phosphoramidon and Heart-Failure

Topics: Glycopeptides; Heart Failure; Hemodynamics; Humans; Indans; Metalloproteases; Propionates; Protease Inhibitors; Pyridines; Thiazepines; Thiorphan

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Animals; Aspartic Acid Endopeptidases; Benzazepines; Benzofurans; Drug Design; Endothelin-Converting Enzymes; Glycopeptides; Heart Failure; Humans; Hypertension; Metalloendopeptidases; Mice; Mice, Knockout; Myocardial Infarction; Organophosphonates; Phenylalanine; Tetracyclines; Tetrazoles

The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF.. Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05).. ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Brachial Artery; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Glycopeptides; Heart Failure; Humans; Male; Metalloendopeptidases; Middle Aged; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Viper Venoms

Increasing evidence suggests that angiotensin-converting enzyme (ACE) inhibitors can increase vascular nitric oxide (NO) production. Recent studies have found that combined inhibition of ACE and neutral endopeptidase (NEP) may have a greater beneficial effect in the treatment of heart failure than inhibition of ACE alone. Amlodipine, a calcium channel antagonist, has also been reported to have a favorable effect in the treatment of patients with cardiac dysfunction. The purpose of this study was to determine whether and the extent to which all of these agents used in the treatment of heart failure stimulate vascular NO production. Heart failure was induced by rapid ventricular pacing in conscious dogs. Coronary microvessels were isolated from normal and failing dog hearts. Nitrite, the stable metabolite of NO, was measured by the Griess reaction. ACE and NEP inhibitors and amlodipine significantly increased nitrite production from coronary microvessels in both normal and failing dog hearts. However, nitrite release was reduced after heart failure. For instance, the highest concentration of enalaprilat, thiorphan, and amlodipine increased nitrite release from 85 +/- 4 to 156 +/- 9, 82 +/- 7 to 139 +/- 8, and 74 +/- 4 to 134 +/-10 pmol/mg (all *p <.01 versus control), respectively, in normal dog hearts. Nitrite release in response to the highest concentration of these two inhibitors and amlodipine was reduced by 41% and 31% and 32% (all #p <.01 versus normal), respectively, in microvessels after heart failure. The increase in nitrite induced by either ACE or NEP inhibitors or amlodipine was entirely abolished by Nw-nitro-L-arginine methyl ester, HOE 140 (a B2-kinin receptor antagonist), and dichloroisocoumarin (a serine protease inhibitor) in both groups. Our results indicate that: 1) there is an impaired endothelial NO production after pacing-induced heart failure; 2) both ACE and NEP are largely responsible for the metabolism of kinins and modulate canine coronary NO production in normal and failing heart; and 3) amlodipine releases NO even after heart failure and this may be partly responsible for the favorable effect of amlodipine in the treatment of heart failure. Thus, the restoration of reduced coronary vascular NO production may contribute to the beneficial effects of these agents in the treatment of heart failure.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin Receptor Antagonists; Coronary Vessels; Cysteine Proteinase Inhibitors; Dogs; Enalaprilat; Glycopeptides; Heart Failure; Kininogens; Kinins; Nitric Oxide; Protease Inhibitors; Ramipril; Receptor, Bradykinin B2; Thiorphan; Vasodilator Agents

Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue.. Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M-like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal.. The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Bradykinin; Captopril; CD13 Antigens; Dipeptides; Female; Glycopeptides; Heart Failure; Humans; Kallidin; Leucine; Male; Membrane Proteins; Middle Aged; Myocardium; Neprilysin; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Substrate Specificity

Coronary dysfunctions identified in the presence of chronic heart failure are an important pathophysiologic abnormality that influences the prognosis of the disease. Because the endothelin pathway plays a significant role in the increased peripheral vascular tone associated with heart failure, we hypothesized that the endothelin pathway may be involved in the abnormal coronary vasomotion associated with this pathologic condition. Experiments were carried out in failing hearts (UM-X7.1 cardiomyopathic hamsters, aged 225-250 days) and normal hearts (Syrian LVG hamsters, also aged 225-250 days). Isolated hearts were perfused at constant flow and exposed to the blocker of the generation of endothelin-1 (ET-1), phosphoramidon (10 microM infusion), as well as to the selective ET(A)-receptor antagonist BQ 123 (10 microM infusion) and to a selective ET(B)-receptor antagonist BQ 788 (1 microM infusion). Coronary and cardiac effects of exogenous ET-1 (0.01-100 pmol) were also studied. Phosphoramidon, BQ 788, and BQ 123 did not altered coronary perfusion pressure either in normal or in failing hearts, whereas cardiac contractility was significantly impaired in the presence of phosphoramidon and BQ 123. Coronary sensitivity to exogenous ET-1 did not demonstrate a significant difference between normal and failing hearts [median effective concentration (EC50), 7 pmol in failing hearts vs. 12 pmol in normal hearts; p = NS]. In the presence of exogenous ET-1, cardiac contractility was significantly increased in both groups. In normal hearts, the exogenous ET-1-induced increase in coronary perfusion pressure was completely antagonized by BQ 123, whereas combined administration of BQ 788 and BQ 123 was necessary to induce complete inhibition in failing hearts. The positive inotropic effect elicited by exogenous ET-1 (EC50) was completely abolished in the presence of BQ 123, whereas BQ 788 had no significant effect. Results indicate that the endothelin pathway does not play a significant role in the altered coronary vasomotion observed in this model of chronic heart failure. On the contrary, the endothelin pathway appears to participate in the maintenance of myocardial contractility. According to these observations, administration of an inhibitor of ET-1 synthesis, as well as the use of an ET(A)-receptor antagonist, may be contraindicated in the presence of poor left ventricular function because the endothelin pathway contributes significantly to the maintenance of cardiac

Topics: Animals; Aspartic Acid Endopeptidases; Blood Pressure; Coronary Circulation; Coronary Vessels; Cricetinae; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Glycopeptides; Heart; Heart Failure; Mesocricetus; Metalloendopeptidases; Oligopeptides; Peptides, Cyclic; Piperidines; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B

The results of early acute haemodynamic studies with anti-endothelin agents are promising. Much still needs to be done, however, before endothelin antagonism is established as a therapeutic strategy in heart failure. We need to know, for example, whether the haemodynamic effects of anti-endothelin drugs are sustained. We need to ensure that there is no reflex activation of other neuroendocrine systems and, preferably, to demonstrate neuroendocrine suppression. Characterisation of the renal actions of endothelin receptor antagonists will also be important. Perhaps the most pressing issue in the development of these agents is elucidation of the role of the endothelial ETB receptor in heart failure. It is now clearly shown that vascular smooth muscle ETB receptors can mediate vasoconstriction in human blood vessels and that these receptors may be particularly important in heart failure. The effect of selective ETB receptor blockade in humans in vivo is not currently known, however, and whether endothelial ETB receptors might tonically offset ETA and ETB receptor mediated smooth muscle contraction remains conjectural. This question is directly relevant to whether selective ETA or non-selective ETA and ETB receptor antagonism might be the better therapeutic strategy in heart failure. ECE inhibition may become another therapeutic option in due course, but at present no specific and selective inhibitors of the enzyme have been developed. The recent demonstration that the selective ETA receptor antagonist BQ-123 improves long term survival in rats with heart failure induced by myocardial infarction suggests that anti-endothelin strategies may hold great therapeutic promise in heart failure.

Topics: Aspartic Acid Endopeptidases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Heart Failure; Humans; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Binding Sites; Glycopeptides; Heart Failure; Molecular Structure; Neprilysin; Organophosphorus Compounds; Protease Inhibitors; Rabbits; Rats

We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of alpha-rat atrial natriuretic peptide (alpha-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating alpha-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/min/kg) was equal to that of exogenously administered alpha-rANP (100 pmol/min/kg) in MI rats, whereas plasma alpha-rANP concentration under NEP inhibition was much lower than that after administration of alpha-rANP. The endogenous alpha-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to alpha-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous alpha-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating alpha-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.

Topics: Animals; Atrial Natriuretic Factor; Drug Synergism; Glycopeptides; Heart Failure; Kidney; Male; Neprilysin; Rats; Rats, Wistar; Recombinant Proteins; Sodium

Topics: Animals; Atrial Natriuretic Factor; Glycopeptides; Heart Atria; Heart Failure; Hemodynamics; Humans; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Thiorphan