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)

Endothelin-1 is a potent vasoconstricting substance that may aggravate circulatory dysfunction in acute myocardial infarction. In 59 patients with acute myocardial infarction peripheral venous blood was sampled, and endothelin-1 was measured by radioimmunoassay. Hemodynamic measurements were performed with a flow-directed thermodilution catheter in 16 patients. Plasma endothelin-1 levels in Killip's classes were as follows: group I (no heart failure, n = 25), 1.97 +/- 0.69 pg/ml; group II (heart failure, n = 16), 2.74 +/- 1.02 pg/ml; group III (pulmonary edema, n = 13), 4.54 +/- 1.17 pg/ml; and group IV (cardiogenic shock, n = 5), 8.91 +/- 3.16 pg/ml (normal control group, n = 12: 1.51 +/- 0.39 pg/ml). There were significant correlations between the plasma endothelin-1 level and mean right atrial pressure (r = 0.554; p < 0.05), mean pulmonary artery pressure (r = 0.589; p < 0.02), and cardiac index (r = -0.534; p < 0.05). There were closer correlations between plasma endothelin-1 level and mean pulmonary artery wedge pressure (r = 0.678; p < 0.005) and total pulmonary vascular resistance (r = 0.831; p < 0.001). These results indicate that endothelin-1 is elevated in accordance with cardiac and pulmonary circulatory distress in patients with acute myocardial infarction, which may further aggravate circulatory dysfunction.
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PMID:Plasma endothelin-1 in acute myocardial infarction with heart failure. 843 94

Plasma levels of endothelin-1 are elevated in patients with chronic heart failure; however, it is unknown whether changes in plasma endothelin-1 levels accurately reflect clinical response to therapy in these patients. To determine this, we measured plasma endothelin-1 in addition to functional, hemodynamic, and other neurohormonal parameters as part of a double-blind, placebo-controlled study of the beta-blocker vasodilator carvedilol in patients with moderate to severe chronic heart failure. Patients were assigned (2:1 randomization) to receive carvedilol (25 mg twice daily, n = 10) or placebo (n = 5) for 14 weeks, with evaluations made before and after therapy. Compared to patients receiving placebo, patients receiving carvedilol improved significantly as assessed by the parameters described. These changes were paralleled by significant falls in endothelin-1 with carvedilol (-2.1 + 3.8 pg/ml) in comparison to placebo (2.2 + 3.9 pg/ml; p < 0.05 for between-group differences). Changes in endothelin-1 after treatment in both groups correlated significantly with changes in symptom severity, New York Heart Association class, 6-minute walk distance (r = 0.64 to 0.80; p < 0.05), hemodynamic parameters (ejection fraction, right atrial pressure, pulmonary artery diastolic pressure, pulmonary wedge pressure, right atrial pressure, and stroke volume index; r = 0.54 to 0.86; p < 0.05), and neurohormonal parameters (serum aldosterone and plasma norepinephrine (r = 0.74 to 0.76; p < 0.05). By stepwise regression analysis, change in endothelin-1 was an independent, noninvasive predictor of functional and hemodynamic responses to therapy in these patients. These findings suggest that endothelin-1 accurately reflects functional, hemodynamic, and neurohormonal responses to beta-blocker therapy in patients with congestive heart failure. Measurement of endothelin-1 may therefore be a useful, noninvasive approach to the evaluation of clinical response to drug therapy in these patients.
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PMID:Changes in plasma endothelin-1 levels reflect clinical response to beta-blockade in chronic heart failure. 857 30

Plasma levels of endothelin-1 are increased in patients with severe congestive heart failure related to various etiologies. However, conflicting data have been published in patients with moderate congestive heart failure. Moreover, the effect of exercise on plasma levels of endothelin-1 is not precisely known. We determined the plasma levels of endothelin-1 in a homogenous group of patients with idiopathic dilated cardiomyopathy in stage II of the New York Heart Association functional classification at rest and at peak exercise. In this group of patients, plasma levels of endothelin-1 were increased compared to a control group (2.9 +/- 0.27 vs. 1.96 +/- 0.24 pmol/l, P < 0.01, mean +/- S.E.M.), as were plasma levels of atrial natriuretic peptide (26.3 +/- 6.3 vs. 2.95 +/- 0.7 pmol/l, P < 0.001), plasma renin activity (12.6 +/- 2.98 vs. 1.75 +/- 0.23 ng/ml per h, P < 0.001) and plasma levels of aldosterone (217 +/- 29.3 vs. 154 +/- 18.8 pg/ml, P < 0.05). In contrast to the other hormones, exercise did not increase plasma levels of endothelin-1. There was no correlation between plasma levels of endothelin-1 and plasma levels of atrial natriuretic peptide, and no correlation between left ventricular ejection fraction, peak oxygen consumption and hormonal values. In conclusion, plasma levels of endothelin-1 are increased in a homogeneous group of patients with idiopathic dilated cardiomyopathy and moderate congestive heart failure. Endothelin-1 could participate in the progression of heart failure. Exercise did not increase the plasma levels of endothelin-1 in contrast to the other hormones.
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PMID:Plasma levels of endothelin-1 at rest and after exercise in patients with moderate congestive heart failure. 858 75

The physiologic significance of endothelin-1 (ET-1) generation in human resistance vessels is unknown. We therefore investigated whether endothelin-converting enzyme (ECE) activity could be demonstrated in human vessels, and the effects of inhibition of the generation or actions of ET-1 on vascular tone in healthy men. Brachial artery infusion of local doses of big ET-1 caused a slow-onset, dose-dependent forearm vasoconstriction that was abolished by co-infusion of the ECE inhibitor phosphoramidon. Phosphoramidon did not affect responses to ET-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% (p = 0.03). Vasoconstriction to ET-1 was completely abolished by co-infusion of the ETA receptor antagonist BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone resulted in progressive vasodilatation, with blood flow increasing by 64% (p = 0.007). These results suggest that endogenous generation of ET-1 contributes to the maintenance of vascular tone in states of normal and elevated blood pressure. ECE inhibitors and ETA receptor antagonists may have potential as vasodilators in the treatment of diseases associated with vasoconstriction, such as hypertension and chronic heart failure.
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PMID:Physiologic role of endothelin in maintenance of vascular tone in humans. 858 57

The effects of experimental chronic heart failure (CHF) on the density and affinity for endothelin-1 (ET-1) binding was studied in the rat heart. Because it has been reported that ET-1 binding sites on cultured cardiocytes are downregulated by pretreatment with ET-1, we also studied the plasma concentrations of ET-1 in rats with CHF. Three weeks after ligation of the left coronary artery, rats developed chronic heart failure (CHF rats). The plasma concentrations of ET-1, as measured by a sandwich-enzyme immunoassay, were significantly higher in CHF rats than in sham-operated rats [4.80 +/- 0.33 vs. 0.91 +/- 0.11 (mean +/- SEM) pg/ml; p < 0.01]. [125I]ET-1 binding experiments on rat cardiac membranes revealed that the binding site density (Bmax) was significantly higher in the CHF rats than in the sham-operated rats (243.0 +/- 20.0 vs. 154.8 +/- 17.4 fmol/mg protein; p < 0.05), whereas the values for the dissociation constant (Kd) were not different between the two groups (28.7 +/- 7.0 vs. 29.8 +/- 1.9 pM). Therefore, in the CHF rats, although plasma concentrations of ET-1 were elevated, the density of myocardial ET receptors was increased. Because ET-1 has potent inotropic and hypertrophic effects on cardiac myocytes, it is suggested that the effects of endogenous ET-1 in the heart are different between the CHF rats and the sham-operated rats.
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PMID:Increased endothelin-1 binding sites in the cardiac membranes in rats with chronic heart failure. 858 42

Endothelin-1 is a recently discovered peptide mainly released from endothelial cells. Hypoxia and ischemia as well as numerous factors such as angiotensin 11, thrombin and transforming growth factor beta 1 stimulate the formation of the peptide. On the other hand the synthesis of endothelin is inhibited by nitric oxide and atrial natriuretic peptide via the formation of cyclic guanosine monophosphate. Released from endothelial cells endothelin-1 mediates transient vasodilation followed by a profound and longlasting vasoconstriction. Endothelin is also a mitogen for smooth muscle proliferation. Endothelins exert their biological effects via activation of specific receptors. Two different receptors have been cloned from mammalian tissues (ET(A) and ET(B) receptors). On vascular smooth muscle cells both receptors mediate contractions. Endothelial cells only express ET(B) receptors linked to the formation of nitric oxide and/or prostacyclin formation. Increased plasma concentrations of endothelin-1 have been described in a variety of diseases such as pulmonary hypertension, arteriosclerosis, renal failure, acute coronary syndromes, heart failure, migraine and vascular diseases. Recently an increasing number of endothelin receptor antagonists have been synthetized, which have been shown to inhibit endothelin-mediated vasoconstriction. Clinical studies are now ongoing to elucidate the pathophysiologic role of endothelin and the potential benefit of the blockade of the system in different disease states.
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PMID:Endothelin and endothelin antagonists: potential role in cardiovascular and renal disease. 873 56

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.
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PMID:The clinical potential of endothelin receptor antagonists in cardiovascular medicine. 874 Dec 30

In congestive heart failure, in addition to a compensatory increase in neurohumoral activation, there is an increase in the endothelial-derived vasoconstrictive and positive inotropic substance, endothelin. Whether downregulation of the cardiac inotropic effects of this endothelial-derived substance occurs, as has been shown to occur with neurohumoral beta- and alpha-adrenergic agonists, remains unknown. In this study we investigated the effects of endothelin-1 [dose-response curve (10(-11) to 10(-7) M)] on the contractile characteristics of isolated papillary muscles from normal dogs and from dogs with heart failure induced by pacing overdrive, with or without removing endocardial endothelium from the papillary muscles. Endothelin-1 caused a similar absolute increase in myocardial contractile indices in all four groups, except for shortening, which increased more in muscles with heart failure without endocardial endothelium. However, in muscles with an intact endocardial endothelium, the relative increase was greater in muscles from pacing overdrive dogs (failing) as compared with normal dogs (tension increase of 110% vs. 53%, p < 0.01 and shortening increase of 127% vs. 24%, p < 0.01). Also, failing muscles with intact endocardial endothelium began responding to endothelin-1 at lower endothelin-1 concentrations (10(-10) vs. 10(-9) M) than normal muscles with intact endocardial endothelium. Endocardial endothelial removal increased the contractile effects of endothelin-1, whether this was done in normal or failing myocardium. This study thus indicates that, in contrast to other positive inotropic substances, in this model of heart failure there is an increase in sensitivity and relative response to endothelin-1. It also indicates that although endocardial endothelial removal increases the relative effects of endothelin-1 in both normal and failing myocardium, the increased responsiveness of failing myocardium is not endocardial endothelial dependent.
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PMID:Altered responsiveness to endothelin-1 of myocardium from pacing-induced heart failure model in the dog. 884 1

The pulmonary circulation plays an important role in the removal of circulating endothelin-1 (ET-1). Plasma ET-1 levels are increased in pulmonary hypertensive states of various etiologies (e.g., idiopathic, heart failure, and congenital anomalies) in proportion to the severity of pulmonary hypertension. It is possible that reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia of those pathologies. The ETA and ETB receptors are abundant in lung tissues: on the vascular endothelium, the ETB receptor is predominant and may contribute to ET-1 extraction through receptor-mediated endocytosis. We designed experiments to determine and quantify the importance of the ETA and ETB receptors in the pulmonary extraction of circulating ET-1 in anesthetized dogs. The single-pass cumulative tracer ET-1 extraction by the lung was measured with the indicator-dilution technique before and 5 min after intrapulmonary injection of the specific ETA antagonist BQ-123 (n = 5, 120-960 nmol) and the specific ETB antagonist BQ-788 (n = 6, 1,000 nmol). The inhibitors had no significant effect on pulmonary and systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was not modified by BQ-123 [control (C): 36 +/- 4%, antagonist (A): 34 +/- 6%] but was completely abolished by BQ-788 (C: 34 +/- 6%, A: 0 +/- 2%, P < 0.001). The pulmonary rate constant (K) for ET-1 removal was also unaffected by BQ-123 (C: 0.050 +/- 0.0085 s-1, A: 0.047 +/- 0.012 s-1) but significantly decreased and became close to zero after BQ-788 (C: 0.058 +/- 0.014 s-1, A: 0.009 +/- 0.007 s-1, P < 0.1). We conclude that the ETB receptor is completely and exclusively responsible for pulmonary ET-1 removal in vivo. Future studies are needed to show whether desensitization or downregulation of the ETB receptor may contribute to the increase in circulating ET-1 levels in conditions associated with pulmonary hypertension. This novel pulmonary endothelial cell function may play a protective role by modulating circulating ET-1 levels in the systemic circulation.
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PMID:Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. 890 61

Occlusion of the diseased coronary artery in humans causes acute myocardial infarction, survivors of which have a high risk for the development of chronic heart failure. Cardiac myocytes and vascular endothelial cells produce endothelin-1 (refs 2-4), which increases the contractility of cardiac muscle and of vascular smooth muscle cells. Endothelin-1 also exerts long-term effects such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. Production of endothelin-1 is markedly increased in the myocardium of rats with heart failure, and acute application of an endothelin-receptor antagonist decreases myocardial contractility in such rats, indicating that myocardial endothelin-1 may help to support contractility of the failing heart. But we report here that the upregulated myocardial endothelin system may contribute to the progression of chronic heart failure, because long-term treatment with an endothelin-receptor antagonist greatly improved the survival of rats with chronic heart failure. This beneficial effect was accompanied by significant amelioration of left ventricular dysfunction and prevention of ventricular remodelling, in which there is usually an increase in the ventricular mass and cavity enlargement of the ventricle.
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PMID:Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. 893 19


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