Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

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.
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PMID:Cardiovascular cyclic nucleotide phosphodiesterases and their role in regulating cardiovascular function. 137 94

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.
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PMID:Maximizing the natriuretic effect of endogenous atriopeptin in a rat model of heart failure. 216 56

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.
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PMID:Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. 1148 Dec 19

Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 +/- 0.62 microg/mg protein (mean +/- S.E.), and 3.21 +/- 0.95) compared with that obtained from the control (0.60 +/- 0.04) or cardiomyopathic (0.95 +/- 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC(50)) of PDE I, II, and III peak activities was 140, 29, and 46 microM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.
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PMID:Changes in cyclic nucleotide phosphodiesterase activity and calmodulin concentration in heart muscle of cardiomyopathic hamsters. 1535 Aug 49

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored.Rats developed arterial hypertension associated with a slight cardiac hypertrophy (+24%). cAMP-PDE4 activity was specifically increased while cGMP-PDE activities were broadly increased (+130% for PDE1; +76% for PDE2; +113% for PDE5) and associated with increased expressions for PDE1A, PDE1C and PDE5A. The cGMP-PDE1 activation by Ca(2+)/CaM was reduced. BNP expression was increased by 3.5-fold, while NOX2 expression was reduced by 66% and AMP kinase activation was increased by 64%. In early cardiac hypertrophy induced by angiotensin II, all specific PDE activities in left cardiac ventricles were increased, favoring an increase in cGMP hydrolysis by PDE1, PDE2 and PDE5. Increased cAMP hydrolysis was related to PDE4. We observed the establishment of two cardioprotective mechanisms and we suggest that these mechanisms could lead to increase intracellular cGMP: i) increased expression of BNP could increase "particulate" cGMP pool; ii) increased activation of AMPK, subsequent to increase in PDE4 activity and 5'AMP generation, could elevate "soluble" cGMP pool by enhancing NO bioavailability through NOX2 down-regulation. More studies are needed to support these assumptions. Nevertheless, our results suggest a potential link between PDE4 and AMPK/NOX2 and they point out that cGMP-PDEs, especially PDE1 and PDE2, may be interesting therapeutic targets in preventing cardiac hypertrophy.
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PMID:Concerted regulation of cGMP and cAMP phosphodiesterases in early cardiac hypertrophy induced by angiotensin II. 2115 82