma cGMP level did not increase further, despite the progressive increase in plasma ANP with the resultant significant increase in PRA (P < 0.05). These findings suggest that attenuation of the inhibitory effect of ANP on renin release during the development of severe heart failure may be an important factor in the activation of the renin-angiotensin system.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Pacing, Artificial; Cyclic GMP; Dogs; Female; Heart Failure; Male; Pulmonary Wedge Pressure; Renin

Increased plasma concentrations of cyclic guanosine monophosphate (cGMP) have been reported in patients with manifest heart failure. At rest, however, cGMP concentrations in patients with asymptomatic left ventricular dysfunction or heart failure in New York Heart Association (NYHA) functional class I do not differ significantly from those of healthy subjects. The purpose of this study was to investigate whether graded exercise on an ergometer improves the sensitivity of cGMP in diagnosing asymptomatic left ventricular dysfunction.. Plasma cGMP concentrations were compared in 17 healthy controls and 98 patients with asymptomatic left ventricular dysfunction or congestive heart failure of different stages (asymptomatic left ventricular dysfunction or NYHA functional class I, 56 patients; NYHA class II, 31 patients; NYHA class III, 11 patients).. Before exercise plasma cGMP concentrations in patients with clinical heart failure (NYHA functional classes II and III) were significantly higher than those in healthy controls. In patients with asymptomatic left ventricular dysfunction or heart failure of functional class I plasma cGMP concentrations were not significantly different from those in healthy subjects. Thirty minutes after exercise, however, cGMP concentrations in patients with asymptomatic left ventricular dysfunction or class I heart failure were significantly higher than those in healthy controls.. Measurement of plasma cGMP concentrations 30 minutes after ergometric exercise testing allows better discrimination between healthy subjects and patients with symptomless left ventricular dysfunction or mild heart failure (NYHA class I) than measurement of such concentrations before exercise.

Topics: Adult; Aged; Biomarkers; Cyclic GMP; Exercise Test; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Time Factors; Ventricular Dysfunction, Left

Recent studies suggest that neurohumoral mechanisms including decreased renal responses to increases in atrial natriuretic factor (ANF) play a central role in the progression from asymptomatic cardiac dysfunction to advanced congestive heart failure (CHF) with sodium retention, vasoconstriction, and reduced exercise tolerance. Recognizing that neutral endopeptidase 24.11 degrades ANF and may be enhanced in CHF, we hypothesized that chronic neutral endopeptidase inhibition (NEP-I) would potentiate renal responses to exogenous ANF and alter the temporal evolution of sodium retention in evolving CHF by potentiation of increased endogenous ANF.. We studied 13 conscious dogs with evolving CHF produced by rapid ventricular pacing at 250 beats per minute. Six of these dogs received NEP-I with candoxatril, 10 mg/kg PO BID, throughout evolving CHF. Responses to exogenous ANF, 10 micrograms/kg IV bolus, were assessed at baseline and after 6 days of CHF. Daily metabolic studies during evolving CHF with chronic NEP-I showed increased sodium excretion and renal cGMP generation consistent with enhanced renal activity of endogenous ANF compared with untreated controls. In addition, renal natriuretic and cGMP responses to exogenous ANF were intact in CHF with chronic NEP-I in contrast to markedly attenuated renal responses to exogenous ANF in untreated CHF. Despite enhanced ANF responsiveness and improved sodium balance in evolving CHF, a moderate degree of sodium retention was observed during chronic NEP-I in evolving CHF.. Enzymatic degradation by neutral endopeptidase limits local renal responses to increases in endogenous and exogenous ANF in CHF independent of changes in systemic hemodynamics or augmented plasma concentrations of ANF. The moderate sodium retention observed during evolving CHF despite chronic NEP-I probably reflects the antinatriuretic effects of hemodynamic and humoral factors independent of ANF activity.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Heart Failure; Hemodynamics; Indans; Kidney; Male; Natriuresis; Neprilysin; Propionates; Sodium; Time Factors

The interactions of the systemic adaptations during and after rapid ventricular pacing, a model of heart failure, were assessed in conscious, unstressed dogs. One week of ventricular tachycardia (260 beats/min) significantly reduced mean +/- SEM cardiac output (2.3 +/- 0.1 to 1.2 +/- 0.1 liter/min), mean arterial pressure (119 +/- 3 to 93 +/- 3 mm Hg), renal blood flow (168 +/- 19 to 96 +/- 9 ml/min), sodium excretion (36 +/- 5 to 10 +/- 4 mEq/d), increased left and right atrial pressures (8 +/- 1 to 21 +/- 1 and 4 +/- 0 to 11 +/- 1 mm Hg, respectively), plasma atrial natriuretic peptide concentration (24 +/- 4 to 141 +/- 38 fmol/ml), plasma cyclic GMP concentration (9 +/- 1 to 16 +/- 4 pmol/ml), and urinary cyclic GMP excretion (0.77 +/- 0.05 to 2.18 +/- 0.34 nmol/min). These changes persisted throughout 3 weeks of pacing. Gradual increases in systemic and renal vascular resistances (to 122 +/- 17 and 1.30 +/- 0.22 mm Hg/liter/min, respectively) and reductions in glomerular filtration rate (65 +/- 6 to 44 +/- 4 ml/min) reached significance during the third week. Resumption of sinus rhythm stimulated a brisk natriuresis and a return of cardiac output, systemic vascular resistance, and hormone concentrations to control values within 7 days. However, increases of left and right atrial pressures (14 +/- 2 and 8 +/- 1 mm Hg, respectively) were still present after 2 months of recovery. In conclusion, persistent increases in cardiac filling pressures were induced by rapid ventricular pacing in conscious, unstressed dogs, whereas the systemic hemodynamic, renal, and hormonal responses were largely reversible during recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Dogs; Female; Glomerular Filtration Rate; Heart Failure; Heart Rate; Heart Ventricles; Hemodynamics; Kidney; Male; Natriuresis; Renin; Tachycardia; Vascular Resistance

To elucidate the extent of the compensatory role of endogenous atrial natriuretic peptide (ANP) in severe congestive heart failure (CHF), we examined the changes in hemodynamics and neuroendocrine and renal functions after incremental administration of an ANP antagonist, HS-142-1 (HS), in dogs with CHF.. We assessed the effects of HS on the suppression of plasma and urinary cGMP levels as a marker of endogenous ANP activity in dogs without CHF. Bolus injections of 0.3 and 1.0 mg/kg HS reduced plasma cGMP levels to 77% and 60% and urinary cGMP excretion to 78% and 61% of the relevant control levels, respectively. Then the study was performed in dogs with CHF induced by chronic rapid ventricular pacing, and the plasma ANP level was sixfold higher than that in the controls. Hemodynamic, hormonal, and renal variables were determined both before and after subsequent incremental administration (0.3, 1.0, and 3.0 mg/kg every 30 minutes) of HS. HS lowered the plasma and urinary cGMP levels dose dependently to 32% and 37% of the control levels, respectively. Mean arterial, pulmonary capillary wedge, and right atrial pressures and cardiac output did not change significantly. However, plasma renin activity, aldosterone level, and norepinephrine level increased rapidly to 226%, 179%, and 252% of the control values, respectively. Urine flow rate and urinary sodium excretion were significantly inhibited, with no concomitant change in glomerular filtration rate or renal plasma flow.. These findings suggest that endogenous ANP contributes to the suppression of the activation of the renin-aldosterone system and sympathetic nervous activity and body fluid retention but that the vasodilative action of this peptide is attenuated in advanced CHF.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Kidney; Male; Norepinephrine; Polysaccharides; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Sympathetic Nervous System

The effects of natriuretic peptides in kidney are blunted in congestive heart failure (CHF). The aim of this study is to examine the changes of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) second messenger productions in CHF. Experiments were conducted on 300-day-old normal and cardiomyopathic hamsters. Blood was collected for ANF measurement. cGMP accumulation studies were done in glomeruli upon ANF and BNP stimulation, and in inner medullary collecting duct (IMCD) cells upon ANF stimulation. Higher plasma ANF levels were found in cardiomyopathic hamsters (811.3 +/- 124.6 vs. 166.6 +/- 13 pg/ml, p < 0.01). ANF-stimulated cGMP accumulations in glomeruli and IMCD cells were higher in cardiomyopathic hamsters. Increased BNP-stimulated cGMP accumulations were also observed in cardiomyopathic hamster glomeruli. These results suggest that the renal hyporesponsiveness to natriuretic peptides in CHF in not due to attenuated ANF and BNP second messenger productions.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cells, Cultured; Cricetinae; Cyclic GMP; Heart Failure; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Mesocricetus; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Second Messenger Systems

The present study was performed to evaluate the effects of nitroglycerin (GTN) on plasma arteriovenous cGMP production and to compare its hemodynamic effects in patients with congestive heart failure (CHF). We also estimated the potential clinical value of plasma arteriovenous cGMP production as an indicator of nitrate tolerance.. Plasma arterial and venous cGMP levels, atrial natriuretic peptide level, and hemodynamic parameters were measured before and after GTN infusion in 14 patients with CHF. Although the plasma levels of arterial cGMP and atrial natriuretic peptide decreased immediately after GTN, the plasma level of venous cGMP did not change. GTN infusion caused a dose-dependent increase in plasma arteriovenous cGMP production, and there was a positive correlation between the decrease of pulmonary capillary wedge pressure and the increase of plasma arteriovenous cGMP production immediately after GTN. Hemodynamic tolerance was observed after both 12 and 24 hours, when plasma arteriovenous GMP production was also attenuated.. These findings indicate that the plasma arteriovenous cGMP difference is a clinical indicator of vasodilatory action of GTN and a useful indicator of nitrate tolerance in patients with CHF.

Topics: Atrial Natriuretic Factor; Captopril; Cyclic GMP; Dose-Response Relationship, Drug; Drug Tolerance; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitroglycerin; Pulmonary Wedge Pressure

Endothelial dysfunction and abnormal vascular responsiveness to vasoconstrictors may play an important role in chronic heart failure (CHF). The purpose of our study was to (1) evaluate whether the vascular response to norepinephrine is abnormal in a rat model of heart failure; (2) investigate the role of alpha 1- and alpha 2-adrenergic receptors; and (3) assess the contribution of the endothelium, and specifically endothelium-derived nitric oxide, to this response.. Concentration-response curves of rat thoracic aortic rings were studied in isolated organ baths at 1 week after coronary artery ligation. In CHF rats, norepinephrine-induced contractions were increased in intact rings compared with rings from sham rats, despite decreased contraction in denuded rings. Decreased alpha 1-receptor sensitivity was demonstrated by the increased EC50 of methoxamine in endothelium-denuded rings from CHF rats, although maximal responses to KCl contraction were also decreased in CHF. There was no difference in the vascular response to clonidine, and acetylcholine-mediated relaxations were preserved in CHF rats, suggesting normal stimulated nitric oxide release. However, nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester, as well as measurements of basal cGMP, demonstrated that basal nitric oxide release was decreased in CHF rats.. This study demonstrates that the increased vascular responsiveness to norepinephrine in intact vessels from rats with heart failure is the result of decreased basal nitric oxide release and suggests that the dissociation of basal and stimulated nitric oxide release may play a pathophysiology role at an early stage of heart failure.

Topics: Animals; Aorta, Thoracic; Arginine; Cyclic GMP; Endothelium, Vascular; Heart Failure; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; Vasoconstriction; Vasoconstrictor Agents

We measured concentrations of guanosine 3',5'-monophosphate (cGMP) in plasma and urine of healthy subjects and patients with congestive heart failure, renal impairment, neoplastic disease, and hepatic cirrhosis. There was no correlation between cGMP concentrations in urine and in plasma. In all patients except those with renal impairment, urinary cGMP concentrations were significantly higher than in healthy persons. Only patients with heart failure or renal impairment showed significantly increased plasma cGMP concentrations. In contrast, cGMP in urine does not relate to the clinically assessed severity of heart failure (New York Heart Association functional classes). Determination of cGMP in plasma results in higher sensitivity and specificity for diagnosing heart failure than measurement of cGMP in urine.

Topics: Adult; Aged; Cyclic GMP; Female; Heart Failure; Humans; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged; Neoplasms; Reference Values; Ventricular Function, Left

During severe congestive heart failure (CHF), a number of sodium-retaining and vasoconstricting mechanisms are activated, including the renin-angiotensin-aldosterone system. In CHF, the renal effects of atrial natriuretic factor (ANF) are attenuated. The interaction of these endocrine factors is a major determinant of the clinical course of CHF. This study was designed to evaluate the role of the renin-angiotensin-aldosterone system in the development of avid sodium retention in CHF, induced in rats by creation of an aorto-caval fistula. Rats with aorto-caval fistula either compensate and maintain a normal sodium balance (UNaV > 1400 microEq/day) or decompensate and develop severe sodium retention (UNaV < 200 microEq/day), which leads to severe CHF. Chronic treatment with losartan, an angiotensin II receptor blocker, 10 mg/day, resulted in dramatic natriuresis (UNaV > 1000 microEQ/day) in decompensated rats, but not in compensated rats or controls. ANF infusion (50 micrograms/kg/hr) increased fractional sodium excretion 46-fold in compensated rats, but only 18-fold in decompensated rats. A similar pattern of responsiveness to ANF was observed in urinary cyclic GMP excretion. Chronic losartan treatment restored the natriuretic and urinary cyclic GMP excretion responses of decompensated rats to ANF. The improvement in the natriuretic response after losartan treatment was associated with a suppression of the previously elevated plasma aldosterone. These results demonstrate the pivotal role of angiotensin II in the development of sodium retention and of the blunted renal response to ANF in CHF, and indicate why losartan is useful therapy for cardiac edema.

Topics: Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Biphenyl Compounds; Cyclic GMP; Drug Interactions; Heart Failure; Imidazoles; Kidney; Losartan; Male; Natriuresis; Rats; Rats, Wistar; Renin-Angiotensin System; Sodium; Tetrazoles

Topics: Biomarkers; Cyclic GMP; Heart Failure; Humans; Monitoring, Physiologic

Neutral endopeptidase (NEP) inhibitors have been shown to strengthen the effects of endogenous atrial natriuretic peptide (ANP). It has been well documented that angiotensin I-converting enzyme (ACE) inhibitors act beneficially in chronic congestive heart failure (CHF). In the present study, renal and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimental CHF in the rat. The effects were compared to those of captopril. The drugs were also administered in combination. In anaesthetized rats with CHF, SCH 34826 (90 mg kg-1 sc) elevated plasma ANP from 382 +/- 85 to 658 +/- 120 ng l-1 compared with vehicle (p = 0.002). In sham-operated control rats, plasma ANP also increased slightly from 52 +/- 6 to 70 +/- 9 ng l-1 (p = 0.05). Plasma renin activity did not change in either group. When given orally for 36 h (90 mg kg-1 b.i.d.), SCH 34826 enhanced natriuresis in controls but not in rats with CHF. Captopril (0.2 mg ml-1 in drinking water) enhanced natriuresis in CHF rats and both natriuresis and kaliuresis in controls. When SCH 34826 and captopril were combined, natriuresis was potentiated in control rats as compared with captopril alone; in rats with CHF, however, a brisk kaliuresis was seen. The excretion of cyclic guanosine monophosphate was enhanced in CHF rats by 52% during treatment with SCH 34826 but not with captopril or combination of the two drugs. Moreover, captopril suppressed aldosterone excretion both in CHF rats and controls when administered alone but not when combined with SCH 34826.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Dioxolanes; Dipeptides; Drug Therapy, Combination; Heart Failure; Kidney; Male; Neprilysin; Rats; Rats, Wistar

Heart failure is usually characterized by a relative insensitivity to atrial natriuretic factor (ANF). Downregulation of ANF receptors has been reported but remains controversial. Renal response to ANF infusion, glomerular ANF receptors, and guanosine 3',5'-cyclic monophosphate (cGMP) production have been studied in rabbits with congestive heart failure (CHF) after traumatic aortic regurgitation and abdominal aortic stenosis. Diuresis and natriuresis induced by ANF infusions were significantly decreased in CHF animals. Plasma cGMP was higher in CHF rabbits before ANF administration than in controls (37.6 +/- 7.2 vs. 17.1 +/- 3.9 pmol/ml, P < 0.02) and increased to a same level after ANF in both groups (48.8 +/- 4.2 vs. 52.5 +/- 2.8 pmol/ml, NS). No difference was found in glomerular ANF receptor density (436 +/- 54 vs. 425 +/- 57 fmol/mg protein, NS) nor in affinity between the two groups (dissociation constant; 240 +/- 24 vs. 347 +/- 49 pM, NS). Moreover, in vitro glomerular cGMP production in response to exogenous ANF was preserved. In conclusion, despite a blunted renal response to ANF in vivo, glomerular ANF receptors were unchanged in this model, and no defect in cGMP production in response to ANF was found. This suggests the existence of an intracellular defect beyond the second messenger.

Topics: Animals; Atrial Natriuretic Factor; Binding, Competitive; Cyclic GMP; Female; Heart Failure; Hemodynamics; Kidney; Kidney Glomerulus; Rabbits; Receptors, Atrial Natriuretic Factor

The effects of a selective neutral endopeptidase inhibitor, SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine), were determined in an experimental model of heart failure.. The symptoms of heart failure were induced by rapid ventricular pacing for one or three weeks in dogs with surgically implanted catheters for measurement of atrial pressures and mean arterial pressure and with ultrasonic flow probes for determination of cardiac output and renal blood flow.. Inhibition of neutral endopeptidase by 10, 30, or 100 mumol.kg-1 SQ 28,603 given intravenously increased sodium excretion, cyclic GMP excretion, and plasma concentrations of atrial natriuretic peptide in a dose related manner in conscious dogs paced for one week. SQ 28,603 (100 mumol.kg-1) stimulated similar natriuretic and cyclic GMP responses in dogs paced for three weeks although baseline glomerular filtration rate was reduced. Because the natriuresis was maintained despite the smaller filtered sodium load, the increase in fractional sodium excretion was significantly greater after three weeks of pacing (from 0.5(0.2) to 3.7(0.7)%) than after one week of tachycardia (from 0.1(0.0) to 2.0(0.3)%). By contrast, SQ 28,603 (100 mumol.kg-1) did not affect renal, haemodynamic, or hormonal variables in normal conscious dogs where baseline atrial natriuretic peptide (18(3) fmol.ml-1) was lower than in the paced animals (104(10) fmol.ml-1).. Inhibition of neutral endopeptidase in dogs with pacing induced heart failure protected endogenous atrial natriuretic peptide from degradation and stimulated sustained natriuresis, presumably via a tubular mechanism.

Topics: Alanine; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Kidney; Male; Natriuresis; Neprilysin; Protease Inhibitors; Urine

The state of the vasodilator systems in congestive heart failure is poorly defined. Plasma atrial natriuretic peptide is increased, whereas endothelium derived relaxing factor activity can be decreased. Atrial natriuretic peptide and endothelium derived relaxing factor both cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP), by activating the particulate and the soluble guanylate cyclase, respectively. This study examines the biological effects of atrial natriuretic peptide and endothelium derived relaxing factor in experimental heart failure by assessing the plasma, urinary, and tissue concentrations of their common second messenger cGMP.. Myocardial infarctions (n = 31) were induced and sham operations (n = 25) were performed on Wistar rats, and the rats were monitored for three months. Aortic and pulmonary cGMP contents were measured, as the aorta is mainly matrix and smooth muscle cells, and the lung is particularly rich in capillaries, hence in endothelial cells. The concentrations of the other second messenger cyclic adenosine monophosphate (cAMP) was also determined, as were those of cGMP dependent protein kinase in the arteries.. 17 of the 31 rats with myocardial infarction had oedema. The total heart weight to body weight ratio and the ratio of the myocardium haemodynamically upstream from the infarcted left ventricle to body weight were increased in proportion to the infarct size. Plasma atrial natriuretic peptide and plasma and urinary cGMP concentrations were increased in proportion to the degree of heart failure (p < 0.0001). The pulmonary cGMP concentration was significantly higher in the rats with myocardial infarction than in the control group (p < 0.0001). Pulmonary cGMP concentrations were correlated with the plasma concentrations of atrial natriuretic peptide and cGMP (r2 = 0.59 and 0.66 respectively, p < 0.0001). The cGMP, cAMP, and cGMP, and cGMP dependent kinase concentrations in the aortic wall of rats with myocardial infarctions were the same as in control rats.. The increase in plasma, urinary, and pulmonary cGMP in rats with myocardial infarctions were highly correlated with the increase in circulating atrial natriuretic peptide. By contrast, the aortic cGMP concentration was unchanged in these rats, despite high plasma atrial natriuretic peptide. In congestive heart failure, a discrepancy seems to exist between pulmonary (mainly endothelium) and aortic wall (mainly smooth muscle cells) cGMP.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Heart Failure; Male; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.

Topics: Absorption; Animals; Cardiac Output, Low; Cardiovascular System; Constriction; Cyclic GMP; Dogs; Glomerular Filtration Rate; Heart Failure; Kidney Tubules; Male; Natriuresis; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Renal Circulation; Sodium; Thorax; Vena Cava, Inferior

Low output heart failure induces abnormalities of endothelium dependent vasodilation, but the mechanisms responsible for this remain unclear. As blood flow can alter endothelial cell function, in particular nitric oxide (NO) release, the activity of endothelium derived relaxing factor (EDRF) was investigated in a rat model of high output heart failure.. The thoracic aorta upstream of an aorto-caval fistula in rats was submitted to hormonal changes (similar to those in heart failure) and to high blood flow (opposite to that found in low output heart failure). Functional and biochemical arterial properties were studied in aorto-caval fistula rats and in sham operated rats three months after operation. The vascular responses were studied by exposing aortic segments from fistula and sham operated rats to increasing concentrations of agonists. Aortic cyclic guanosine monophosphate (cGMP) concentration was assessed as an index of NO synthase activity. The effect of NO synthase blockade on functional and biochemical arterial properties was also studied.. Plasma atrial natriuretic factor (ANF) was increased in fistula rats compared to sham operated rats. The concentrations of acetylcholine or the calcium ionophore A23187 required to produce 10% and 50% maximum relaxation (EC10 and EC50) were similar in the two groups. Relaxation in response to low concentrations of Sin-1 (an NO donor) was shifted rightwards in fistula rats and EC10 was greater than in the controls. The aortic cGMP concentration was higher in aorto-caval fistula rats than in sham operated rats (p = 0.008). The differences between aorto-caval fistula rats and sham operated rats were probably the result of increased basal EDRF-NO release in the former, since NO synthase blockade abolished the differences in both aortic cGMP and the dose-response curve to Sin-1.. The arterial wall upstream of a chronic aorto-caval fistula has increased cGMP content and hyposensitivity to Sin-1, which may be due to enhanced basal EDRF-NO release. These changes, strikingly different from those found in the low output heart failure, suggest that haemodynamic rather than neuroendocrine factors play a determinant role in the altered vasodilator response in heart failure.

Topics: Acetylcholine; Animals; Atrial Natriuretic Factor; Calcimycin; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Failure; Male; Molsidomine; Nitric Oxide; Rats; Rats, Wistar; Vasodilation

Alterations in myocardial function and systemic vascular tone are well documented in congestive heart failure (CHF), but little information is available on the effects of CHF on pulmonary vessels. We examined the mechanisms of tone regulation of canine pulmonary arteries during pacing-induced CHF.. Rings 3-4 mm wide from lobar pulmonary arteries were prepared from normal dogs, dogs paced at 210 beats per minute for 3 weeks (paced group, nonfailure), and dogs also paced at 240 beats per minute during the fourth week to induce severe heart failure (CHF group). Contractile responses to 60 mmol/L KCl and phenylephrine and relaxation responses to acetylcholine, bradykinin (endothelium-dependent cyclic GMP [cGMP]-mediated), isoproterenol, arachidonic acid, prostacyclin (receptor-dependent cyclic AMP [cAMP]-mediated), forskolin (direct stimulator of adenylate cyclase), a forskolin analogue (devoid of adenylate cyclase-dependent activity), and RO 20-1724 (phosphodiesterase inhibitor) were characterized. The paced group did not show alterations in vascular reactivity. Contractile response to phenylephrine and cGMP-mediated relaxation responses were not altered in the CHF group; however, receptor-mediated cAMP-induced relaxation responses were significantly inhibited (p < 0.05). Relaxation responses to isoproterenol (10(-6) mol/L), arachidonic acid (10(-5) mol/L), and prostacyclin (10(-5) mol/L) were reduced by 56%, 72%, and 74%, respectively. The relaxation response to RO 20-1724 was not affected by CHF, and this probe did not enhance the impaired relaxation response to isoproterenol. Forskolin-induced relaxation was not altered, and the forskolin analogue produced minimal relaxation compared with forskolin.. These findings suggest that in pacing-induced CHF, canine pulmonary arteries show a selective defect in receptor coupling to cAMP-dependent relaxation mechanisms. There is no evidence of enhanced degradation of cAMP.

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Colforsin; Cyclic AMP; Cyclic GMP; Dogs; Heart; Heart Failure; Myocardial Contraction; Phosphodiesterase Inhibitors; Pulmonary Artery; Receptors, Cell Surface; Vasodilation

Plasma levels of cyclic nucleotides were determined by radioimmunoassay in 196 cardiac patients and 50 normal persons. Plasma levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increased with the deterioration of cardiac function. The level of cGMP was correlated with the cardiothoracic ratio, ratio of pre-ejection period and left ventricular ejection time, the intracardiac diameter, left ventricular ejection fraction and left ventricular short axis shortening (r = 0.55, r = 0.50, r = 0.55, r = -0.53 and r = -0.50, respectively; P < 0.001). There were only weak correlations between the level of cAMP and the cardiothoracic ratio, the ratio of pre-ejection period and the left ventricular ejection time, left ventricular ejection fraction, and left ventricular short axis shortening (r = 0.35, r = 0.38, r = -0.28 and r = -0.31, respectively; P < 0.01). The correlations between cGMP and mean pulmonary artery pressure (r = 0.48; P < 0.05) and mean left atrial pressure (r = 0.55; P < 0.01) were also significant. In patients who had received cardioversion and valve replacement the plasma cGMP level decreased significantly. During the follow-up period, 29 of 108 patients died (26.9%), the initial plasma levels of cAMP and cGMP in the dead group were significantly higher than those in the survival group (27.41 +/- 1.13 and 31.11 +/- 3.33 vs. 21.56 +/- 0.60 and 17.45 +/- 1.05 nmol/l, respectively; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Heart Function Tests; Humans; Least-Squares Analysis; Male; Prognosis; Severity of Illness Index; Survival Analysis

We assayed the concentrations of atrial natriuretic factor and guanosine 3',5'-phosphate in the plasma and urine of six healthy subjects, 12 patients with coronary artery disease and 11 patients with congestive heart failure. Patients with coronary artery disease had normal levels of atrial natriuretic factor in the plasma and urine and a normal excretion of guanosine 3',5'-phosphate, while those with congestive heart failure had a raised level of atrial natriuretic factor in the plasma, an increased excretion of 3',5'-guanosine phosphate and normal excretion of atrial natriuretic factor. Thus, measurement of atrial natriuretic factor in the urine can not replace the assay of the peptide in plasma.

Topics: Aged; Atrial Natriuretic Factor; Coronary Disease; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Reference Values

The systemic hemodynamic, renal and hormonal responses to SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine) the selective inhibitor of neutral endopeptidase 3.4.24.11, the angiotensin-converting enzyme inhibitor captopril and their combination were determined in conscious dogs after 1 or 3 weeks of rapid ventricular pacing. Coadministration of captopril (100 or 10 mumol/kg i.v.) and SQ 28,603 (10 mumol/kg i.v.) significantly reduced mean arterial pressure, systemic vascular resistance and renal vascular resistance and increased cardiac output, stroke volume and renal blood flow in the conscious dogs paced for 1 week. This pattern of hemodynamic improvement was not predicted by the activity of the individual inhibitors. The combination of inhibitors did not significantly increase sodium excretion because of the variability introduced by the depressor activity; however, the pressure-natriuresis curve was steeper and shifted leftward, indicating that sodium excretion was maintained at lower renal perfusion pressures. The increases in urinary and plasma levels of cyclic GMP and atrial natriuretic peptide stimulated by SQ 28,603 were not affected by captopril. The data indicated that the hemodynamic and renal responses produced by SQ 28,603, presumably by elevating atrial natriuretic peptide levels, were enhanced by suppression of angiotensin II or that the combination of inhibitors protected other vasodilator/natriuretic peptides from degradation. Qualitatively similar responses to SQ 28,603, captopril and the combination of inhibitors were obtained in dogs paced for 3 weeks. In summary, the combined angiotensin-converting enzyme and neutral endopeptidase 3.4.24.11 inhibitors improved systemic hemodynamics and maintained renal function in conscious dogs with pacing-induced heart failure.

Topics: Alanine; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Captopril; Cardiac Pacing, Artificial; Cyclic GMP; Dogs; Female; Heart Failure; Hemodynamics; Kidney; Male; Neprilysin; Renin

The aortocaval fistula is a classic model of pure cardiac volume overload in rats. This model is characterized by dilation of the ventricular cavities and eccentric cardiac hypertrophy. There are also changes in peripheral arterial flow: high flow in the proximal part of the aorta, upstream of the shunt, and low flow in the distal aorta, downstream of the shunt. The chronic effects of converting enzyme inhibition in this model of volume overload have not yet been measured. We tested the effect of blood pressure and flow on cardiac mass and aortic dilatory pathway in normotensive Wistar and spontaneously hypertensive rats (SHR) with an aortocaval fistula. One half of the sham-operated rats and the normotensive and hypertensive rats with aortocaval fistulas were treated for 1 month with perindopril (2 mg/kg by daily gavage). Urine and plasma were collected at death, the heart was weighed, and the proximal (thoracic) and distal (abdominal) aortas were quickly removed and frozen in liquid nitrogen for measurement of cyclic guanosine monophosphate (cGMP). Blood pressure was always higher in SHR than in Wistar rats, in sham-operated rats than in those with aortocaval fistulas, and in untreated than in perindopril-treated rats. Similarly, the heart weight/body weight ratio was higher in SHR than in Wistar rats, in those with aortocaval fistulas than in sham-operated rats, and in untreated than in Wistar rats, in those with aortocaval fistulas than in sham-operated rats, and in untreated than in perindopril-treated rats. The aortocaval fistula increased the plasma atrial natriuretic factor and perindopril reduced it.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aorta, Thoracic; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Indoles; Male; Myocardium; Organ Size; Perindopril; Rats; Rats, Inbred SHR; Rats, Wistar

1. The pericardial fluid of 20 open heart surgery patients with acquired heart disease was analysed for atrial natriuretic peptide by radioimmunoassay. 2. The concentration of atrial natriuretic peptide in the pericardial fluid was significantly higher than in the corresponding plasma (316.8 +/- 50.0 versus 121.7 +/- 29.1 pg/ml; P < 0.01) and was higher in patients with congestive heart failure than in those without heart failure (469.3 +/- 78.6 versus 181.8 +/- 26.7 pg/ml; P < 0.001). Pericardial and plasma atrial natriuretic peptide concentrations showed a significant positive correlation. Pericardial fluid and plasma samples were fractionated using both reverse-phase high-performance liquid chromatography and gel permeation chromatography. Each fraction was assayed for atrial natriuretic peptide by radioimmunoassay, revealing the presence of beta-atrial natriuretic peptide as well as alpha- and gamma-atrial natriuretic peptide. 3. The pericardial fluid concentration of cyclic GMP, the intracellular second messenger for atrial natriuretic peptide, was significantly higher in patients with congestive heart failure than in patients without heart failure.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Diseases; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pericardium

To evaluate the role of endogenous atrial natriuretic peptide (ANP) in patients with congestive heart failure (CHF), the relationship between plasma ANP and cyclic guanosine monophosphate (cGMP) levels and the prognosis of patients with CHF was examined. In patients with chronic mild to moderate CHF, there was a positive correlation between plasma ANP and cGMP levels (r = 0.81, p less than 0.001). However, there was no significant correlation between these plasma levels in patients with chronic severe CHF, in whom the cGMP concentration reached a plateau in spite of high levels of ANP. The ANP extraction level and the cGMP production level in the pulmonary and systemic circulation correlated significantly in patients with mild CHF. In contrast, there was no significant correlation between the 2 parameters in patients with severe CHF, and the molar ratios of cGMP production to ANP extraction in the pulmonary and systemic circulation were significantly lower than those in patients with mild CHF. In 44 patients with chronic severe CHF who were followed up over 2 years, plasma ANP levels provided more sensitive and specific prognostic information than any other parameters. These results indicate that ANP receptors coupled to guanylate cyclase may be down-regulated in patients with chronic severe CHF, suggesting that high plasma ANP levels as a prognostic predictor may be associated with limitations of compensation by endogenous ANP.

Topics: Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Follow-Up Studies; Heart Failure; Humans; Prognosis; Pulmonary Artery; Regression Analysis; Second Messenger Systems; Sensitivity and Specificity

Circulating concentrations of human atrial natriuretic peptide (hANP) are elevated in patients with heart failure; however, the natriuretic effect of hANP is blunted in these patients. In this study, the relationship between urinary cGMP, the second messenger for the natriuretic effect of hANP in vivo, and endogenous hANP was examined in six patients with heart failure and four normal subjects. In addition, right heart catheterization for the determination of central hemodynamics was performed in the heart failure patients. The heart failure patients were in New York Heart Association Classes II to IV and were receiving no medications at the time of the study. Supine plasma hANP and urinary cGMP concentrations were determined on two occasions in each subject, as were right and left atrial pressures in the heart failure patients. At the time of study, the patients were in positive sodium balance, and control subjects were in normal sodium balance. Plasma hANP and urinary cGMP excretion rates were elevated in heart failure patients as compared with those in controls: hANP, 139.0 +/- 42.0 versus 22.0 +/- 6.1 pg/mL (P less than 0.05); urinary cGMP, 1.14 +/- 0.31 versus 0.35 +/- 0.05 nmol/min (P less than 0.05). In heart failure patients, right atrial pressure correlated positively with plasma hANP (r = 0.96; P less than 0.01) and urinary cGMP concentrations (r = 0.93; P less than 0.05) and the excretion rate (r = 0.92; P less than 0.05). Moreover, plasma hANP was strongly correlated with urinary cGMP concentration (r = 0.91; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuresis; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

This study was designed to evaluate the role of endogenous atrial natriuretic peptide in the pulmonary circulation in patients with chronic heart failure.. Plasma atrial natriuretic peptide concentrations in patients with heart failure have been reported to be higher than those in normal subjects and to increase as the severity of heart failure progresses. Although endogenous atrial natriuretic peptide is thought to improve the condition of patients with heart failure by reducing preload and afterload, recent findings have indicated that a high plasma atrial natriuretic peptide level is a prognostic predictor in patients with heart failure.. To evaluate the pathophysiologic role of endogenous atrial natriuretic peptide in the pulmonary circulation, plasma atrial natriuretic peptide and cyclic guanosine monophosphate (cGMP) levels were determined in the main pulmonary artery and pulmonary capillary wedge region in 80 patients with chronic congestive heart failure (New York Heart Association functional classes II to IV).. The plasma atrial natriuretic peptide level decreased significantly from the main pulmonary artery to the pulmonary capillary wedge region, whereas the plasma cGMP level increased significantly from the main pulmonary artery to the pulmonary capillary wedge region. In patients with mild chronic heart failure (n = 50), the plasma atrial natriuretic peptide level correlated with the cGMP level in the main pulmonary artery (gamma = 0.71, p less than 0.001). The atrial natriuretic peptide extraction level, calculated as (Atrial natriuretic peptide in the main pulmonary artery--Atrial natriuretic peptide in the pulmonary capillary wedge region) x Cardiac output x (1-hematocrit/100) (ng/min), also correlated with the cyclic guanosine monophosphate production level, calculated as (cGMP in the pulmonary capillary wedge region--cGMP in the main pulmonary artery) x Cardiac output x (1-hematocrit/100) (nmol/min) (gamma = 0.78, p less than 0.001). In contrast, such correlations were not found in patients with severe chronic heart failure (n = 30). In these patients, the atrial natriuretic peptide extraction level was significantly higher but there was no significant difference in the cGMP production level between the two groups (mild and severe chronic heart failure). Therefore, the molar ratio of cGMP production to atrial natriuretic peptide extraction in the pulmonary circulation was significantly lower in patients with severe chronic heart failure (88 +/- 16 vs. 480 +/- 41, p less than 0.001).. These results indicate that down-regulation of atrial natriuretic peptide receptors coupled to guanylate cyclase may occur in the pulmonary vascular beds of patients with severe chronic heart failure.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Artery; Pulmonary Circulation

1. The acute hormonal, renal and haemodynamic effects of SCH 39370, a new neutral endopeptidase (NEP) inhibitor, were evaluated in rats with congestive heart failure (CHF) produced by coronary ligation. 2. Left ventricular systolic pressure and left ventricular end diastolic pressure were significantly decreased by SCH 39370 treatment. 3. SCH 39370 improved cardiac function by increasing cardiac index and decreasing total peripheral resistance. 4. SCH 39370 induced a transient but significant diuresis and natriuresis. 5. These effects were associated with significant increases in urinary atrial natriuretic peptide (ANP) and cyclic GMP excretion, but not with an increase in plasma ANP levels. 6. The results suggest that NEP inhibition may be a new therapeutic method for treating CHF possibly by potentiating the biological activities of endogenous ANP.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Cyclic GMP; Dipeptides; Female; Heart Failure; Hemodynamics; Kidney; Pharmaceutical Vehicles; Protease Inhibitors; Rats; Rats, Inbred Strains; Vascular Resistance; Ventricular Function, Left

The purpose of this study was to evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) as a pulmonary artery vasodilator in patients with acute respiratory failure receiving artificial ventilation. Twenty-one consecutive patients were studied, 12 without and 9 with preexisting cardiopulmonary disease. Pulmonary artery plasma ANP levels were significantly higher than the levels obtained in the superior vena cava and radial artery. Plasma ANP levels correlated significantly with the plasma levels of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP). In the 12 patients without prior cardiopulmonary disease, plasma ANP levels correlated significantly with mean pulmonary arterial pressure (MPAP). This correlation was not found in the nine patients with preexisting cardiopulmonary disease. The cGMP/ANP ratio, indicating the biologic effect of ANP, was also higher in the patients without preexisting cardiopulmonary disease. These results are compatible with clearance and vasodilator activity of ANP in the pulmonary vascular bed, but only in patients without preexisting cardiopulmonary disease.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Failure; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Radial Artery; Respiration, Artificial; Respiratory Insufficiency; Vena Cava, Superior

The relationship between plasma levels of cyclic nucleotides and mortality was studied in 108 patients with congestive heart failure (CHF) in whom plasma cAMP and cGMP, were determined by radioimmunoassay and were followed-up for 36 to 48 months. 29 patients died. The plasma concentrations of cAMP and cGMP in the dead group were significantly higher than those in the survival group (27.41 +/- 6.11 and 31.11 +/- 18.23 vs 21.56 +/- 5.37 and 17.45 +/- 9.35 nmol/L, respectively, mean +/- s, P < 0.001). Compared with patients with cAMP concentrations below the median value of 22.31 nmol/L, those with higher levels of cAMP had a higher mortality rate (46.3% vs 7.4%, P < 0.001). Patients with cGMP levels above the median value of 17.24 nmol/L also had a higher mortality rate than those with lower levels (40.7% vs 13.0%, P < 0.01). Multivariate stepwise regression analysis including age, cardiac function classification, heart rate, serum potassium and sodium, plasma cAMP, cGMP and cAMP/cGMP was carried out and revealed that only plasma cAMP and cGMP could provide independent prognostic information. Thus plasma levels of cyclic nucleotides was considered the excellent predictor for patients with CHF.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Regression Analysis

We have described five phosphodiesterase (PDE) isozymes that can be found in cardiac and vascular smooth muscle of animals and humans. Much of the evidence for the role that these isozymes have in the regulation of cellular processes has been generated through, or awaits, the identification of selective and potent PDE inhibitors. While selective inhibitors of the cGMP-inhibitable (cGi)-PDE isozyme have been approved for use in the acute treatment of heart failure, selective inhibitors of the cGMP-PDE have not been extensively explored as potential candidates for the treatment of cardiovascular diseases. More potent selective inhibitors of the cGMP-PDE isozyme are needed to determine whether these pharmacological potentiators of EDRF and ANP will be useful in the therapy of angina, hypertension or heart failure.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Humans; Isoenzymes; Kinetics; Milrinone; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Infarction; Myocardium; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyridones; Rats

The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Pressure; Cattle; Cyclic GMP; Dipeptides; Diuresis; Female; Furosemide; Heart Failure; Hemodynamics; Injections, Intravenous; Natriuresis; Neprilysin

The pharmacokinetics of synthetic atrial natriuretic factor (ANF) and its effects on cyclic GMP, urinary sodium excretion, and hemodynamics were compared in 18 control subjects with normal hemodynamics and 12 patients with severe heart failure. Human 99-126 ANF was administered intravenously (0.2 micrograms/kg i.v. followed by 0.07 micrograms/kg/min for 30 min). As compared with controls, baseline plasma ANF concentration was higher in the heart failure group (329.2 +/- 166.1 vs. 33.6 +/- 17.3 pg/ml in controls, means +/- SD, p less than 0.01). Synthetic ANF increased plasma ANF concentration by similar amounts, but the elimination half-life (t 1/2) for synthetic ANF was longer in the heart failure group (6.5 +/- 2.6 vs. 3.8 +/- 0.8 min, p less than 0.05). Baseline plasma cyclic GMP concentration was higher in the heart failure group (13.8 +/- 6.8 vs. 4.2 +/- 2.2 pmol/ml, p less than 0.01) but ANF increased plasma cyclic GMP concentration to a lesser degree (14.4 +/- 7.6 pmol/ml, p less than 0.05 vs. 24.9 +/- 10.1 pmol/ml, p less than 0.001). Baseline urinary sodium excretion was less in the heart failure group (13.3 +/- 14.0 vs. 53.7 +/- 37.3 mumol/min, p less than 0.01) and ANF induced a smaller increase in urinary sodium excretion (22.1 +/- 32.3 mumol/min, p less than 0.05 vs. 305.7 +/- 242.9 mumol/min, p less than 0.001). Baseline plasma norepinephrine (NE), renin, and aldosterone were higher in the heart failure group. Synthetic ANF increased plasma NE only in the control group, had no effect on renin, and decreased aldosterone in both groups. Hemodynamic responses were similar in both groups except the decreased arterial blood pressure (BP) was accompanied by increased heart rate (HR) only in the controls. Therefore, in heart failure, the t 1/2 of ANF is prolonged and there appears to be a limit for further increase in cyclic GMP. These changes may explain in part the blunted renal response to ANF.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Electrocardiography; Heart Failure; Heart Rate; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Norepinephrine; Renin; Sodium

Sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was examined in microsomes prepared from the left ventricular myocardium of eight heart transplant recipients with end-stage idiopathic dilated cardiomyopathy and six unmatched organ donors with normal cardiac function. At cAMP concentrations less than or equal to 1.0 microM, sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was functionally homogeneous. cAMP phosphodiesterase activity was inhibited competitively by cGMP (Ki = 0.031 +/- 0.008 microM) and the cilostamide derivative OPC 3911 (Ki = 0.018 +/- 0.004 microM), but was essentially insensitive to rolipram. Vmax and Km were 781.7 +/- 109.2 nmol/mg per min and 0.188 +/- 0.031 microM, respectively, in microsomes prepared from nonfailing hearts and 793.9 +/- 68.9 nmol/mg per min and 0.150 +/- 0.027 microM in microsomes prepared from failing hearts. Microsomes prepared from nonfailing and failing hearts did not differ with respect to either the ratio of cAMP phosphodiesterase activity to ATP-dependent Ca2+ accumulation activity or the sensitivity of cAMP phosphodiesterase activity to inhibition by OPC 3911. These data suggest that the diminished inotropic efficacy of phosphodiesterase inhibitors in failing human hearts does not result from changes in the level, kinetic properties, or pharmacologic sensitivity of sarcoplasmic reticulum-associated cAMP phosphodiesterase activity.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adult; Calcium; Cardiomyopathy, Dilated; Cyclic GMP; Heart Failure; Humans; Kinetics; Middle Aged; Myocardium; Sarcoplasmic Reticulum

Plasma levels of atrial natriuretic factor are increased in chronic heart failure; however, it is still controversial whether these raised levels contribute to the diuresis and natriuresis in this setting. To address this issue the potential contribution of endogenous atrial natriuretic factor in the renal excretion of a moderate oral sodium load in a rat model of chronic heart failure was studied.. A monoclonal antibody against atrial natriuretic factor was used for specific antagonisation of its in vivo effects. Animals were subjected to oral sodium loading (30 ml.kg-1 0.9% NaCl, 2.5% dextrose) at baseline, immediately after, and 5 d after injection of monoclonal antibody or control solvent.. Sham operated rats and rats with chronic heart failure due to myocardial infarction (infarct size 35(SEM 4)% of left ventricle) were studied 4-5 weeks after surgery.. The renal excretion of cyclic guanosine monophosphate (cGMP), which represents a specific marker for the activation of the atrial natriuretic factor system, was markedly increased in infarcted rats, at 17.9(SEM 3.4) vs 5.8(1.2) nmol.kg-1, p less than 0.01. Atrial natriuretic factor antibody given immediately before sodium loading reduced the natriuretic response (0-4 h period) in infarcted rats from 1270(171) to 805(76) mumol.kg-1 (p less than 0.01) but not in sham operated animals. Similarly, the excretion of cGMP was only decreased by atrial natriuretic factor antibody in infarcted rats, from 29.8(6.3) to 20.7(3.7) nmol.kg-1. The reduction in sodium and cGMP excretion in infarcted rats was confirmed with a purified antibody preparation.. Endogenous atrial natriuretic factor appears to be involved in the natriuresis following a moderate oral volume load in chronic heart failure. Thus the raised concentrations found in chronic heart failure may contribute to the regulation of urinary sodium excretion under these conditions despite the fact that the diuretic effects of exogenous atrial natriuretic factor are attenuated in chronic heart failure.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Male; Myocardial Infarction; Natriuresis; Potassium; Rats; Sodium

In eight patients (63 +/- 7.9 years) with angiographically documented dilated cardiomyopathy, we studied the acute effects of a beta-adrenergic stimulation with dobutamine on the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP). For this purpose, a four-point dose-response curve was prepared for dobutamine starting with an initial dose of 2.5 micrograms kg-1 min-1, which was increased by 2.5 micrograms kg-1 min-1 at a time up to altogether 10 micrograms kg-1 min-1. Each stage lasted 15 min. ANP and cGMP were determined from the mixed venous blood before the start (t0), at 5 micrograms kg-1 min-1 after 30 min (t1), at 10 micrograms kg-1 min-1 after 60 min (t2) and after subsidence of the drug effect after 90 min (t3). ANP dropped from 380 +/- 151 pg ml-1 (normal range up to 55 pg ml-1) by 38% to 235 +/- 90 pg ml-1 after 30 min and by another 17% to 171 +/- 45 pg ml-1 after 60 min. After the effect of dobutamine had subsided, an increase by 41% to 325 +/- 139 was reached. There was a parallel drop of the mean cGMP level from 5.4 +/- 1.4 pmol.ml-1 by 28% to 3.89 +/- 1.4 pmol.ml-1 (30 min) and by another 14% to 3.2 +/- 0.7 pmol.ml-1 (60 min). After 90 min it was 18% below the initial value, being 4.4 +/- 1.3 pmol.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Dobutamine; Dose-Response Relationship, Drug; Heart Failure; Hemodynamics; Humans; Male; Middle Aged

We studied the hormonal, renal and hemodynamic effects of prolonged treatment with SCH 39370, a new neutral endopeptidase (NEP) inhibitor, in experimental congestive heart failure (CHF). Coronary-ligated CHF rats and sham-operated controls received vehicle or SCH 39370 30 mg/kg s.c. twice daily for six days. In rats with heart failure, SCH 39370 elevated the high plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) levels 2-fold both initially and at the end of the experiment. Initially, water balance was more negative in SCH 39370-treated CHF rats than in those treated with vehicle. In all SCH 39370-treated rats, ANP, cGMP and electrolyte excretion and diuresis were pronounced for 6 h after injection but attenuated thereafter. Blood pressure and pulse remained unchanged. On reverse phase high performance liquid chromatography (HPLC), ANP-(99-126) appeared to be the only circulating form of ANP in rats with heart failure. Three forms have been discovered in patients with heart failure. HPLC revealed only intact ANP in plasma of rats with heart failure during SCH 39370 treatment. NEP inhibitors may provide a new tool for treating chronic heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Cyclic GMP; Dipeptides; Endopeptidases; Heart Failure; Hemodynamics; Kidney; Kidney Function Tests; Male; Metalloendopeptidases; Protease Inhibitors; Pulse; Rats; Rats, Inbred Strains; Renin; Water-Electrolyte Balance

Rats with chronic aortocaval (AV) fistula, an experimental model of congestive heart failure, display high plasma levels of atrial natriuretic factor (ANF) and a blunted natriuretic response to ANF infusion. We previously reported that rats with AV fistula either develop progressive sodium retention (urinary sodium excretion, UNaV less than 100 microeq/24 h) or compensate (UNaV greater than 1,200 microeq/24 h). To gain further insight into the mechanism of renal hyporesponsiveness to ANF, we evaluated the effect of ANF on renal guanosine 3',5'-cyclic monophosphate (cGMP) production in sham-operated control rats and in the two groups of rats with AV fistula. Infusion of synthetic ANF-(99-126) (at either 10 or 50 micrograms.kg-1.h-1) resulted in a reduced fractional sodium excretion (P less than 0.05) in both compensated rats (0.7 +/- 0.2 and 7.9 +/- 1.6%) and sodium-retaining rats (0.3 +/- 0.1 and 0.5 +/- 0.1%) compared with controls (8.5 +/- 1.2 and 13.7 +/- 2.3% for low and high doses, respectively). Similarly, urinary cGMP excretion corrected by glomerular filtration rate (UcGMPV/GFR) during low-dose ANF infusion was significantly reduced (P less than 0.05) in both groups with AV fistula (compensated: 39 +/- 10 pmol/ml; sodium-retaining: 55 +/- 13 pmol/ml) compared with controls (115 +/- 16 pmol/ml). During high-dose ANF infusion, compensated rats, but not sodium-retaining rats, displayed a significant increase in UcGMPV/GFR. The differences in UcGMPV/GFR are probably not due to variations in urine flow because furosemide infusion to a separate group of rats with AV fistula increased urine flow approximately eightfold but did not increase UcGMPV/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Dose-Response Relationship, Drug; Heart Failure; Kidney; Male; Rats; Rats, Inbred Strains

The renal and hormonal effects of atrial natriuretic peptide given as a bolus injection (2.0 micrograms/kg) were studied in 12 patients with congestive heart failure before and after treatment with captopril for 4 weeks and in 13 healthy control subjects. Atrial natriuretic peptide caused a rise in urinary excretion of sodium and urinary flow in the controls, whereas no increases were observed in the patients. Both proximal and distal fractional reabsorption of sodium, as evaluated by the lithium clearance technique, decreased less in the patients than in the controls. Basal plasma concentrations of atrial natriuretic peptide and cyclic guanosine monophosphate (cGMP), and the basal urinary excretion of cGMP, were elevated in the patients. The increases in both plasma and urinary cGMP after administration of atrial natriuretic peptide were blunted in heart failure. Basal glomerular filtration rate and renal plasma flow were reduced, and filtration fraction increased, in the patients. A positive correlation (r = 0.958, P less than 0.01) was found between renal plasma flow and the relative increase in urinary excretion of sodium in the patients with heart failure. Treatment with captopril did not improve the natriuretic and diuretic effect of exogenous atrial natriuretic peptide, but resulted in an increase in filtration fraction after administration of atrial natriuretic peptide not present before captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Captopril; Cyclic GMP; Diuresis; Down-Regulation; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Male; Middle Aged; Natriuresis; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Renal Circulation; Renin-Angiotensin System

The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition.

Topics: Alanine; Angiotensin II; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Heart Failure; Hemodynamics; Kidney; Male; Neprilysin; Sodium

The aim of this prospective study was to investigate both vasoconstricting and vasodilating plasma hormones and plasma factors regulating the circulatory homeostasis in patients with endstage congestive heart failure before and early after orthotopic heart transplantation and to evaluate factors which may influence their regulation. 19 patients with endstage congestive heart failure were analyzed serially before and 3-4 weeks after orthotopic heart transplantation. A significant decrease in plasma concentrations of noradrenaline (457 +/- 202 vs. 204 +/- 88 pg/ml; p less than 0.001), adrenaline (43 +/- 32 vs. 26 +/- 11 pg/ml), atrial natriuretic peptide (341 +/- 218 vs. 139 +/- 64 pg/ml; p less than 0.005), cyclic guanosine monophosphate (13.8 +/- 7.8 vs. 6.6 +/- 2.2 pmol/ml, p less than 0.05) and in plasma renin activity (16.6 +/- 13.0 vs. 2.0 +/- 2.4 ng AI/ml/h; p less than 0.01) was found after transplantation. The data indicate that the marked increase in plasma catecholamine concentrations and renin activity in endstage congestive heart failure is reversible as early as 3-4 weeks after heart transplantation. This is most likely the consequence of normalization of cardiac function. While elevation of atrial natriuretic peptide and cyclic guanosine monophosphate as well as increased vasoconstrictor activity in heart failure appear to be related to impaired ventricular function, the persistent moderate elevation of both vasodilating agents after transplantation may be compensatory to counteract cyclosporin-induced arterial hypertension after heart transplantation.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Epinephrine; Female; Heart Failure; Heart Transplantation; Hormones; Humans; Male; Middle Aged; Norepinephrine; Prospective Studies; Renin; Vasoconstriction; Vasodilation

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Cyclic GMP; Endothelins; Heart Failure; Hematocrit; Humans; Renin

Topics: Aged; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Female; Heart Failure; Hemodynamics; Humans; Male; Peptide Fragments

Concentrations of atrial natriuretic peptide (ANP) are increased in plasma of patients with impaired cardiac and renal function. The second messenger of ANP, cyclic guanosine monophosphate (cGMP), is released into the plasma specifically upon stimulation of cells with ANP. Although nitrates can also activate intracellular cGMP synthesis, we detected no increase in plasma cGMP concentrations after infusions of glycerol trinitrate. Because immunoreactive ANP is highly susceptible to degradation and nonspecific influences in blood samples, determinations of ANP require immediate centrifugation and storage of plasma at -20 degrees C. In contrast, we found that cGMP is stable for five days in vitro in blood samples containing EDTA. In 147 healthy blood donors, the upper cutoff value for plasma cGMP was 6.60 nmol/L, not significantly different (P greater than 0.05) from that for 222 patients with disorders other than cardiovascular and renal. In 69 patients with manifest congestive heart failure (NYHA stages II-IV), 65 had increased cGMP values. Using the above cutoff value for cGMP gave diagnostic sensitivity of 94.2% and specificity of 93.7%. Plasma cGMP may thus provide an alternative for routine clinical measurements of ANP in cardiac diseases in the absence of renal disorders.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Radioimmunoassay; Reference Values; Sensitivity and Specificity; Specimen Handling

Previous studies have demonstrated that the biological actions of atrial natriuretic factor (ANF) are mediated via increases in its intracellular second messenger guanosine 3',5'-cyclic monophosphate (cGMP). Because cGMP egresses rapidly from target cells after ANF binding to particulate guanylate cyclase-linked receptors, extracellular cGMP may be a useful biological marker for the action of ANF in vivo under pathophysiological conditions. The present studies tested the hypothesis that the avid sodium retention and renal ANF resistance characteristic of chronic congestive heart failure (CHF) are associated with attenuated renal cGMP responses to ANF. We assessed the natriuretic and cGMP responses to endogenous and exogenous ANF during the evolution of CHF produced by 6 days of rapid ventricular pacing in conscious dogs (n = 6). Simultaneous measurement of plasma and urinary cGMP concentrations allowed determination of the net renal generation of cGMP, an indicator of the renal contribution to total urinary cGMP excretion. In early CHF, increased sodium excretion and renal cGMP production were observed in association with increases in plasma ANF. Exogenous ANF administration (10 micrograms/kg iv) before CHF also produced parallel increases in sodium excretion and renal cGMP production. In more advanced CHF produced by 6 days of pacing, we observed avid sodium retention in association with reversal of earlier increases in renal cGMP production despite progressive increases in circulating ANF. Natriuretic and renal cGMP responses to exogenous ANF were similarly attenuated in chronic CHF. These studies suggest that 1) renal cGMP production is a useful biological marker for the renal natriuretic action of ANF; 2) endogenous ANF contributes to the maintenance of sodium excretion in early CHF via increases in renal cGMP production; and 3) the avid sodium retention and renal ANF resistance in advanced CHF are, in part, linked to attenuated renal cGMP responses to endogenous and exogenous ANF.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Heart Failure; Kidney; Male; Natriuresis; Renin; Second Messenger Systems

Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115 +/- 268 to 498 +/- 173 ml/min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0 +/- 7.8 to 34.9 +/- 12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14 +/- 0.02 to 0.02 +/- 0.01 ml/min, P less than 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dogs; Heart Failure; Kidney; Lung; Metabolic Clearance Rate; Protease Inhibitors

The effect of pharmacological manipulation of atriopeptin (AP) activity on sodium excretion and blood pressure was examined in the rat aortovenocaval (A-V) fistula model of cardiac failure. Introduction of an A-V shunt led to a marked and sustained elevation of plasma AP immunoreactivity and urinary cGMP levels. Further elevation of plasma AP levels by infusion of exogenous peptide induced modest increases in urinary sodium and cGMP excretion and a decrease in blood pressure but these responses were significantly attenuated compared to sham-operated animals. In contrast, low-dose infusion of M + B 22948 (a cGMP phosphodiesterase inhibitor) or thiorphan [a neutral endopeptidase (membrane metallo-endopeptidase, EC 3.4.24.11) inhibitor] induced a natriuresis in A-V fistula rats, which exceeded that seen in control animals given these compounds and matched the peak natriuresis produced in sham-operated animals by high doses of AP. In the doses used, these compounds had little effect on blood pressure. The greater renal efficacy of M + B 22948 in A-V fistula rats is consistent with postreceptor facilitation of AP activity. The effect of thiorphan on sodium excretion was accompanied by a pronounced increase in urinary cGMP and AP immunoreactivity excretion (and was attenuated by anti-AP monoclonal antibody) but could not be explained solely in terms of an increase in circulating AP levels. It is proposed that thiorphan allows filtered AP to reach renal tubule sites that are normally inaccessible to the peptide and are thus protected from down-regulation by high circulating AP levels. The implication of these observations for patients in cardiac failure is the potential for using pharmacological agents to maximize the response to endogenous AP without compromising cardiac function.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Disease Models, Animal; Heart Failure; Male; Purinones; Rats; Rats, Inbred Strains; Reference Values; Sodium; Thiorphan

Thirty-seven patients with volume-retaining disorders (liver cirrhosis with ascites, n = 8; heart failure NYHA III-IV, n = 12; endstage renal failure, n = 17) and twelve healthy age-matched controls were given a small dose (33 micrograms) of hANF (human atrial natriuretic factor). We tested the resulting hemodynamic and renal effects as well as the effect on plasma cyclic GMP levels and compared them with the properties of platelet ANF receptors. The ANF injection evoked an increase in cyclic GMP plasma levels of 19.3 +/- 2.2 nM in healthy controls. This increase tended to be smaller in the cirrhosis group (15.5 +/- 3.3 nM) and in the heart failure group (16.8 +/- 2.3 nM) than in the dialysis group (20.5 +/- 2.5 nM). The invasion rates of cyclic GMP were comparable in all groups, but the evasion rates increased more in the heart failure and endstage renal failure groups (27.9 +/- 7.7 min and 26.1 +/- 3.4 min, respectively) than in the cirrhosis and control groups (14.9 +/- 1.9 min and 14.2 +/- 1.9 min, respectively). Patients with endstage renal failure and congestive heart failure showed a smaller decrease in diastolic blood pressure than controls and patients with liver cirrhosis. Renal actions of ANF were diminished in cirrhosis and heart failure patients. Binding capacities of platelet ANF receptors were higher in the control group (12.2 +/- 1.5 receptors/cell) than in the patient groups (cirrhosis, 7.8 +/- 1.2; endstage renal failure, 8.0 +/- 0.9; heart insufficiency, 8.0 +/- 1.0 receptors/cell), with no differences among the patient groups. Binding affinities were not significantly different. Correlation analysis showed that the relationship between the actions of ANF and the increases in plasma cyclic GMP levels is loose and cannot predict the hemodynamic or renal effects of exogenous ANF in a given patient. Although the behavior of plasma cyclic GMP levels fails to predict the responsiveness of the body to ANF in a given patient, it does reflect the differences between the patient groups and the control group. In contrast, we found no correlation between the properties of platelet ANF receptors and ANF action.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Platelets; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Recombinant Proteins; Water-Electrolyte Balance

STUDY OBJECTIVE--The aim was to investigate the relationship between urinary cyclic guanosine monophosphate (GMP) excretion and activation of the heart endocrine function in two rat models of cardiac failure. DESIGN--Left ventricular infarction and aging in spontaneously hypertensive rats (SHR) are two models that could lead to congestive heart failure. In the first the degree of failure depends on the length of the infarcted area. In the second the degree of failure depends on time. Urinary cyclic GMP, plasma atrial natriuretic factor (ANF), and degree of congestive heart failure were evaluated in both models. EXPERIMENTAL ANIMALS--31 male Wistar rats were used for myocardial infarction and sham operated controls. Spontaneously hypertensive (SHR) rats (2, 6, 12 and 24 months old, n = 10 per group) were used for the age overload studies. MEASUREMENTS AND MAIN RESULTS--In myocardial infarction, the amount of left ventricular ANF mRNA, plasma ANF concentration, and urinary cyclic GMP excretion were correlated and were proportional to the degree of cardiac failure, as assessed by the increase in right ventricular mass and the decrease in blood pressure. In male SHR (aged 6-24 months), plasma ANF and urinary cyclic GMP were correlated, increased with age, and were proportional to the heart to body weight ratio. These correlations between plasma ANF, daily urinary cyclic GMP excretion, and left ventricular hypertrophy persisted in two year old SHR. The presence of pleural extravasation in these old animals was also characterised by significant increases in both plasma ANF and urinary cyclic GMP. The plasma ANF and the daily urinary cyclic GMP excretion were negative prognostic indicators of life expectancy in two year old SHR. CONCLUSIONS--Urinary cyclic GMP excretion, correlated with the plasma ANF level, is a non-invasive indicator of congestive heart failure in two models of overloaded left ventricle in rats.

Topics: Aging; Animals; Atrial Natriuretic Factor; Cyclic GMP; Heart Failure; Male; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred Strains

The natriuretic, diuretic, and hypotensive responses to infused atrial natriuretic peptide (ANP) were measured in rats 4 weeks after myocardial infarction induced by coronary artery ligation. Rat [1-28]-ANP was infused intravenously in doses of 0.1, 0.3, and 1.0 microgram/kg/min for 30 min each under pentobarbital anesthesia. There was a marked natriuresis, diuresis, and fall in blood pressure in rats with infarction but each response was significantly attenuated when compared with sham-operated controls (ANOVA: p less than 0.01, p less than 0.05, and p less than 0.01, respectively). Urinary cyclic guanosine monophosphate (cGMP) excretion in rats with infarction was higher than that of controls but rose to the same absolute level in both groups in response to ANP infusion (0.3 microgram/kg/min). Reduced ANP responsiveness may result from impaired postreceptor mechanisms or from physiological antagonism by angiotensin II. Reduced ANP responsiveness may partly explain impaired salt handling in heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Coronary Vessels; Cyclic GMP; Female; Heart Failure; Myocardial Infarction; Rats; Rats, Inbred Strains; Sodium; Urodynamics

In conscious dogs, we examined the hypothesis that the effects of atrial natriuretic peptide (ANP) are mediated by cyclic GMP and tested whether stimulation of the intracellular pathway beyond the ANP receptor level still exerts ANP-like effects during tolerance to ANP in heart failure. We studied the hemodynamic, renal, and hormonal effects of the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP) in conscious dogs before and after induction of congestive heart failure by right ventricular pacing. In healthy dogs, 8-Br-cyclic GMP (1-100 micrograms/kg/min) dose-dependently decreased mean arterial pressure (MAP -19% by 100 micrograms/kg/min) and total peripheral resistance (TPR -22%) with no change in cardiac output (CO) and right atrial pressure, increased urine flow (UF 52%), and sodium excretion (UNaV 135%). Plasma renin (62%) and norepinephrine (NE 24%) were increased. In dogs with heart failure, 8-Br-cyclic GMP induced a similar arteriolar dilation (MAP -16%, TPR -23%) with no change in CO and preload. However, the effects on renal excretory function were abolished or markedly attenuated (UF -4%, UNaV 7%). Plasma renin (163%) and aldosterone (40%) were increased. Our findings support the hypothesis that the renal effects of ANP are mediated by cyclic GMP in vivo. The attenuation of renal effects of 8-Br-cyclic GMP in heart failure does not prove but is in agreement with the hypothesis that an intracellular defect beyond cyclic GMP production might be involved in the tolerance to ANP in heart failure.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Blood Pressure; Cardiac Output; Cyclic GMP; Dogs; Female; Heart Failure; Hemodynamics; Hormones; Kidney; Norepinephrine; Renin; Vascular Resistance

To determine a possible basis for the decreased action of atrial natriuretic factors (ANF) in congestive heart failure, we compared the cardiomyopathic hamster (CMH) in frank congestive failure, and the age-matched, normal, F1B strain of Golden Syrian Hamsters. Scatchard analysis of competitive binding studies revealed two classes of glomerular receptors. The CMH exhibited decreased binding overall and a markedly decreased number of high affinity receptors but comparable receptor affinity compared to the F1B. In contrast, the low affinity receptor population in the CMH had a much greater affinity compared to the F1B while receptor number was similar. Plasma ANF levels were substantially elevated in the CMH compared to the F1B and in-vitro generation of cGMP was significantly lower in the CMH. Such abnormalities could contribute to the resistance to ANF in this disease.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Cyclic GMP; Heart Failure; Kidney Glomerulus; Kinetics; Mesocricetus; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Second Messenger Systems

We measured plasma concentrations of norepinephrine, cyclic AMP, cyclic GMP, atrial natriuretic peptides (ANP) and beta-adrenoceptor density (Bmax) and affinity (Kd) of lymphocytes in patients with congestive heart failure and correlated these parameters with symptoms and hemodynamic indices. Plasma concentration of norepinephrine, cyclic AMP, cyclic GMP and ANP significantly increased in patients with congestive heart failure. Plasma concentrations of norepinephrine were related to the severity of the heart failure, plasma cyclic AMP concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Peripheral blood lymphocytes were stimulated by isoproterenol, and cyclic AMP level in lymphocytes was assayed. In normal subjects the generation of cyclic AMP after stimulation decreased with age. The response of lymphocytes in patients of NYHA classes III and IV was significantly lower than in the normal age-matched controls. A significant correlation between plasma norepinephrine concentration and increase of lymphocyte cyclic AMP was demonstrated. From these results it was suggested that beta-adrenergic receptors in congestive heart failure were desensitized. Beta receptor numbers of lymphocytes significantly decreased in NYHA class III and IV, but did not decrease in class I and II. There was no significant difference in Kd associated with congestive heart failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment, although remaining at a high value. A significant correlation between the cyclic GMP and ANP concentration was found in patients with congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Lymphocytes; Male; Middle Aged; Norepinephrine; Prognosis; Receptors, Adrenergic, beta

Plasma concentrations of cyclic nucleotides were determined by radioimmunoassay in 196 cardiac patients. The results showed that plasma concentrations of cyclic AMP and cyclic GMP increased with the deterioration of cardiac function. Plasma cyclic GMP concentrations were correlated positively to the cardiothoracic ratios (CTR), PEP/LVET, and the intracardiac diameters measured by echocardiography respectively (r = 0.55 r = 0.50, and r = 0.55, P less than 0.001), and were correlated negatively to the left ventricular ejection fractions (LVEF) and LV short axis shortenings (LVSAS) (r = -0.53 and r = -0.50 respectively, P less than 0.001). There were only weak correlations between plasma cyclic AMP concentrations and CTR, PEP/LVET ratios, LVEF and LVSAS (r = 0.35, r = 0.38, r = 0.28, and r = -0.31, respectively, P less than 0.01). The correlations between plasma cyclic GMP concentrations and mean pulmonary artery pressures (r = 0.48, P less than 0.05) and mean left atrial pressures (r = 0.55, P less than 0.01) were also significant. In patients who had received cardioversion and valve replacement, plasma cyclic GMP concentrations decreased significantly. Thus the plasma concentrations of cyclic nucleotides could be used as a useful parameter in evaluation of cardiac function and therapeutic effect.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Electric Countershock; Female; Heart; Heart Failure; Heart Valve Prosthesis; Humans; Male; Middle Aged

Vasoactive humoral factors were measured in 27 patients before and during the first week of conventional treatment of acute heart failure. On admission, all patients were given frusemide intravenously, followed by oral digoxin and diuretic therapy. Before drug treatment, plasma renin activity and plasma angiotensin II concentrations were within normal ranges in the group of patients without previous diuretic treatment, but were significantly higher in those 16 patients already on diuretic drugs when admitted to hospital. After diuretic treatment, however, even the former group revealed activation of the renin-angiotensin system. Plasma concentrations of catecholamines were increased initially but normalized within 1 day. A majority of the patients initially had very high plasma concentrations of atrial natriuretic peptide (mean 276.9 +/- 39.0 pg ml-1) which decreased but did not normalize during the study period. High plasma levels of arginine vasopressin (mean 56.8 +/- 14.6 pg ml-1) were found, but tended to be reduced during treatment. Thus, patients with acute heart failure displayed increased plasma concentrations of atrial natriuretic peptide, arginine vasopressin and catecholamines, but these vasoactive hormones decreased in parallel to clinical improvement during diuretic therapy. In contrast, the renin-angiotensin system became clearly activated.

Topics: Acute Disease; Aged; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Catecholamines; Cyclic GMP; Diuretics; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Neurotransmitter Agents

The plasma and cardiac levels of immunoreactive (IR) atrial natriuretic factor (ANF) were measured during the entire lifespan of cardiomyopathic hamsters, which eventually develop spontaneous congestive heart failure, and were correlated with immunohistochemical, ultrastructural, and immunocytochemical changes in the secretory apparatus of atrial and ventricular cardiocytes. Plasma IR-ANF rose in the early stages of the disease, reached a maximum in moderate heart failure, and declined thereafter but remained above control values. The peptide decreased constantly in the atria during the evolution of the disease but increased markedly in the ventricles. Its highest levels were found in the inner half of the left ventricle. In atrial cardiocytes, the size and complexity of the Golgi complex increased with the progression of the disease, whereas the number, size, and IR-ANF content (as assessed by the immunogold technique) of secretory granules decreased constantly. In ventricular cardiocytes, the size of the Golgi complex increased, and typical secretory granules were present in approximately 20% of these cells, regardless of their localization in the myocardium. The results suggest that stimulation of ANF secretion in atrial cardiocytes leads to a dissociation between synthesis and release, the latter being maximal according to ultrastructural and immunocytochemical criteria. In ventricular cardiocytes, the same stimulation culminates in increased synthesis and the possibility of release via two pathways: one constitutive, the other regulated. Thus, the elevated plasma levels of IR-ANF in congestive heart failure may be derived from secretion by both atrial and ventricular cardiocytes.

Topics: Animals; Atrial Natriuretic Factor; Cricetinae; Cyclic GMP; Heart Atria; Heart Failure; Heart Ventricles; Immunohistochemistry; Microscopy, Electron; Myocardium; Necrosis

The relation of plasma levels of atrial natriuretic peptide (ANP) to those of cyclic 3', 5'-guanosine monophosphate (cGMP) was studied in 43 patients with various heart diseases. Plasma levels of both ANP and cGMP were significantly (p less than 0.001) elevated in 34 patients with chronic heart diseases, and a significant positive correlation was observed between the two variables (r = 0.706, p less than 0.01). Clinical improvement of congestive heart failure resulted in a concomitant decrease in plasma ANP and cGMP levels in 6 patients. In 3 patients with paroxysmal atrial fibrillation, plasma levels of ANP and cGMP increased markedly during arrhythmia. These results indicate that increased circulating ANP may stimulate cGMP production in target cells, which in turn raises plasma levels of cGMP in humans.

Topics: Aged; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged

To study the role of alpha-human atrial natriuretic polypeptide (alpha-hANP) in body fluid regulation, we measured the plasma concentration of alpha-hANP and renal function in 9 patients with congestive heart failure (CHF), 10 with chronic renal failure (CRF) and 8 normotensives (NT) before and during alpha-hANP infusion at 0.025 microgram/kg.min. The plasma concentration of alpha-hANP was significantly higher in the CHFs and CRFs than in the NTs (319, 168 and 72 pg/ml, respectively). Alpha-hANP infusion decreased mean blood pressure in a similar manner in the 3 groups (-5%, p less than 0.01 each). Increases in urinary sodium excretion and glomerular filtration rate during alpha-hANP infusion, however, were greater in the CHFs and CRFs than in the NTs. Furthermore, the higher the preinfusion level of renal vascular resistance (RVR), the greater was the reduction in RVR by alpha-hANP (r = -0.80, p less than 0.001). The metabolic clearance rate (MCR) of alpha-hANP was significantly smaller in the CHFs and CRFs than in the NTs (38, 35 and 67 ml/min.kg, respectively). These results suggest that the renal vasodilatory actions of alpha-hANP seem to be enhanced in patients with increased RVR and that the elevation of the basal plasma concentration of alpha-hANP in CHFs and CRFs may be in part due to the low MCR.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Glomerular Filtration Rate; Heart Failure; Humans; Infusions, Intravenous; Kidney; Kidney Failure, Chronic; Metabolic Clearance Rate; Middle Aged; Natriuresis; Renal Circulation; Vascular Resistance; Vasodilation

The discovery of the atrial natriuretic factor (ANF) has opened a new field in modern biology. After rapid isolation and identification of this new peptide from atrial granules, it is now evident that this new hormone has a wide variety of actions with general implication in the control of vascular tone, sodium and water balance, hormonal secretion as well as neuronal functions. The major mode of action of this hormone is transmitted via its interaction with a membrane enzyme, particulate guanylate cyclase, leading to increases of cGMP levels. This nucleotide is a faithful marker of ANF action correlating with all functions ascribed to ANF up to date. Significant increases of ANF as well as of cGMP have been discovered in heart and renal failure, secondary hypertension and other states with altered salt-water balance, impairment of heart function and particularly increase of atrial pressure. The increases of levels and relative inefficiency of increased ANF have to be carefully interpreted in face of increased levels of cGMP. It can be expected that new pharmacological developments will occur in this area issuing from both our increasing knowledge concerning the peripheral mode of action of this hormone, its physiological implications as well as its pharmacological effectiveness in diseases with altered salt-water balance, cardiac function and blood pressure disregulation.

Topics: Atrial Natriuretic Factor; Cyclic GMP; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Metabolic Clearance Rate; Plasma Volume; Vasodilation; Water-Electrolyte Balance

To examine the interrelationship between human atrial natriuretic polypeptide (hANP) and cyclic 3'5'-guanosine monophosphate (cyclic GMP), plasma concentrations of these compounds were determined in 61 disease-free humans, as controls, and in 35 patients with congestive heart failure. Levels of plasma hANP (199.6 +/- 53.7 pg/ml) and cyclic GMP (12.6 +/- 1.7 pmol/ml) in patients with congestive heart failure were significantly higher than in the control subjects (hANP 57.1 +/- 2.8 pg/ml, cyclic GMP 5.2 +/- 0.3 pmol/ml). Although plasma hANP concentrations in the patients with congestive heart failure tended to increase with the severity of cardiac dysfunction, there was no significant correlation between the levels of plasma hANP and the grade of heart failure, classified according to the New York Heart Association. However, a significant correlation was found between plasma hANP and cyclic GMP concentrations in both the healthy subjects and the patients with congestive heart failure, and a weak positive correlation between plasma hANP and cyclic 3'5'-adenosine monophosphate (cyclic AMP) concentration in the patients with congestive heart failure. Thus, changes in plasma cyclic GMP concentration depend to some extent on the plasma concentrations of hANP.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Heart Failure; Humans; Middle Aged; Tachycardia, Paroxysmal

The effects of the benzimidazole-pyridazinone pimobendan (UD-CG 115 BS) on systemic haemodynamics, myocardial performance and the distribution of cardiac output were studied in open-chest anaesthetized pigs. After intravenous bolus injections (0.1-0.5 mg X kg-1, n = 7) increases in heart rate (up to 37%), LVdP/dtmax (up to 54%) and decreases in systemic vascular resistance (up to 33%) and left ventricular filling pressure (up to 50%) were observed, while cardiac output was unchanged. Vasodilation occurred in nearly all regional vascular beds, but was most pronounced in the adrenals (200%), followed by stomach (150%), small intestines (130%), heart (125%) and brain (110%). O2-consumption was not affected in spite of the increases in heart rate and myocardial inotropy. To evaluate the direct effects on the myocardial, pimobendan was also infused (1-5 micrograms X kg-1 X min-1, n = 7) directly into the left anterior descending coronary artery. In addition to a marked vasodilation of the coronary bed (140%), also a lowering of the left ventricular filling pressure (up to 20%) and cardiac output (15%) was observed, but no changes in regional myocardial function, LVdP/dtmax and systemic vascular resistance occurred. Immediately after intracoronary bolus injections (1 mg X kg-1, n = 4), vasodilation of the coronary vessels was apparent, but myocardial contractility was not affected. This may explain that cyclic AMP content, determined in biopsies excised 30 s after injection, was unaltered. It may be concluded that pimobendan exerts actions on the cardiovascular system which may be useful in the treatment of heart failure.

Topics: Animals; Cardiac Output; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Heart Failure; Myocardial Contraction; Myocardium; Pyridazines; Swine

Plasma concentrations of cyclic nucleotides (adenosine monophosphate (AMP) and guanosine monophosphate (GMP) were measured by an ultrasensitive radioimmunoassay in 138 patients with heart failure due to various causes. Measurements were related to the New York Heart Association classification of symptoms, plasma noradrenaline concentrations, and mean pulmonary artery pressures. Serial concentrations of cyclic AMP and GMP were also measured daily in four patients treated for acute left ventricular failure. Plasma concentrations of cycle AMP were related to the severity of the heart failure, plasma noradrenaline concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment although remaining at a high value. The cyclic GMP concentrations were significantly higher in patients with mitral stenosis than in those with other types of heart failure.

Topics: Adult; Aged; Blood Pressure; Cyclic AMP; Cyclic GMP; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Stenosis; Norepinephrine; Pulmonary Artery; Time Factors

Developing myocardial infarction is shown to be accompanied by raised plasma cAMP and cGMP levels which peak within the first few hours of the disease. Two patterns of changes were noted in the content of cyclic nucleotides: cAMP increase prevailing (a more typical pattern) and cGMP increase prevailing. Primary ventricular fibrillation was recorded in some patients belonging to the latter group. The development of cardiac failure is accompanied by a more stable rise of plasma cAMP.

Topics: Adult; Aged; Angina Pectoris; Coronary Disease; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Time Factors

A single oral dose of 1.0 to 2.0 mg prazosin was given to 14 patients with congestive heart failure to assess its effect. Prazosin increased cardiac index (+27.5%) and decreased pulmonary arterial diastolic pressure (-29.1%), systemic vascular resistance (-27.7%), mean blood pressure (-11.8%), and double products (-12.9%). Plasma renin activity (¿.8%) and plasma concentrations of norepinephrine (+67.5%) and cyclic adenosine monophosphate (AMP) (+10.6%) rose. There was a negative correlation between plasma cyclic AMP concentration and the increase of plasma cyclic AMP concentration after prazosin (Y = -0.53X + 18.7). There were no changes in heart rate and plasma cyclic guanosine monophosphate concentration. The effects were maximum at 3 hr and lasted 5 hr. The results indicate that oral prazosin has a beneficial hemodynamic effect in patients with congestive heart failure, and that the pathologic effects of prazosin, "alpha-blocker." induces a rise in plasma renin activity as well as in plasma concentrations of norepinephrine and cyclic AMP.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Prazosin; Quinazolines; Renin

Topics: Adolescent; Adult; Aged; Aging; Child; Cyclic AMP; Cyclic GMP; Exercise Test; Heart Failure; Humans; Male; Middle Aged; Nucleotides, Cyclic