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)

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a novel non-peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [125I][Sar1, Ile8]angiotensin II for angiotensin AT1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [125I][Sar1, Ile8]angiotensin II to the angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration-response curve for angiotensin II with a pA2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F2alpha or endothelin-1 even at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues, YM358 was approximately 3-10 times more potent than losartan in antagonizing angiotensin AT1 receptors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of angiotensin II in a dose-dependent manner. In conscious normotensive rats, YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced pressor response in a dose-dependent manner. YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that YM358 is a potent, AT1-selective and competitive nonpeptide angiotensin receptor antagonist. Moreover, YM358 is both orally active and long-lasting. This pharmacological profile suggests that YM358 would be suitable for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.
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PMID:Pharmacological profile of YM358, a novel nonpeptide angiotensin AT1 receptor antagonist. 936 70

The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors.
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PMID:Circulatory and myocardial effects of endothelin. 942 21

Serum levels endothelin-1,2 aldosterone, renin activity were performed in 52 patients with chronic congestive heart failure during captopril therapy. The investigations were done before therapy, after 10-15 days therapy and after disappearance symptoms of heart failure. The levels endotelin-1,2,aldosterone and renin activity were determined using radioimmunologic methods. Fraction ejection and peripheral vascular resistance were determined by echocardiography technics. It was found that serum endothelin levels in patients with chronic congestive heart failure were increased proportionally to functional class of heart failure and decreased after disappearance symptoms of heart failure. An increase in plasma endothelin concentration has not correlated with ejection fraction, aldosterone concentration and renin activity. These studies have demonstrated that in patients with congestive heart failure on captopril therapy endothelin serum levels positively correlates with peripheral vascular resistance. No correlation was found between ejection fraction and activity renin-angiotensin-aldosterone system. These findings indicated that captopril therapy decreases endothelin production.
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PMID:[Does captopril decrease endothelial production of endothelin?]. 946 3

Endothelin-1, a member of a novel family of regulatory peptides, is the most potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino-acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral circulations, enhances responses to other vasoconstrictors, and is comitogenic. Recent studies have shown that the endothelins are essential for normal fetal development, and that endothelin-1 plays an important physiological role in the regulation of basal vascular tone and blood pressure in healthy humans. There is now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a range of cardiovascular diseases associated with sustained vasoconstriction, such as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage. In addition, endothelin-1 appears to act in opposition to nitric oxide to promote the atherosclerotic process. There are a large number of oral and intravenously active endothelin antagonists entering clinical development and a number of clinical studies, particularly with endothelin receptor antagonists, are now under way. Such studies are beginning to define the role of the endothelins in cardiovascular disease and to confirm the potential of the endothelin system as an important new therapeutic target.
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PMID:The endothelin system in cardiovascular physiology and pathophysiology. 954 47

Elevated endothelin-1 (ET-1) levels are found in atherosclerosis, myocardial ischemia, and heart failure, and are correlated with increased mortality rates. Contrary to expectations, elevations of endogenous ET-1 levels in transgenic mice are not associated with increases in arterial blood pressure or with vasospasm, although these effects can be observed after i.v. ET-1 administration. The aim of this study was to determine the regulatory effects of ET-1 on the expression of vasodilator beta-adrenergic receptors and their ability to activate adenylyl cyclase. Smooth-muscle cells were incubated with ET-1 (10(-7) mol/L) for 3 days. The density of ET-1 or beta-adrenergic receptor binding sites was determined using a radioligand binding procedure. Adenylyl cyclase activity was measured to assess any functional changes in the beta-adrenergic receptor density. ET-1 incubation reduced ET-1 binding sites by 70%. In contrast, the beta-adrenergic receptor density increased from 354 +/- 35 to 538 +/- 50 fmol/mg protein (p < 0.01; n = 7) after 3 days. ET-1 increased beta-adrenergic receptors dose-dependently. Incubation with ET-1 for different periods of time showed an initial decrease of 30% after 6 h of ET-1 incubation. However, after 24 h ET-1 induced an increase of beta-adrenergic receptors, reaching a maximal amount after 48 h. An increased stimulation of beta-adrenergic receptor-activated adenylyl cyclase was observed after 3-day ET-1 incubation compared to controls. These data demonstrate that chronic ET receptor activation by ET-1 results in a functionally significant increase in beta-adrenergic receptor density and adenylyl cyclase activity.
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PMID:Dynamic regulation of beta-adrenergic receptors by endothelin-1 in smooth-muscle cells. 959 6

Plasma levels of immunoreactive endothelin-1 (ET-1) are elevated in chronic heart failure (CHF) and have been reported to correlate closely with pulmonary hemodynamic measurements. We investigated the effects of exogenous ET-1 on the pulmonary vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. ET-1 was infused at 1, 5, and 15 pmol/min into a distal pulmonary artery of 10 patients with LVD. Hemodynamics were measured by a thermodilution catheter and arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. Systemic hemodynamic changes occurred with ET-1 infusion in a dose-dependent fashion. Mean arterial pressure (100 +/- 8-107 +/- 11 mm Hg; p < 0.01) and systemic vascular resistance (1,699 +/- 375-2,033 +/- 427 dynes/s/cm-5; p < 0.001) rose, whereas the cardiac index fell from 2.43 +/- 0.53 to 2.20 +/- 0.491/min/m2 (p < 0.002). However, mean pulmonary artery pressure (21 +/- 7 mm Hg) and pulmonary vascular resistance (151 +/- 43-147 +/- 43 dynes/s/cm-5) did not change. Exogenous ET-1, when infused into patients with LVD, causes systemic but not pulmonary vasoconstriction.
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PMID:Pulmonary and systemic responses to exogenous endothelin-1 in patients with left ventricular dysfunction. 959 62

The potent vascular, cardiac, and renal actions of endothelin-1 (ET-1) suggest a role for this vasoconstrictor peptide in the pathophysiology of heart failure (HF). Recent studies have shown increased levels of ET-1 peptide accompanied by increased ETB receptor binding in the left ventricle during experimental HF. However, much less is known about the regulation of mRNA expression of these genes in HF. We compared the levels of mRNA expression for ET-1 and ET receptors (ETA and ETB) in the left ventricle of rats with HF induced by coronary artery ligation (n = 6) vs. sham-operated animals (n = 6). Levels of mRNA for ET-1 were determined by ribonuclease protection assay (RPA) using beta-actin as the internal control, whereas ET receptors were quantified by quantitative-competitive RT-PCR. Compared with sham animals, ET-1, ETA, and ETB receptor mRNA levels were markedly upregulated in the left ventricle by 6.6 +/- 1.8-fold (p < 0.01), 3.2 +/- 0.6-fold (p < 0.05), and 3.5 +/- 1.0-fold (p < 0.05), respectively. ET-1 mRNA levels were measured in two additional groups of rats (HF and sham; n = 6 each) treated for 4 weeks with the selective ETA receptor antagonist LU135252. This treatment had no significant effect on ET-1 mRNA expression in sham animals but reduced the upregulation of ET-1 expression in the HF group by 41 +/- 19% (p < 0.05). This study confirms the potential importance of ET-1 in HF and suggests that increased expression of ET-1 and ET receptors in the failing ventricle may contribute to alteration in basal cardiac contractility and myocardial remodeling.
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PMID:Coordinated upregulation of the cardiac endothelin system in a rat model of heart failure. 959 63

Accumulating evidence suggests that endogenous endothelin-1 (ET-1) may contribute to the development of heart failure. In this study we determined sites of ET-1 synthesis and production in the failing human myocardium by immunohistochemistry and in situ hybridization for ET-1 and endothelin-converting enzyme-1 (ECE-1). Myocardial tissues were obtained from 19 patients with heart failure and from four noncardiac patients as controls. In both failing and nonfailing hearts, apparent immunoreactivity for ET-1 and ECE-1 was consistently seen in cardiac myocytes. Endothelial cells of intramyocardial coronary arteries and veins had only weak or focal ET-1 and apparent ECE-1 immunoreactivities. On the other hand, in situ hybridization showed strong signals for ET-1 and ECE-1 mRNAs in vascular endothelial cells but a lesser intensity of signals in cardiac myocytes. Apparent immunoreactivity and strong hybridization signals for both ET-1 and ECE-1 were seen in macrophages, which were abundant in infarcted regions of ischemic cardiomyopathy and in myocardium of septic patients but were rare in healthy hearts. These results suggest that, in failing human heart, vascular endothelial cells and macrophages rather than cardiac myocytes appear to be the principal ET-1 synthetic sites, although ET-1 peptides are abundantly present in cardiac myocytes of both failing and nonfailing hearts. Endogenous ET-1 may play a pathophysiologic role in human heart failure.
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PMID:Expression of endothelin-1 and endothelin-converting enzyme-1 mRNAs and proteins in failing human hearts. 959 1

The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.
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PMID:Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure. 959 2

Endothelin-1, discovered in 1988, is a 21-amino-acid peptide and currently the most potent vasoconstrictor and pressor substance known. Generated by vascular endothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 is known to potentiate the actions of other vasoconstrictor substances and act as a comitogen in addition to directly causing vasoconstriction. There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis. Studies using endothelin receptor antagonists show that endothelin-1 plays an important role in the maintenance of vascular tone and blood pressure in healthy humans, predominantly via an effect on the vascular smooth muscle ETA receptors. The endothelin receptor antagonist bosentan also effectively lowers blood pressure in hypertensive subjects and produces sustained and favorable effects on systemic and pulmonary hemodynamics in patients with chronic heart failure. A good side-effect profile, together with a potential for inhibition of atherogenesis, makes the endothelin receptor antagonists a potentially interesting class of novel agents for the treatment of cardiovascular disease.
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PMID:Clinical experience with endothelin antagonists. 960 70


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