Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin (ET) binding sites in male Wistar rat brains subjected to a 20-min four-vessel occlusion (transient forebrain ischemia model) which induces hippocampal neuron death, and in human brains with Alzheimer disease, were mapped by quantitative in vitro autoradiography employing [125I]ET-1 as a radioligand. Rats were decapitated 4 or 7 days after ischemia. In the rat brain, the [125I]ET-1 binding sites were remarkably increased in the hippocampal CA1 and dentate gyrus, ventral thalamic nucleus, and cortical vessels 4 and 7 days after ischemia, when many reactive astroglia were observed. The [125I]ET-1 binding sites decreased in the cerebral cortex affected by Alzheimer disease. The binding was abolished by 1 microM unlabeled ET-1, ET-3, sarafotoxin S6b, and BQ788 (an ETB antagonist) but not by BQ123 (an ETA antagonist), suggesting that the [125I]ET-1 binding sites are as ETB receptors. The present findings raise the possibility that a glial ET system could be responsible for the occurrence of ischemic neuron cell death.
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PMID:Endothelin receptors in ischemic rat brain and Alzheimer brain. 858 5

We investigated the effects of bosentan, a nonpeptide endothelin (ET) receptor antagonist, on ET-induced changes in coronary flow and myocardial ischemic and reperfusion injury in the isolated rat heart. Bosentan (10(-5) M ) attenuated coronary constriction induced by ET-1 and dilatation induced by the ETB agonist IRL 1620. In hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion, bosentan (10(-5) M) significantly improved the recoveries of the left ventricular developed pressure, dP/dtmax, and coronary flow at the end of reperfusion, compared to vehicle-treated controls. During reperfusion, left ventricular end-diastolic pressure was significantly lower in the bosentan group than in the vehicle group. Acetylcholine-induced, endothelium-dependent vasodilatation was significantly attenuated at the end of reperfusion in controls but not in bosentan-treated hearts. We conclude that bosentan reduces myocardial and endothelial injury after ischemia/reperfusion in the isolated rat heart, indicating a pathophysiologic role of endogenous ET.
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PMID:The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart. 858 41

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

We studied the effects of the specific endothelin (ETA) receptor antagonist, BQ-123, on reperfusion injury in a rat model of kidney transplantation. First, Sprague-Dawley rats were divided into three groups: a sham nephrectomy (SNEPH), an autotransplantation (AUTO-Tx), and an allotransplantation (ALLO-Tx) group. In a fourth group, ALLO-Tx + BQ, allografts were flushed with 20 micrograms BQ-123 containing cold Ringer's lactate before transplantation. For the allograft groups, kidneys from white Wistar albino rats were transplanted into allogeneic Sprague Dawley recipients. Grafts were allowed 120 min of reperfusion after 40 min of cold ischemia. ET-1,2 plasma concentrations in the renal venous blood, and kidney tissue prostaglandin (PG) E2 and leukotriene (LT) B4 levels were studied. Diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels, as the products of lipid peroxidation, and protein carbonyls (PC) and protein sulphydryls (PS), as the parameters of protein oxidation, were also analyzed in the kidney tissue. Plasma ET concentrations increased significantly in the AUTO-Tx and ALLO-Tx groups (P < 0.05 and P < 0.01, respectively) but this increase was reversed in the ALLO-Tx + BQ group. None of the lipid peroxidation products except DCs (P < 0.05) increased in the AUTO-Tx group, whereas they all increased in the ALLO-Tx group (P < 0.01). Protein oxidation parameters also changed significantly (P < 0.01) in the ALLO-Tx group but did not in the AUTO-Tx group (P < 0.05). The differences in PGE2 and LTB4 levels were not significant. Histopathologic examination revealed prominent glomerular and tubular injury in the AUTO-Tx and ALLO-Tx groups but less in the ALLO-Tx + BQ group. In the last group, all parameters of lipid peroxidation (P < 0.001 for all) and PCs decreased, and PSs were preserved (P < 0.001 for both) when compared with the AUTO-Tx and ALLO-Tx groups. We conclude that BQ-123, in addition to inhibiting the binding of ET-1,2 to the ETA receptor, may also inhibit the release and/or synthesis of ET-1,2 and prevent reperfusion injury in kidney transplantation.
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PMID:BQ-123, a specific endothelin (ETA) receptor antagonist, prevents ischemia-reperfusion injury in kidney transplantation. 872 87

The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.
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PMID:Endothelins as cardiovascular peptides. 873 84

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 present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/ reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/ reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.
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PMID:Role of endothelin in the pathophysiology of renal ischemia-reperfusion in normal rabbits. 887 51

Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.
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PMID:Mac-1 inhibitor affects certain hemostatic parameters during myocardial stunning in swine. 890 73

The reactive oxygen metabolites (ROMs) and the vascular endothelial factors such as endothelins (ETs) and thromboxane A2 (TxA2) were found to be mediators of the reperfusion component of ischemia-reperfusion (I/R) injury. Captopril (CPT), a sulfydryl (-SH) group containing angiotensin-converting enzyme inhibitor, has been shown to reverse I/R injury by its ROM scavenging effect. In this experimental study, the effects of CPT and BM 13.177 (a TxA2 receptor antagonist) were assessed on liver I/R injury in rats. Four groups of Wistar albino rats were either sham-operated, control, CPT or BM 13.177-treated. The middle and left lateral hepatic arteries and portal veins were occluded in each group but the sham and the corresponding agents were given to the animals prior to I/R injury. After I/R injury, blood was drawn from the suprahepatic inferior vena cava for ET-1-like activity assay and liver tissue samples were obtained for the determination of prostaglandin E2 (PGE2), leukotriene C4 (LTC4) and histopathologic examination. PGE2 and ET-1 levels were increased significantly in the control group compared with the sham-operated group. In the CPT group, LTC4, PGE2 and ET-1 levels were significantly increased compared with the control group, while only ET-1 levels were not different from those of the control group in the BM 13.177-treated group. It is concluded that ET-1 release increases in response to I/R injury in rat liver and CPT further increases this release. It also appears that CPT has a stimulatory effect on arachidonic acid metabolism in addition to its free radical scavenging effect.
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PMID:Endothelin release is augmented with captopril in rat ischemia-reperfusion injury of the liver. 890 98

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


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