UMLS:C0151744 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coronary constrictor actions of endothelin-1 (ET-1) are enhanced after myocardial ischemia/reperfusion (I/R), possibly owing to enhanced ETA-receptor-mediated constriction and/or loss of the opposing ETB-receptor-mediated vasodilatation. We examined the actions of ET-1, ET-2, and ET-3 and the selective ETB-receptor agonist sarafotoxin 6c (Sx6c) after I/R in perfused rat heart. To examine the effects of a loss of ETB-receptor-mediated vasodilatation on coronary constrictor responses to ET-1, we used repeated doses of Sx6c to desensitize ETB receptors. After I/R, the coronary constrictor effects of all three ETs were enhanced, whereas their initial vasodilator effects were inhibited. The pure coronary dilator effect of Sx6c observed in control hearts was also inhibited after I/R. After desensitization of ETB receptors, the coronary constrictor action of ET-1 was enhanced by an amount equivalent to the vasodilatation that had been lost. This enhancement of constriction was not as marked as that noted after I/R, suggesting that the enhanced coronary constrictor action of ET-1 after I/R is not simply due to loss of opposing ETB-receptor-mediated vasodilatation and that other mechanisms are involved. The most likely explanation is upregulation of functional ETA receptors after I/R because ETB-receptor stimulation did not cause coronary constriction in this preparation. The vasoconstrictor enhancement therefore is likely to be the combined effect of receptor upregulation and vasodilator loss.
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PMID:Responses to endothelins-1, -2, and -3 and sarafotoxin 6c after ischemia/reperfusion in isolated perfused rat heart: role of vasodilator loss. 753 62

Endothelin is the most potent mammalian vasoconstrictor yet discovered. Its three isoforms play leading roles in regulating vascular tone and causing mitogenesis. The isoforms bind to two major receptor subtypes (ETA and ETB), which mediate a wide variety of physiologic actions in several organ systems. Endothelin may also be a disease marker or an etiologic factor in ischemic heart disease, atherosclerosis, congestive heart failure, renal failure, myocardial and vascular wall hypertrophy, systemic hypertension, pulmonary hypertension, and subarachnoid hemorrhage. Specific and nonspecific receptor antagonists and ECE inhibitors that have been developed interfere with endothelin's function. Many available cardiovascular therapeutic agents, such as angiotensin-converting-enzyme inhibitors, calcium-entry blocking drugs, and nitroglycerin, also may interfere with endothelin release or may modify its activity. The endothelin antagonists have great potential as agents for use in the treatment of a wide spectrum of disease entities and as biologic probes for understanding the actions of endothelin in human beings.
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PMID:Endothelin and endothelin antagonism: roles in cardiovascular health and disease. 766 Oct 79

Previous work indicated that endothelin (ET) may be involved in the pathogenesis of myocardial ischemia, although the relative importance of the ET receptor subtypes is presently not clear. The purpose of this study was to determine the role of myocardial ET-B receptors in mediating ischemic/reperfusion damage in isolated rat hearts. Saturation binding analyses were conducted with [125I]ET-1 and [125I]IRL-1620 to assess changes in ET-A and ET-B receptor binding. Total ET receptor density (Bmax) was greater in atrial versus ventricular tissue. ET-A Bmax was 8 to 10-fold greater than ET-B Bmax. In ischemic and ischemic/reperfused atrial tissue neither the equilibrium dissociation constant (Kd) nor Bmax for ET-B receptors was changed. The ET-B receptor Kd in ischemic or ischemic/reperfused ventricular tissue was also unchanged. In ischemic ventricular tissue there was a trend towards an increased ET-B Bmax, which was accentuated after ischemia/reperfusion. No changes were found in ET-A Bmax or Kd in ischemic ventricular or atrial tissue. The physiological importance of this receptor subtype in ischemic myocardium was determined using the selective ET-B agonist, sarafotoxin S6c. In non-ischemic tissue no effect on coronary flow or function were observed with sarafotoxin S6c. Furthermore, no changes were seen in ischemic time to contracture or any of the reperfusion indexes of myocardial damage. The sarafotoxin S6c utilized was active as it inhibited [125I]ET-3 binding to ET-B receptors (Ki = 0.1 nM). Thus, the pro-ischemic effect of ET-1 seems to be mediated by ET-A receptors. ET-B receptors do not appear to play a role in the pathogenesis of myocardial ischemia.
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PMID:Role of endothelin receptor subtype B (ET-B) in myocardial ischemia. 796 63

In contrast to in vitro studies, experiments in intact animals could not detect a positive inotropic effect of endothelin-1 (ET-1). We presumed that the ET-induced direct positive inotropy is antagonized in vivo by an indirect cardiodepressant effect due to a mainly ETA-mediated and ET-induced coronary constriction, with consequent myocardial ischemia. To confirm this hypothesis we examined in thoracotomized rats the effects of a nonselective activation of ETA and ETB receptors by 1 nmol/kg ET-1 with and without the vasodilator adenosine (2.0 mg/kg/min), and the effects of a selective activation of ETB receptors by the ETB agonist IRL 1620 (2 nmol/kg) on myocardial contractility and energy metabolism (ATP, ADP, AMP). In addition to recordings in the intact circulation, isovolumic measurements (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility. ET-1 had no positive inotropic effect (peak dP/dtmax -2% vs. control, n.s.) due to a marked vasoconstriction with a consequent fall in the myocardial ATP content (-17%; p < 0.01). Adenosine antagonized the ET-induced vasoconstriction in part, normalized myocardial energy metabolism (ATP -7%), and thus unmasked the positive inotropic effect of ET-1 (peak dP/dtmax +20%; p < 0.01). Selective activation of ETB receptors by IRL 1620 had only a small vasoconstrictor effect, which did not produce myocardial ischemia (ATP + 10%; n.s.) and thus caused a positive inotropic effect in vivo (peak dP/dtmax +22%; p < 0.01). The positive inotropic effect of ET-1 is not detectable in vivo as its marked, mainly ETA-mediated, vaso- and coronary constriction causes myocardial ischemia that thus produces an indirect negative inotropic effect.
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PMID:Effects of endothelin-1 and IRL 1620 on myocardial contractility and myocardial energy metabolism. 858 48

We investigated changes in vascular reactivity to endothelin (ET) and local release of ET-like immunoreactivity (ET-LI) induced by myocardial ischemia and reperfusion in a pig model of coronary thrombosis and thrombolysis and studied the possible mechanisms producing the changed vascular reactivity to ET-1. We induced coronary thrombosis by inserting a copper coil into the left anterior descending coronary artery (LAD) and achieved thrombolysis with tissue plasminogen activator (t-PA). Vascular reactivity to ET-1 in the nonischemic and ischemic/reperfused LAD diagonal branches was evaluated in vitro. ET-LI was analyzed in plasma from the great cardiac vein and aorta for estimation of local release. The vasoconstrictor response to ET-1 was enhanced twofold (p < 0.01) in the ischemic/reperfused arteries as compared with the nonischemic arteries. The vasoconstriction induced by the ETB receptor agonist [Ala 1,3,11,15] ET-1 or serotonin was not significantly affected by ischemia/reperfusion. The ETA receptor antagonist BQ-123 reversed the ET-1-induced vascular contraction to a similar degree in ischemic/reperfused and control arteries. The ET-1-induced vasoconstriction of control arteries was not affected by inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA) or cyclooxygenase with indomethacin. During reperfusion, the myocardial venoarterial plasma concentration difference of ET-LI and blood flow increased, resulting in an increased overflow of ET-LI. Our results demonstrate that coronary thrombosis and thrombolysis evokes enhanced local release of ET-LI during the reperfusion period and increases the vasoconstrictor effects of ET-1 through a mechanism related to ETA receptor activation but unrelated to altered endothelial function. These changes may play a role in the development of ischemic/reperfusion injury and no-reflow phenomenon.
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PMID:Myocardial release of endothelin (ET) and enhanced ET(A) receptor-mediated coronary vasoconstriction after coronary thrombosis and thrombolysis in pigs. 863 92

The role of endothelin (ET) in acute myocardial infarction and proarrhythmic potential was investigated in a rabbit model. One group of rabbits underwent 30 min of circumflex occlusion and 3 h of reperfusion with measurements of myocardial blood flow and myocardial levels of ET-1 messenger RNA (mRNA). In a second group, the systemic and coronary effects of exogenous ET were studied in animals pretreated with either saline, FR139317, an ETA-receptor antagonist, or PD145065, an ETA-and ETB-receptor antagonist. In a third study, animals undergoing 30 min of circumflex occlusion followed by 48 h of reperfusion were treated with exogenous ET-1, FR139317, PD145065, or saline. Arrhythmias were recorded and infarct size measured at 48 h. These studies revealed that ischemia and reperfusion was followed by a progressive microcirculatory failure ("no-reflow phenomenon") in rabbits. This was associated with a 2.6-fold elevation in levels of myocardial ET-1 mRNA in the ischemic zone in comparison to the nonischemic zone (p = 0.04). Exogenous ET-1 caused elevation in coronary and systemic vascular resistance that was significantly blocked by antagonism of the ETA receptor. In rabbits subjected to myocardial ischemia and reperfusion, ET-1 infusion led to a higher incidence of ventricular arrhythmias, whereas ET-receptor antagonism with PD145065 significantly reduced ventricular arrhythmias. Exogenous ET-1 and FR139317 failed to alter infarct size (AN) of the area at risk (AR) compared with control [AN/AR(%) was 46 +/- 8, 55 +/- 9, and 47 +/- 7, respectively]. However, PD145065 significantly decreased AN/AR (22 +/- 7; p < or = 0.02). The increased production of ET-1, resulting from increased levels of mRNA after reperfusion, may contribute to the no-reflow phenomenon. Although the vasoconstrictor effects of ET-1 can be blocked by ETA-receptor antagonism alone, only blockade of both the ETA and ETB receptors significantly reduced infarct size. These data suggest that production of ET increases in the heart during ischemia and is deleterious to the reperfused myocardium.
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PMID:Role of endothelin in a rabbit model of acute myocardial infarction: effects of receptor antagonists. 896 Oct 75

Endothelin (ET) has been implicated in cardiovascular disorders such as stroke and myocardial ischemia. Given the important role of the resistance vasculature in the control of blood flow, we investigated the ET receptors that mediate vasoconstriction in human small pial and coronary arteries supplying the brain and heart, respectively. ETA receptors were localized by autoradiography to the vascular smooth-muscle layer of pial, intracerebral, and intramyocardial arteries. In contrast, little ETB binding was observed. ET-1 was a more potent constrictor than ET-3 in both pial and coronary arteries. Biphasic ET-3 responses were obtained in four of 15 coronary arteries tested. The ETB agonist sarafotoxin S6c had little or no effect in these vessels. The nonpeptide, selective ETA receptor antagonist PD156707 caused a parallel shift to the right of the concentration-response curve to ET-1, yielding pA2 values of 9.17 +/- 0.07 and 8.38 +/- 0.17 in pial and coronary arteries, respectively. Slopes from Schild analysis were not significantly different from unity. These data suggest that ETA receptors predominate on the smooth-muscle layer of human small pial arteries. Coronary arteries also express mainly ETA receptors. However, a small population of contractile ETB receptors may also be present in some patients.
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PMID:Relative contribution of endothelin A and endothelin B receptors to vasoconstriction in small arteries from human heart and brain. 959 5

We have determined the ability of the endothelin A (ETA)-selective antagonist PD156707 to block constrictor ET-1 responses in blood vessels from the diseased human heart. ET-1 potently contracted nonatherosclerotic coronary arteries from patients with cardiomyopathy (pD2 = 7.96 +/- 0.15; n = 6), atherosclerotic coronary arteries from patients with ischemic heart disease (pD2 = 8.26 +/- 0.20; n = 4), and saphenous vein grafts that had developed "atherosclerotic" disease after coronary artery bypass (pD2 = 8.41 +/- 0.09; n = 6). PD156707 (100 nM) antagonized the vasoconstrictor response to ET-1 in each of the three preparations, with estimated pA2 values of 7.91 +/- 0.20, 8.05 +/- 0.14, and 8.07 +/- 0.02, respectively. These data suggest that the upregulation of ETB receptors that has been reported in human atherosclerotic coronary arteries does not contribute significantly to the ET-1-mediated constrictor response in these vessels in vitro.
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PMID:PD156707: a potent antagonist of endothelin-1 in human diseased coronary arteries and vein grafts. 959 48

The positive inotropy of endothelin-1 (ET-1) described by in vitro studies is not detectable in vivo because this effect is antagonized by cardiodepressive effects due to ET-induced vasoconstriction with subsequent myocardial ischemia. This vasoconstriction is mainly mediated by ETA receptors. In a previous in vivo study with a selective ETB receptor agonist, we showed that ETB receptors play an important role in the ET-induced positive inotropy. The present in vivo study examined whether selective ETA receptor blockade can unmask the ETB receptor-mediated positive inotropy of endogenous ET-1 by preventing its cardiodepressive effects via ETA receptors. In an open-chest rat model, we compared the acute hemodynamic and inotropic effects of the highly selective ETA receptor antagonist BQ-610 (100 micrograms/kg) with NaCl controls during and after a 7-min infusion. In addition to measurements in the intact circulation, the effects on myocardial contractility were studied by isovolumic registrations (peak LVSP, peak dP/dtmax), which are independent of peripheral vascular effects. Acute blockade of the ETA receptors by BQ-610 had no effect on blood pressure and heart rate. BQ-610 caused vasodilatation (total peripheral resistance -7.5% vs. control at the end of infusion; p < 0.01) with a consecutive increase in stroke volume (+15.3%; p < 0.01), cardiac output (+15.4%; p < 0.001), and ejection fraction (+10.4%; p < 0.01). The isovolumic measurements indicated a significant positive inotropic effect of BQ-610 (peak LVSP + 4.2%, p < 0.01; peak dP/dtmax + 5.5%, p < 0.01). Therefore, selective ETA receptor blockade by BQ-610 improves the hemodynamics in the intact circulation by causing a reduction in afterload and an increase in myocardial contractility. The positive inotropic effect of BQ-610 may be mediated by the positive inotropy of endogenous ET-1 via ETB receptors after selective ETA receptor blockade.
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PMID:Hemodynamic and inotropic effects of the endothelin A antagonist BQ-610 in vivo. 959 54

-In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 microg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.
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PMID:Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610. 993 Oct 95

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