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

Arterial tone and water-electrolyte homeostasis are regulated by several peptides, including angiotensin II (AII), bradykinin (BK), atrial natriuretic peptide (ANP) and endothelins (ETs). Changing the concentrations of these peptides in the plasma, tissue, or urine by decreasing the levels of angiotensin II and endothelins and increasing BK and ANP concentrations, is one way of modulating the hemodynamic load. The metabolism of these peptides in essentially controlled by three enzymes, angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin converting enzyme (ECE), which all belong to the group of zinc metallopeptidases. Inhibition of these peptidases by a single compound (a dual inhibitor) that inhibits at once angiotensin II formation and BK and ANP inactivation, causes vasodilatation with reduction in blood pressure with reduction in blood pressure and increases natriuresis. The design of these inhibitors has often be relied on structure-activity studies, based on active-site models derived from structural data on thermolysin (TLN). The results of a large number of pharmacological experiments and those issued from some clinical studies using selective or mixed inhibitors show that in spontaneously hypertensive rats, dual ACE/NEP inhibitors such as S21,402 produce dose-related decreases (-15 to -40 mmHg) in mean arterial pressure and reductions in left ventricular hypertrophy and cardiac size. These compounds produce also an increase in urinary levels of BK, ANP and cGMP associated with enhanced urine output and sodium excretion. Moreover inhibition of NEP appears to improve the cardio- and reno-protective effects resulting from ACE inhibition and could also reduce hypertrophy of vascular walls. Inhibition of ECE seems to result in a weak reduction in blood pressure, an effect which could be emphasized by using dual ECE/ACE or ECE/NEP inhibitors. According to these results mixed dual inhibitors could be of great interest for the treatment of severe hypertension and chronic heart failure. Potent triple inhibitors blocking ACE, NEP and ECE could also be developed.
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PMID:Cell surface metallopeptidases involved in blood pressure regulation: structure, inhibition and clinical perspectives. 976 15

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.
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PMID:Endothelin as a regulator of cardiovascular function in health and disease. 979 9

The endothelins are a family of three structurally related peptides. Endothelin-1 (ET-1) is formed from the big endothelin by the action of the endothelin converting enzyme. It acts on two types of receptor, ETA and ETB. ET-1 is a powerful vasoconstrictor but also has a number of other effects: positive inotropism and stimulation of cell growth, for example. Endothelin is found in the general circulation but its role is mainly local in maintaining vascular tone. The endothelin system is activated in cardiac failure and increased concentrations of plasma endothelin increased, ET-1 converting enzyme and increased density of endothelin receptors are observed. The action of the endothelin system and its relationships with other neuro-hormonal systems activated in cardiac failure are not fully understood but research is under way which should clarify these mechanisms in the next few years. In view of the properties of endothelin, inhibition of its action might be particularly useful in patients with cardiac failure. Its action can be blocked either by preventing its synthesis by inhibiting the endothelin converting enzyme or by blocking the endothelin receptor. Endothelin receptor blockade is associated with beneficial haemodynamic changes, an action on ventricular remodelling and possibly an improved prognosis. Many substances, either selective for ETA receptors or mixed ETA and ETB receptor blockers, are under development. The benefits of these products will require confirmation by large scale clinical trials.
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PMID:[Endothelins in chronic cardiac insufficiency]. 989 17

In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.
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PMID:Pathophysiology of endothelin in the cardiovascular system. 1009 94

Endothelin (ET)-1 has a positive inotropic effect and induces hypertrophy in cardiomyocytes. We previously reported that the peptide level of ET-1 is increased in the failing heart of rats with chronic heart failure (CHF) and that treatment with an ETA-receptor antagonist greatly improves survival in rats with CHF. However, precise analysis for alteration of the myocardial ET system in the failing heart is not known. In this study, we used rats with CHF due to chronic myocardial infarction. Sham-operated rats served as a control. The results showed that the level of preproendothelin (preproET)-1 mRNA and the peptide level of ET-1 were markedly increased in the heart of rats with CHF, whereas the expression of endothelin-converting enzyme (ECE)-1 mRNA in the heart did not differ between CHF and control rats. The intensity of ET-1 staining (ET-1-like immunoreactivity) in cardiomyocytes was markedly stronger in rats with CHF than in control rats, and the fibrotic tissues of the infarcted area were not stained. The mRNA and protein levels of both ETA and ETB receptors in the heart were significantly higher in rats with CHF than in control rats. The present study suggests that the increase in ET-1 peptide level in the heart of the rats with CHF originated from upregulation of preproET-1 mRNA, which was not attendant with the alteration of ECE-1 mRNA expression, and that both the ETA- and ETB-receptor systems are greatly accelerated in the failing heart.
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PMID:Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart. 1019 43

Endothelins (ET) comprise a group of substances which are produced and have regulatory functions in different systems of the organism. The main cardiovascular ET is ET-1 which is so far the most potent vasoconstrictor substance. In the pathophysiology of cardiac insufficiency ET-1 promotes cardiac hypertrophy, is involved in vasoconstriction, delayed relaxation and reduced left ventricular contractility. The ET-1 level correlates with pulmonary vascular hypertension. By vasoconstriction of renal arteries ET leads to volume retention. Big-ET is a very efficient neurohumoral marker in the diagnosis of developed cardiac failure which can lead to more accurate prognostic stratification. ET-1 is probably important for assessment of the diagnosis of cardiac insufficiency only in severe cardiac failure. The favourable effect of ET block in cardiac insufficiency was proved for the non-selective ETA/ETB blocker and selective ETA blocker. The selective ETB blocker has an adverse haemodynamic effect in treatment of heart failure but by suppression of aldosterone it can prevent fluid retention. In the treatment of cardiac failure blockers of endothelin converting enzyme seem perspective as they reduce adversely activated neurohumoral factors.
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PMID:[Endothelins and chronic cardiac insufficiency]. 1095 66

Endogenous peptidases participate in a major way in the formation of peptide pressor substances such as angiotensin II (A II) and endothelin (ET) as well as in the degradation of depressor substances, e.g. atrial natriuretic peptide (ANP) or bradykinin. They include on the one hand the angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE), on the other hand kinase II for bradykinin and neutral endopeptidase 24.11 (NEP) for ANP. Inhibition of these enzymatic reactions leads to a decline of vasopressors A II and ET and conversely delays the break-down of vasodilatating bradykinin and ANP. The main haemodynamic consequence of this double inhibition is a reduced peripheral vascular resistance and decline of the blood pressure. The concurrent block of both systems (dual inhibition) is more effective than the isolated block of one substance. The first dual endopeptidase inhibitors were ACE inhibitors blocking the conversion of angiotensin I to A II and inhibiting at the same time the degradation of bradykinin by kininase II which is identical with ACE. At present further substances were synthetized with a dual inhibitory effect e.g. on ECE and on NEP (phosphoramidone, thiorphan, ecadatril etc.). Under experimental conditions they have a long-term antihypertensive effect on the vascular wall and heart muscle. The development of another dual ACE and NEP inhibitor has reached already the stage of clinical tests and the first clinical studies. The preparation omapatrilate in amounts of 2.5-80 mg significantly reduced the BP in a dose-dependent way in mild and medium advanced essential hypertension. Normalization of the blood pressure, i.e. a drop below 140/90 mm Hg, was achieved with omapatrilate monotherapy in as many as 83% of patients with hypertension stage I and in 53% patients with essential hypertension stage II. The drop of blood pressure after 20-80 mg/day depended on the degree of hypertension and was comparable or better than monotherapy with lisonopril 20 mg/day or amlodipine 10 mg/day. Treatment with omapatrilate was well tolerated. Dual peptidase inhibitors interfering with the formation of pressor substances and with the degradation of depressor substances seem to be a perspective class of antihypertensives also useful in the treatment of other cardiovascular diseases (heart failure, primary pulmonary hypertension). Before its final inclusion in the therapeutic pattern, further comparative and clinical mortality studies must be implemented.
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PMID:[Dual endopeptidase inhibitors--a new direction in the development of hypertensive agents]. 1104 16

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.
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PMID:Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction. 1107 22

Endothelins are 21 amino acid peptides that are produced ubiquitously by vascular endothelial cells, smooth muscle cells, and other cells in different organs. Endothelins are secreted as big-endothelins that are converted to active proteins by the endothelin-converting enzyme. These peptides possess many biological activities, such as vasoconstriction and mitogenesis, and are involved in numerous physiological and pathophysiological processes in humans. Elevated plasma levels of endothelin have been associated with heart failure, and increased immunoreactivity for endothelin is observed in transplant coronary artery disease. In this brief review, we will discuss the regulation of endothelin in cardiac transplantation and the pathological role this peptide plays in renal impairment, systemic hypertension, graft rejection and arteriosclerosis after heart transplantation.
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PMID:Endothelin and cardiac transplantation. 1115 88

Endothelins, endothelin-1 (ET1), endothelin-2 (ET2) and endothelin-3 (ET3), are the most potent vasoconstrictor peptides released by endothelial cells. ET production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products and cytokines, whereas nitric oxide and prostacyclin reduce ET production. ET bind to ETA and ETB receptors and produce marked and sustained rise in blood pressure, intense vasoconstriction of coronary arteries and have positive inotropic and chronotropic effects on myocardium. Besides, they influence neuroendocrine, renal and smooth muscle functions. ET appears to function mostly as a paracrine or an autocrine hormone. ET may have a role in hypertension, atherosclerosis, heart failure, coronary artery disease, renal insufficiency, vascular hypertrophy, respiratory and cerebrovascular conditions. Several antagonists of ET acting at receptor level or influencing endothelin converting enzyme (ECE) are under investigation and have great potential as agents for use in the treatment of wide spectrum of disease entities and as biologic probes for understanding the actions of ET in human beings.
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PMID:Endothelins and anti-endothelins. 1122 90


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