UMLS:C0018801 - FACTA Search

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

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.
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PMID:Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels. 1008 17

Molsidomine, coronary drug which acts similar to organic nitrates, belongs to the drug class of sydnones . SIN-1A metabolite of Molsidomine has pharmacologically active group of NO, which by increasing levels of cGMP, decreases levels of intracellular calcium ions in smooth muscle cells. This effect leads to relaxation of smooth muscle vasculature, inhibits platelets aggregation and has indirect antiproliferative effect. In clinical observations no effect of tolerance to the drug was observed. Experimental data show additional mechanism of action of the drug: SIN-1C metabolites protects the reoxygenated cardiomyocyte from post-reperfusion damage. Indications for use of Molsidomine are: ischaemic heart disease, chronic heart failure and pulmonary hypertension. Effects of Molsidomine use in acute myocardial infarction and unstable angina were compared in clinical trials to effects of nitroglycerin use. Both drugs were found equally potent, but authors underline the fact of better Molsidomine tolerability comparing NTG, but longer serum half-time of Molsidomin effects that control of the treatment is worse. In clinical trials it was suggested that intravenous use of Molsidomine metabolite SIN-1 during PTCA procedures is more effective than use of isosorbide dinitrate in the same procedures. In other clinical trials molsidomin was found to produce beneficial effects in patients with heart failure due to ischaemic cardiomyopathy, dilatative cardiomyopathy, in essential hypertension, pulmonary artery hypertension in COPD patients and in congestive heart failure.
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PMID:[Molsidomine: importance in treatment of circulation disorders]. 1022 68

Plasma concentrations of the recently discovered hormones adrenomedullin (ADM), from vascular tissue, and brain natriuretic peptide (BNP), secreted by myocardium, are elevated in patients with heart failure. We tested the hypotheses that short-term increments in circulating levels of these hormones, within the pathophysiological range, would have biological effects and that the 2 hormone systems interact. Eight patients with heart failure (left ventricular ejection fractions <35%) received 4-hour infusions of BNP (3.0 pmol. kg(-1). min(-1)) alone, ADM (2.7 pmol. kg(-1). min(-1) and 5.4 pmol. kg(-1). min(-1) for 2 hours each) alone, ADM and BNP combined, and placebo. BNP and ADM infusions raised plasma levels of the respective peptide within the pathophysiological range. Arterial blood pressure fell (P<0.05) with all peptide infusions, but cardiac output was unchanged. Heart rate increased with ADM and combined infusions (P<0.01). Sodium excretion rose (P<0.05), and creatinine clearance was sustained during both BNP and combined infusions. Urine volume increased in response to BNP alone (P=0.02). Despite a >2-fold increase in plasma renin with both ADM and combined infusions (P<0.05), plasma aldosterone remained lower than time-matched placebo levels. Plasma noradrenaline was increased by combined, BNP, and higher dose ADM infusions (P<0.05). ADM suppressed plasma cGMP (P<0.05) and inhibited the plasma cGMP response to BNP (P<0.05). The vascular hormones ADM and BNP, produced by myocardium, at plasma concentrations within the pathophysiological range have hemodynamic, renal, and hormonal effects and measurable interactions in patients with heart failure.
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PMID:Bioactivity and interactions of adrenomedullin and brain natriuretic peptide in patients with heart failure. 1040 26

Heme oxygenase (HO)-1 is a stress protein (HSP 32) and, together with HO-2, catalyses oxidation of the heme molecule to generate carbon monoxide, a gas with vasodilatory properties, and bilirubin, an antioxidant. Right-sided heart failure (RHF) resulted in a two-fold increase in the HO-1 transcript (;1.8 kb) in the right ventricle (RV) of RHF dogs compared to that of controls. In contrast, the left ventricle showed no increase in HO-1 mRNA in RHF. The change in HO was unique to HO-1, because neither the HO-2 transcripts (;1.3 and 1.9 kb) nor the HSP 70 mRNA was altered in either ventricle. This increase in HO-1 mRNA in RV was accompanied by a two-fold increase in immunoreactive HO-1 protein, as judged by Western blot analysis, as well as by a significant increase in cGMP levels. There was, however, no significant increase in RV total nitric oxide synthase activity in RHF. Furthermore, since norepinephrine infusion also increased HO-1 transcript and protein levels, the HO-1 system probably was induced in RHF by the increased interstitial norepinephrine levels known to occur in failing myocardium. This differential regulation and induction of HO-1 gene in the failing ventricle might be one of the defense mechanisms by which the heart attempts to protect from stress caused by congestive heart failure.
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PMID:Chamber-specific regulation of heme oxygenase-1 (heat shock protein 32) in right-sided congestive heart failure. 1042 55

The effects of exogenous and endogenous. NO on myocardial functions such as contraction, relaxation and heart rate have recently gained considerable scientific interest. .NO stimulates myocardial soluble guanylate cyclase to produce cGMP, which activates two major target proteins. A small increase in cGMP levels predominantly inhibits phosphodiesterase III, while high cGMP levels activate cGMP-dependent protein kinase. Accordingly, submicromolar .NO concentrations improve myocardial contraction, while submillimolar .NO concentrations decrease contractility. The latter action includes direct inhibitory .NO effects on ATP synthesis and voltage-gated calcium channels. Overall, the inotropic effects of exogenous .NO are small and probably of minor importance for myocardial contractility. Cardiomyocytes are capable of expressing eNOS and iNOS. Endogenous .NO has effects on myocardial contraction, similar to that of exogenous .NO. Various NOS inhibitors can substantially reduce myocardial contractility in vitro and in vivo, suggesting that basal endogenous .NO production supports myocardial contractility. There is also evidence for a .NO-dependent cardiodepressive effect of cytokines that is mediated by expression of iNOS. This is consistent with the negative inotropic effects of .NO at high concentrations. Cardiodepressive actions of endogenous .NO production may play a role in certain forms of heart failure. Finally, .NO also has an effect on heart rate. Physiologic .NO concentrations can stimulate heart rate by activating the hyperpolarization-activated inward current (If) and this effect decreases at submillimolar .NO concentrations. In summary, physiological concentrations of .NO increase contractility and heart rate under basal conditions, while high .NO concentrations induce the opposite effects.
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PMID:Regulation of basal myocardial function by NO. 1061 6

Voltage-gated L-type Ca(2+) channels control depolarization-induced Ca(2+) entry in different electrically excitable cells, including mammalian heart. Important molecular and functional details providing new insight into L-type channel structure and modulation are reviewed in this article. This includes the identification of amino acid residues responsible for drug binding, the role of accessory subunits and alternative splicing for fine-tuning channel activity and modulation by protein kinases (A, C, tyrosine kinases), cGMP-dependent pathways, calmodulin and Ca(2+). Alterations in Ca(2+) channel activity under pathological conditions such as in heart failure or during ischemia could provide new clues for the development of drugs to treat cardiovascular diseases.
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PMID:Pharmacology, structure and function of cardiac L-type Ca(2+) channels. 1057 1

Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium are suggested to be involved in regulating myocardial contractility. However, the characteristics and modulation of NPRs in relation to cardiac failure are not well defined. This study examined the properties of NPRs in ventricular endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were localized in right (RV) and left ventricular (LV) endocardium. Binding affinities of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by Southern blot analysis. Production of cGMP by particulate GC in endocardial cell membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22) >> brain NP (BNP)(1-26) > ANP(1-28). We also examined the modulation of these NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to hypertrophied RV endocardium almost disappeared and cGMP production by NPs was significantly decreased. In rats with pulmonary hypertension, plasma levels of ANP and BNP were increased by fivefold compared with controls. The results indicate that there is a differential distribution of NPRs in the cardiac chambers, with the most abundant binding sites in RV endocardium, that NPR-B is the predominant GC-coupled NPR in ventricular endocardium, and that endocardial NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may be associated with an increment of endogenous NP production caused by mechanical overload in hypertrophied ventricle.
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PMID:Modulation of endocardial natriuretic peptide receptors in right ventricular hypertrophy. 1060 Aug 47

The effects on myocardial function and loading conditions of clinically relevant doses of the natriuretic peptides (NP) have not been established. The actions of single doses (100 ng x kg(-1) x min(-1) iv over 30 min) of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) were studied in conscious normal dogs and in dogs with pacing-induced heart failure. All three NP reduced end-diastolic pressure in normal dogs, and ANP and BNP reduced end-diastolic volume. In heart failure ANP and BNP reduced EDP, and ANP reduced EDV. Arterial elastance was unchanged in normal dogs and in dogs with heart failure. ANP increased end-systolic elastance (E(es)) in normal dogs, whereas BNP tended to increase E(es) (P = 0.06). In dogs with heart failure, no inotropic effect was seen. In normal dogs, all NP reduced the time constant of isovolumic relaxation (tau), and ANP and BNP reduced tau in dogs with heart failure. Increases in plasma cGMP in dogs with heart failure were blunted. The NP reduced preload and enhanced systolic and diastolic function in normal dogs. Effects of ANP and BNP on preload and diastolic function were maintained in heart failure. Lack of negative inotropic effects in heart failure supports the validity of the NP as therapeutic agents.
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PMID:Effects of natriuretic peptides on load and myocardial function in normal and heart failure dogs. 1064 81

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.
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PMID:Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart. 1067 77

Complex paracrine interactions exist between endothelial cells and cardiac myocytes in the heart. Cardiac endothelial cells release (or metabolize) several diffusible agents (e.g., nitric oxide [NO], endothelin-1, angiotensin II, adenylpurines) that exert direct effects on myocyte function, independent of changes in coronary flow. Some of these mediators are also generated by cardiac myocytes, often under pathological conditions. This review focuses on the role of NO in this paracrine/autocrine pathway. NO modulates several aspects of "physiological" myocardial function (e.g., excitation-contraction coupling; myocardial relaxation; diastolic function; the Frank-Starling response; heart rate; beta-adrenergic inotropic response; and myocardial energetics and substrate metabolism). The effects of NO are influenced by its cellular and enzymatic source, the amount generated, the presence of reactive oxygen species, interactions with neurohumoral and other stimuli, and the relative activation of cyclic GMP-dependent and -independent signal transduction pathways. The relative physiological importance of endothelium- and myocyte-derived NO remains to be established. In pathological situations (e.g., ischemia-reperfusion, left ventricular hypertrophy, heart failure, transplant vasculopathy and rejection, myocarditis), NO can potentially exert beneficial or deleterious effects. Beneficial effects of NO can result from endothelial-type nitric oxide synthase-derived NO or from spatially and temporally restricted expression of the inducible isoform, inducible-type nitric oxide synthase. Deleterious effects may result from (1) deficiency of NO or (2) excessive production, often inducible-type nitric oxide synthase-derived and usually with concurrent reactive oxygen species production and peroxynitrite formation. The balance between beneficial and deleterious effects of NO is of key importance with respect to its pathophysiological role.
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PMID:Paracrine and autocrine effects of nitric oxide on myocardial function. 1076 May 46

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