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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure. 1767 Aug 61

Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca(2+) channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca(2+) channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase-cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock.
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PMID:Nitric oxide and cardiac function. 1770 39

The objective of this study was to understand the mechanism of action of nitric oxide (NO) in the heart by determining whether nitric oxide (NO) released from sodium nitroprusside (SNP) induces p38 mitogen activated protein kinase (p38 MAPK) phosphorylation and whether this is mediated through a cyclic GMP (cGMP)/protein kinase G (PKG) pathway. p38 MAPK activation was examined by Western blotting of whole cell lysates of embryonic chick cardiomyocytes with antibodies specific to the native or phosphorylated forms of p38 MAPK. SNP, 1 mM, which released significant amounts of NO as determined by Griess reaction, induced p38 MAPK phosphorylation that was apparent within 10 min, was significantly (p<0.05) greater than control at 60 min and remained higher than initial levels up to the 4 h end point of the experiment. This could not be attributed to hydrogen peroxide release from SNP as catalase did not affect SNP-induced p38 MAPK phosphorylation. SB202190, a relatively selective inhibitor of p38 MAPK, mainly p38alpha MAPK, inhibited SNP-induced p38 MAPK phosphorylation. SNP-induced p38 MAPK phosphorylation was not altered by pre-treatment with the PKG inhibitor KT 5823 or by ODQ a potent and selective inhibitor of NO-sensitive guanylyl cyclase. p38 MAPK phosphorylation was not induced by the cell permeable cGMP analogue, 8-Br-cGMP. In summary, considering that new therapeutic strategies aimed at NO and p38 MAPK are being considered for myocardial injury and heart failure, these data demonstrate that SNP induces p38 MAPK phosphorylation through a pathway that is independent of NO-induced activation of cGMP/PKG pathways and suggest that non cGMP/PKG regulatory proteins leading to p38 MAPK phosphorylation merit further investigation to address this therapeutic target.
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PMID:Sodium nitroprusside activates p38 mitogen activated protein kinase through a cGMP/PKG independent mechanism. 1770 40

Platelet hyperaggregability and associated thrombosis have been documented in a number of cardiovascular disease states. While one of the current mainstays of anti-thrombotic treatment (i.e. aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists) has been directed at reducing platelet activation and aggregation, it is apparent that there are limitations to the effectiveness of these therapies. Nitric oxide (NO) plays an important role in platelet physiology. The ability of NO to regulate cyclic guanosine-3,'5'-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. NO is not only of the endothelial source, it is also released from activated platelets, providing a negative feedback. Studies in patients with symptomatic ischemia, chronic heart failure, diabetes and various risk factors for cardiovascular disease have demonstrated that platelets from these subjects exhibit reduced responsiveness to the anti-aggregating efficacy of NO: a phenomenon termed "platelet NO resistance". It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor or EDRF), and as such may contribute to the increased risk of ischemic events. NO resistance also accounts for reduced pharmaco-activity of exogenous NO donors, e.g. organic nitrates. Platelet NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical and inactivation of soluble guanylate cyclase. NO resistance has both diagnostic and prognostic implications. The current review examines the association of platelet NO resistance with pathological hyperaggregability and discusses potential therapeutic strategies targeting this abnormality.
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PMID:Platelet hyperaggregability: impaired responsiveness to nitric oxide ("platelet NO resistance") as a therapeutic target. 1832 4

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.
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PMID:Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure. 1838 May 34

Four major natriuretic peptides have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and Dendroaspis-type natriuretic peptide (DNP). Natriuretic peptides play an important role in the regulation of cardiovascular homeostasis maintaining blood pressure and extracellular fluid volume. The classical endocrine effects of natriuretic peptides to modulate fluid and electrolyte balance and vascular smooth muscle tone are complemented by autocrine and paracrine actions that include regulation of coronary blood flow and, therefore, myocardial perfusion; modulation of proliferative responses during myocardial and vascular remodeling; and cytoprotective anti-ischemic effects. The actions of natriuretic peptides are mediated by the specific binding of these peptides to three cell surface receptors: type A natriuretic peptide receptor (NPR-A), type B natriuretic peptide receptor (NPR-B), and type C natriuretic peptide receptor (NPR-C). NPR-A and NPR-B are guanylyl cyclase receptors that increase intracellular cGMP concentration and activate cGMP-dependent protein kinases. NPR-C has been presented as a clearance receptor and its activation also results in inhibition of adenylyl cyclase activity. The wide range of effects of natriuretic peptides might be the base for the development of new therapeutic strategies of great benefit in patients with cardiovascular problems including coronary artery disease or heart failure. This review summarizes current literature concerning natriuretic peptides, their receptors and their effects on fluid/electrolyte balance, and vascular and cardiac physiology and pathology, including primary hypertension and myocardial infarction. In addition, we will attempt to provide an update on important issues regarding natriuretic peptides in congestive heart failure.
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PMID:Natriuretic peptides in vascular physiology and pathology. 1870 4

Mineralocorticoid receptor (MR) blockers attenuate cardiac remodeling in experimental models of heart failure, myocardial infarction and pressure-overload, in which the renin-angiotensin-aldosterone system is activated. Mice lacking the gene encoding guanylyl cyclase-A (GC-A), a common receptor for atrial and brain natriuretic peptide (ANP and BNP, respectively), show marked cardiac hypertrophy and fibrosis, which are almost completely inhibited by both genetic and pharmacological blockade of type 1 angiotensin II receptors. However, the effect of eplerenone, a specific MR blocker, on cardiac remodeling in GC-A knockout (GC-A KO) mice remains unknown. Male 12-week-old GC-A KO mice were assigned to control, eplerenone and hydralazine groups (n=6-7/group). Treatment with eplerenone at a dose of 100 mg/kg body weight/d reduced heart weight/body weight ratios, interstitial fibrosis and blood pressure to levels similar to those seen in wild type mice, in association with reduced transcription of atrial natriuretic peptide, brain natriuretic peptide, transforming growth factor-beta1, collagen I and collagen III. Although hydralazine (5 mg/kg body weight/d) exerted a similar effect on blood pressure, it did not inhibit the cardiac remodeling in GC-A KO mice. In conclusion, eplerenone attenuates cardiac remodeling in GC-A KO mice, most likely in a blood pressure-independent manner, which suggests that signaling downstream of MR is involved in the ventricular remodeling of GC-A KO mice.
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PMID:The specific mineralocorticoid receptor blocker eplerenone attenuates left ventricular remodeling in mice lacking the gene encoding guanylyl cyclase-A. 1871 75

Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.
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PMID:Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. 1877 78

Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.
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PMID:[Recent findings on nitrates: their action, bioactivation and development of tolerance]. 1894 54

The nitric oxide (NO) signalling pathway is altered in cardiovascular diseases, including systemic and pulmonary hypertension, stroke, and atherosclerosis. The vasodilatory properties of NO have been exploited for over a century in cardiovascular disease, but NO donor drugs and inhaled NO are associated with significant shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and non-specific effects such as post-translational modification of proteins. The development of pharmacological agents capable of directly stimulating the NO receptor, soluble guanylate cyclase (sGC), is therefore highly desirable. The benzylindazole compound YC-1 was the first sGC stimulator to be identified; this compound formed a lead structure for the development of optimized sGC stimulators with improved potency and specificity for sGC, including CFM-1571, BAY 41-2272, BAY 41-8543, and BAY 63-2521. In contrast to the NO- and haem-independent sGC activators such as BAY 58-2667, these compounds stimulate sGC activity independent of NO and also act in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects. Recently, aryl-acrylamide compounds were identified independent of YC-1 as sGC stimulators; although structurally dissimilar to YC-1, they have a similar mode of action and promote smooth muscle relaxation. Pharmacological stimulators of sGC may be beneficial in the treatment of a range of diseases, including systemic and pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, and renal fibrosis. An sGC stimulator, BAY 63-2521, is currently in clinical development as an oral therapy for patients with pulmonary hypertension. It has demonstrated efficacy in a proof-of-concept study, reducing pulmonary vascular resistance and increasing cardiac output from baseline. A full, phase 2 trial of BAY 63-2521 in pulmonary hypertension is underway.
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PMID:NO-independent, haem-dependent soluble guanylate cyclase stimulators. 1908 34


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