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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 effects of endothelin (ET)-A (ETA)- and ETB-receptor agonist and antagonists were studied in isolated buffer-perfused rat lungs subjected to 45 min of ischemia followed by 105 min of reperfusion (I/R). For the I/R group after 30 and 90 min of reperfusion, the Kfc had increased three- and fivefold above control values, respectively (P < 0.01), and the number of circulating neutrophils in the perfusate decreased by 65 +/- 7.65%. Both an ETA-receptor antagonist (BQ-610) and an ETAB-receptor antagonist (PD-156707-0015) given before the ischemic period protected the lung endothelial barrier from injury associated with I/R. Also, these compounds attenuated the I/R-induced neutrophil accumulation in the lung (31.94 +/- 4.16 and 34.38 +/- 1.05%, respectively; P < 0.01 compared with I/R). Neither an ETB-receptor agonist (IRL-1620) nor an ETB-receptor antagonist (IRL-1038) affected the I/R-induced endothelial injury. In addition, they did not alter the number of circulating polymorphonuclear cells during I/R. ET-1 administration alone caused a dose-dependent increase in pulmonary arterial pressure, but no measurable increase in microvascular permeability occurred. We conclude that ET-1 is involved in I/R-induced lung endothelial injury and speculate that it acts in concert with some other coactivator(s), most likely platelet-activating factor, through ETA receptors. This mechanism requires polymorphonuclear leukocyte activation with subsequent release of oxygen radicals and/or expression of adhesive molecules on the neutrophil surface.
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PMID:Blocked ETA receptors prevent ischemia and reperfusion injury in rat lungs. 884 4

The role of endothelin ETA and ETB receptors as well as of nitric oxide (NO) and prostanoids in the effects of endothelin-1 on the coronary circulation was studied in anesthetized goats. Where blood flow in the left circumflex coronary artery (coronary blood flow) (electromagnetically measured), systemic arterial pressure, left ventricle pressure and d P/dt, and heart rate were recorded. Endothelin-1 (0.01-0.3 nmol), intracoronarily injected, produced marked, dose-dependent reductions in basal coronary blood flow, ranging from 5% for 0.01 nmol to 75% for 0.3 nmol; 0.1 and 0.3 nmol endothelin-1 also reduced systolic ventricle pressure and dP/dt. The effects of endothelin-1 on coronary blood flow were diminished during intracoronary infusion of BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp). specific antagonist for endothelin ETA receptors. 2-16 nmol/min) in a dose-dependent way, but not during the infusion of BQ-788 (N-[N-[N-[(2.6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-1-leucyl]-1- (methoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, specific antagonist for endothelin ETB receptors. 2-4 nmol/min). IRL 1620 (Suc-[Glu9, Ala11.15]endothelin-1-(8-21), specific agonist for endothelin ETB receptors. 0.01-0.3 nmol), intracoronarily injected. slightly reduced basal coronary blood flow only when 0.1 and 0.3 nmol were applied (maximal reduction about 25%); 0.3 nmol IRL 1620 also reduced systolic ventricle pressure and dP/dt. The effects of IRL 1620 were not modified by BQ-123 or BQ-788. NG-nitro-1-arginine methyl ester (L-NAME, inhibitor of NO synthesis, 47 mg/kg by i.v. route) reduced resting coronary blood flow by 10% and increased mean systemic arterial pressure and systolic ventricle pressure by 22 and 20%. respectively, without changing systolic ventricle dP/dt and heart rate. With L-NAME, the reductions of coronary blood flow by endothelin-1 were potentiated (P < 0.05), and those by IRL 1620 were not changed (P > 0.05). Meclofenamate (cyclooxygenase inhibitor, 4-6 mg/kg by i.v. route) modified neither the basal values of hemodynamic variables nor the coronary effects of endothelin-1 and IRL 1620. Therefore, endothelin-1 produces marked coronary vasoconstriction, which may be mediated by endothelin ETA receptors, with no participation of endothelin ETB receptors. NO, but not prostanoids, may produce a basal coronary vasodilator tone and may inhibit endothelin-1-induced coronary vasoconstriction. Also, it is suggested that the coronary vasoconstriction by endothelin-1 may impair cardiac performance due to heart ischemia.
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PMID:Coronary vasoconstriction by endothelin-1 in anesthetized goats: role of endothelin receptors, nitric oxide and prostanoids. 896 Aug 82

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) synthesis is enhanced at sites of ischemia or in injured vessels. The purpose of this study was to explore the possibility of autocrine stimulation of endothelial cell migration by members of the endothelin family. Experiments with microvascular endothelial cell transmigration in a Boyden chemotactic apparatus showed that endothelins 1 and 3, as well as a selective agonist of ETB receptor IRL-1620, equipotently stimulated migration. Endothelial cell migration was unaffected by the blockade of ETA receptor, but it was inhibited by ETB receptor antagonism. Based on our previous demonstration of signaling from the occupied ETB receptor to constitutive nitric oxide (NO) synthase (Tsukahara, H., Ende, H., Magazine, H. I., Bahou, W. F., and Goligorsky, M. S. (1994) J. Biol. Chem. 269, 21778-21785), we next examined the contribution of ET-stimulated NO production to endothelial cell migration. In three independent cellular systems, 1) migration and wound healing by microvascular endothelial cells, 2) wound healing by Chinese hamster ovary cells stably expressing ETB receptor with or without endothelial NO synthase, and 3) application of antisense oligodeoxynucleotides targeting endothelial NO synthase in human umbilical vein endothelial cells, an absolute requirement for the functional NO synthase in cell migration has been demonstrated. These findings establish the permissive role of NO synthesis in endothelin-stimulated migration of endothelial cells.
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PMID:Permissive role of nitric oxide in endothelin-induced migration of endothelial cells. 899 56

The present study was designed to investigate if TAK-044, a novel endothelin (ET) ETA/ETB receptor antagonist, inhibits ischemia-reperfusion liver injury. The initial study showed the presence of both ETA and ETB receptors in canine hepatic membrane fractions using the specific binding assay of labeled ET-1 with ET isomers and TAK-044. The nonselective ETA/ETB receptor antagonist TAK-044 inhibited the specific binding of ET-1 to the receptors in a concentration-dependent manner. In subsequent studies using a canine 70% partial liver ischemic model (60 minutes), we found that an intravenous injection of TAK-044 (3 mg/kg) before ischemia significantly inhibited the release of serum liver enzymes (aspartate transaminase, alanine transaminase, mitochondrial glutamic oxaloacetic transaminase, and an increase of indocyanine green retention rate after reperfusion, compared with the control group. Elevation of the portal venous pressure was also suppressed significantly during the portal triad occlusion, and a rapid restoration of oxygen pressure in the liver tissue after reperfusion was observed in the TAK-044-treated group. Morphometric analysis revealed that the hepatocyte swelling and sinusoidal contraction 1 hour after reperfusion were significantly less severe in the treated group than in the control group. The sludging of erythrocytes in the sinusoidal lumens was also minimal in the treated group. In conclusion, the significant suppression of hepatic microcirculatory disturbance and tissue injury after ischemia-reperfusion were shown in the TAK-044-treated group. This finding indicates that the pretreatment of TAK-044 is useful as a hepatoprotective agent against ischemia-reperfusion injury, which is otherwise produced by a pathway involving ET-1.
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PMID:Hepatoprotective effect of the endothelin receptor antagonist TAK-044 against ischemia-reperfusion injury in the canine liver. 909 1

The acute effect of cyclosporine A (CSA) on myocardial function after ischemia and reperfusion and the mechanism of action was investigated in isolated working guinea-pig hearts. Myocardial function was experimentally infringed by imposing short-term global ischemia and reperfusion (15 min each). External heart work (EHW), determined before and after ischemia, served as the criterion for quantitation of recovery. Control hearts were perfused with modified Krebs-Henseleit buffer, other hearts received buffer supplemented with CsA +/- an endothelin receptor antagonist or exogenous endothelin +/- an inhibitor of nitric oxide (NO) synthesis. To assess the importance of endothelial production of mediators directly, NO release in coronary effluent (continuously measured with an amperometric sensor) and release of 6-keto-prostaglandin F1, (6-keto-PGFb), a stable metabolite of prostacyclin (PGI2), were determined in non-working. Langendorff hearts. Oxidative stress during reperfusion was assessed by measuring glutathione release in coronary venous effluent. Cyclosporine A (0.8 microM) improved post-ischemic function significantly (59% recovery of EHW nu 31% for controls). At 0.08 microM. CsA was without beneficial effect (30% recovery). The endothelin (ET)A- and ETB-receptor antagonist bosentan inhibited the protective action of 0.8 microM CsA (32% recovery). Exogenous ET-1 (80 pM) improved recovery to 53%, an effect which was blocked by the inhibitor of NO-synthase, NG-nitro-L-arginine (NOLAG. 1 microM. 31% recovery. In the control group, post-ischemic NO release in coronary effluent recovered from zero to about 100% of the pre-ischemic value by 10 min. but then decreased rapidly during the subsequent 15 min of reperfusion. In hearts treated with 0.8 microM CsA, NO release stayed at 100% of the pre-ischemic value throughout reperfusion, the difference between controls and CsA-treated hearts being significant after 20 min of reperfusion. On the other hand, coronary venous release of 6-keto-PGF1a was not different between the groups. Release of glutathione during early reperfusion first 5 min) was significantly lowered (P < 0.05) to about 50% in CsA (0.8 microMI- and ET-I-treated compared with controls (8.8 nmol/min). Cyclosporine A acts as a cardioprotective agent in our model of ischemia and reperfusion, presumably by elevating the level of endogenous nitric oxide and thereby reducing oxidative stress.
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PMID:Cardioprotection by cyclosporine A in experimental ischemia and reperfusion--evidence for a nitric oxide-dependent mechanism mediated by endothelin. 914 Aug 13

There is evidence that endothelin (ET) is involved in disturbances of the hepatic microcirculation after warm ischemia. In this study we investigated the influence of a mixed ETA-, ETB-receptor antagonist (Bosentan) on ischemia-reperfusion damage of the liver by means of intravital fluorescence microscopy (IVM). Clamping of the left liver lobe (= warm ischemia) was performed in 16 male Wistar rats for 70 min. The treatment group (N = 8) received 15 mg/kg Bosentan (Ro-47-0203) 1 min prior to reperfusion. Controls (N = 8) received an equivalent amount of Ringer's solution. Between 20 and 90 min after reperfusion, leukocyte-endothelial cell interactions in sinusoids and postsinusoidal venules as well as perfusion of hepatic acini were studied. Application of Bosentan improved sinusoidal blood flow, attenuated manifestations of microvascular perfusion failure, and decreased the number of rolling leukocytes in postsinusoidal venules. Our results provide further evidence that ET is involved in postischemic impairment of hepatic microhemodynamics during reperfusion.
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PMID:Effects of mixed ETA and ETB-receptor antagonist (Ro-47-0203) on hepatic microcirculation after warm ischemia. 920 Nov 1

This study was designed to investigate whether or not a novel nonselective endothelin A/B (ETA/ETB) receptor antagonist (TAK-044) provides hepatoprotection during porcine liver transplantation. The grafts were stored in chilled Euro-Collins solution and recirculated following reflush with lactated Ringer's with (TAK group) or without (control group) TAK-044 (10 mg/kg). Intracellular (cytoplasma, mitochondria, and nucleus) calcium (Ca) concentrations were measured in the hepatic biopsy materials obtained serially at varying time point from donor laparotomy to recipient closure using an electron probe X-ray microanalyzer. Liver function tests also were determined. The cold and warm ischemia times of the grafts were comparable between the two groups. The peak endothelin-1 T-1) concentration after recirculation was significantly higher in the TAK group than in the control group (129 +/- 30 pg/ml vs 26 +/- 6.5 pg/ml). However, release of liver enzymes, increases in total bile acid, and deterioration of indocyanine green retention rate were significantly suppressed in the TAK group. In the control group, the intracellular Ca concentrations, especially in the mitochondrial fraction, were elevated markedly following recirculation of the hepatic arterial flow. In the TAK group, this effect was suppressed. Thus, the supplementary use of the nonselective ETA/ETB receptor antagonist TAK-044 via a rinse route may alleviate an early postreperfusion microcirculatory disturbance of the liver grafts without adverse effects by the increased ET-1 on the systemic circulation.
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PMID:Hepatoprotective effect of a nonselective endothelin receptor antagonist (TAK-044) in the transplanted liver. 924 65

Both endothelin and nitric oxide (NO) have been proposed to act as pathophysiological factors in ischemia-related neural damage. This review is concerned with the participation of the glial endothelin-NO system in ischemia-related neuronal cell death. In the rat brain with cerebral apoplexy, endothelin, endothelin receptors and NO synthase (NOS) were rich in the glial cells of damaged brain areas. The brain subjected to transient forebrain ischemia contained astrocytic endothelins and microglial expressions of the ETB-receptor and NOS aggregating in the damaged CA1 subfield of the hippocampus at 7 days after the ischemia. Astrocytic endothelin, ETB-receptor and NOS became more apparent at 28 days after the ischemia, corresponding to a time when neural tissue-repair/remodeling after damage occurs, whereas no activities of the endothelin-NO system are observed in microglia. In the in vitro experiment, endothelin was found to modulate the release of NO from the hippocampal slices subjected to transient forebrain ischemia. There may be a cross-talk between the endothelin system and NO in the astrocytes and microglia during the process of ischemia-related neuronal cell death and neural tissue-remodeling.
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PMID:[The glial endothelin-nitric oxide system in ischemia-related neuronal cell death]. 955 70


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