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

Endothelin (ET)-1 is a potent vasoconstrictor peptide produced in the myocardium that can exert important effects on cardiac myocyte growth and phenotype; cardiac natriuretic peptides (ANP and BNP) are known to act as physiological antagonists of ET-1. In this study a comparative determination of ET-1 receptors and of the local productions of ET-1 and of ANP and BNP was made in different sites of failing and nonfailing hearts. Tissue from right and left atrium, right and left ventricle and interventricular septum from seven adult heart transplant recipients with end-stage idiopathic dilated cardiomyopathy (functional class III and IV, with ejection fraction < 35%) and from four postmortem subjects without cardiac complications was analyzed. In failing hearts we observed a tendency to increase of density of binding sites, most evident in left ventricle (62.6+/-22.6 fmol/mg protein vs. 29.0+/-3.3, mean +/- SEM, p = ns). A prevalence of ET-A subclass, observed in all samples, resulted more pronounced in failing hearts where this increase, found in all the cardiac regions, was more evident in left ventricle (p = 0.0007 vs nonfailing hearts). The local concentrations of ET-1, ANP and BNP resulted significantly increased in failing hearts with respect to controls in all sides of the heart. In failing hearts we have observed a tendency to increase in endothelin receptor density mainly due to a significant upregulation of ET-A subtype and a parallel increase of the tissue levels of ANP, BNP and ET-1 indicating an activation of these systems in heart failure.
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PMID:Endothelin-1, endothelin-1 receptors and cardiac natriuretic peptides in failing human heart. 1140 Sep 14

Heart failure is characterized both by an activation of the endothelin system and an increased vasoconstrictor contractile response to the peptide. Given its pharmacological profile, it is likely that endothelin (ET-1) plays a deleterious role in the development of heart failure, and that blockers of the endothelin system are beneficial in this disease. Indeed, in rats with heart failure, ET(A) and dual ET(A)-ET(B) receptor antagonists reduce arterial pressure as well as left ventricular end diastolic pressure. The same antagonists also prevent the degradation of left ventricular function, as evidenced by the increased left ventricular fractional shortening and wall thickening. ET(A) and ET(A)-ET(B) antagonists also reduce LV dilatation and LV fibrosis, but do not affect LV hypertrophy. Moreover, comparison between selective ET(A) and combined ET(A)-ET(B) antagonists reveal no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. However, only combined ET(A)-ET(B) antagonists significantly decreased heart rate. ET(B) antagonists alone do not affect blood pressure or LV hemodynamics, but reduce LV fibrosis. With regard to survival, we have shown that long term treatment with the dual ET(A)-ET(B) antagonist bosentan increased survival to the same extent as an angiotensin converting enzyme inhibitor. However, the effect of selective ET(A) antagonists on survival is more controversial, since we found that the non-peptide ET(A) antagonists LU 135252 did not affect survival of rats with myocardial infarction, while others have shown that the peptide ET(A) antagonist BQ-123 increased survival in the same model. These conflicting data regarding the efficacy of selective ET(A) vs dual ET(A)-ET(B) blockade points out the need for controlled long term studies comparing the effects of theses two pharmacological approaches on survival.
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PMID:Endothelin antagonism in experimental ischemic heart failure: hemodynamic, structural and neurohumoral effects. 1144 4

The availability of potent and orally active nonpeptide endothelin (ET) receptor antagonists has generated a host of information on the pathophysiological role of ET-1 in a number of preclinical models including hypertension, renal failure, heart failure and pulmonary hypertension. Convincing data are available to show that ET-1 receptor antagonists are beneficial in humans as far as reversal of deranged systemic and regional hemodynamics associated with CHF and pulmonary hypertension. As in other disease areas, the issue of whether ET(A)-selective or ET(A/B) antagonists are more suited for CHF treatment remains unresolved. ET(B) receptors may mediate some critical processes in the kidney such as sodium and water excretion in addition to releasing vasodilator substances such as NO and prostacyclin from endothelial cells. In heart failure and chronic renal diseases, preservation of ET(B)-mediated responses in the kidney and pulmonary endothelium might be beneficial. On the other hand, blockade of ET(B)-mediated vasoconstriction, smooth muscle cell proliferation and fibrosis by ET(B) antagonists might be beneficial. In clinical trials so far, the hemodynamic effects of mixed antagonists of ET receptors and ET(A) selective antagonists seem equivalent.
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PMID:Endothelin and heart failure. 1144 8

Endothelin (ET)-1, a 21-amino acid peptide, is the predominant isoform of the endothelin peptide family. ET-1 is ubiquitously expressed and stimulates vasoconstriction and cell proliferation. Enzymes such as endothelin converting enzymes (ECE), chymases, and non-ECE metalloproteinases contribute to the synthesis of ET-1, which is regulated in an autocrine fashion in vascular and nonvascular cells. Endothelin ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of nitric oxide and prostacyclin, and inhibition of ECE-1 expression. Most cardiovascular diseases, such as arterial hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, pulmonary hypertension, and renal failure are associated with local activation of the endothelin system. Experimental studies and first clinical trials suggest that ET-1 is importantly involved in the functional and structural changes in the cardiovascular system, and that many of the actions of ET-1 are mediated through pressure-independent mechanisms. Endothelin antagonists promise to be successful as a new class of drugs for the treatment of cardiovascular diseases.
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PMID:The therapeutic potential of endothelin receptor antagonists in cardiovascular disease. 1147 15

Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.
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PMID:The pregnancy hormone relaxin is a player in human heart failure. 1164 Dec 45

In chronic heart failure and acute myocardial infarction, the tissue level of endothelin (ET)-1 in the heart, as well as its plasma level, has been reported to increase markedly. There is, however, little information about what in these pathologic conditions leads to increased production of ET-1, and which type of cell in the heart produces ET-1. We examined the mRNA and peptide expression of ET-1 using cultured rat neonatal cardiomyocytes, in which mitochondrial dysfunction was induced by rotenone, a mitochondrial respiratory chain complex I inhibitor, because one of the common features in failing or ischemic hearts is an alteration in energy metabolism due to mitochondrial dysfunction. Rotenone increased glucose use by the culture cells within 12 h of addition without affecting cell viability, and depressed the mitochondrial membrane potential after 72 h, indicating the induction of mitochondrial dysfunction in cardiomyocytes. Rotenone induced significant increase in the expression level of mRNA for ET-1 within 1 h of addition. In accordance with this finding, immunoreactive ET-1 in culture medium increased 3 times after 24 h of incubation, suggesting active secretion of ET-1 from cultured cells treated with rotenone. Immunocytochemical analysis verified significant increase of ET-1 peptide in cardiomyocytes, confirming the production of ET-1 by cardiomyocytes. These results suggest that derangement of mitochondrial function in cardiomyocytes itself could lead to the increased production of ET-1 in cardiomyocytes, and that this mechanism may contribute to the increased production of ET-1 in failing and ischemic hearts.
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PMID:Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat cardiomyocytes. 1170 88

Endothelin (ET)-1 is an endothelium-derived peptide with potent vasoconstrictor and proliferative properties. The ET system is activated in several cardiovascular disease states associated with functional and structural vascular changes, including hypertension and heart failure. The two ET receptor subtypes are known as ET(A)R and ET(B)R. The former is located mainly on vascular smooth muscle cells and is responsible for mediating vasoconstriction and proliferation. The latter is present predominantly on endothelial cells and mediates vasorelaxation as well as ET-1 clearance. Activation of smooth muscle ET(B)R causes vasoconstriction. Selective ET(A)R antagonists as well as nonselective ET(A)R-ET(B)R antagonists have been developed. Studies with animal models and early-phase clinical trials provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension, and atherosclerosis. However, the complexity of biologic effects mediated by two different receptor subtypes complicates therapy with selective versus nonselective ET receptor antagonists. In addition to subtype selectivity and potency, changes in receptor subtype distribution under different pathologic conditions and different patient populations will play a crucial role in the evaluation of these potentially therapeutic drugs.
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PMID:Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. 1179 30

A role of the potent and long-acting vasoconstrictor peptide endothelin (ET)- I in the pathophysiology of chronic human heart failure has been postulated, based upon indirect evidence such as elevated plasma ET-1 levels and their relationship to the degree of haemodynamic impairment. Acute heart failure shares many features of chronic heart failure, albeit in an exaggerated fashion. As both the mixed ETA/ETB-receptor antagonist bosentan and the selective ETA receptor antagonist BQ 123 acutely improved the haemodynamics of chronic heart failure patients, there seems to be good reason to believe that ET-1 receptor antagonism may also be of benefit in the setting of acute heart failure. However, appropriate trials will have to be performed to document the clinical benefit of such an approach. Finally, the question remains open as to whether mixed ET-1 receptor antagonists like bosentan will prove better, worse or equal to antagonists that block the ETA, receptor only.
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PMID:Rationale and perspective of endothelin-1 antagonism in acute heart failure. 1181 79

In a group of 124 patients the authors investigated the importance of assessment of plasma levels of big endothelin and endothelin 1 in patients with chronic heart failure as compared with other currently used non-invasive parameters. A six fold increase of plasma levels of both substances was found in patients in functional class NYHA IV as compared with patients in class NYHA II-III. But even patients in the milder stage of NYHA had twice as high values as compared with the standard of the healthy population. Similarly patients with interstitial pulmonary oedema had a twice as high level of both parameters as compared with patients who had a normal finding on X-ray or merely a redistribution of the pulmonary vascularization. The sensitivity of assessment of plasma levels is such that this examination could become part of the basic diagnosis.
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PMID:[Big endothelin and chronic heart failure]. 1185 84

Heart failure (HF) is characterized by activation of both neurohumoral and sympathetic nervous systems. Specifically, HF is associated with increases in vasopressin (VP) and endothelin (ET) and in arterial baroreflex dysfunction. Hypothesis was that central ET-1 potentiates VP secretion in HF due to impaired pressor response and diminished arterial baroreflex inhibition. Male Sprague-Dawley rats were studied 42 to 54 days after sham or coronary ligation (HF) and 7 days after sinoaortic denervation (SAD). Conscious rats received intracerebroventricular artificial cerebrospinal fluid (CSF), 10 pmol of ET-1, 40 nmol BQ123, or both. Basal mean arterial pressure (MAP) did not differ, but heart rate and left ventricular end-diastolic pressure were significantly higher in HF and HF/SAD. Baseline VP was higher in both HF and HF/SAD: 5.9 +/- 0.4 pg/ml and 5.6 +/- 0.7 pg/ml versus sham 2.8 +/- 0.2 and sham-SAD 1.6 +/- 0.2 (p < 0.001). ET-1 increased MAP in sham rats by 16.0 +/- 1.4 mm Hg, but only by 7.4 +/- 2.2 mm Hg in HF (p < 0.05 versus sham) and 5.8 +/- 2.4 mm Hg in HF/SAD (p < 0.01 versus sham SAD). Tachycardic response was attenuated in HF/SAD compared with HF alone. After ET-1, VP increased by 3.3 +/- 2.7 pg/ml in sham and 13.3 +/- 2.6 pg/ml in HF (p < 0.05), but only by 2.3 +/- 0.7 pg/ml in HF/SAD (p < 0.01 versus HF). BQ123 blocked all responses to exogenous ET-1 but had no effect on baseline values. Thus, ET-evoked a lower pressor response in HF due to an impaired ability to increase heart rate and cardiac output. ET-1-induced VP release in HF was higher than in controls as a result of lower pressor response or impaired arterial baroreflex. In contrast to rats with normal left ventricular function, sinoaortic denervation in HF failed to potentiate either pressor response or VP secretion. These findings suggest that acute, though modest, increases in afterload may increase left atrial pressure more in HF/SAD such that cardiopulmonary reflexes may be activated or natriuretic peptides may be released that further restrain both pressor and VP responses.
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PMID:Endothelin 1-induced pressor response and vasopressin release in rats with heart failure. 1207 80


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