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)

An extremely potent and highly specific non-peptide, subnanomolar endothelin (ET) receptor antagonist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of 125I-labeled ET-1 to cloned human ET receptor subtypes ETA and ETB (Ki = 0.2 and 18 nM, respectively). SB 209670 produces concentration-dependent inhibition of ET-1-mediated vasoconstriction in isolated vascular tissues and in vivo following either intravenous or intraduodenal administration. SB 209670 produces a dose-dependent reduction in blood pressure in hypertensive rats, protects from ischemia-induced neuronal degeneration in a gerbil stroke model, and attenuates neointima formation following rat carotid artery balloon angioplasty. SB 209670 will be useful in characterizing and classifying the physiological and pathophysiological effects of ET.
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PMID:SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist. 805 55

The purpose of the present study was to clarify the role of endothelin-1 (ET-1) in the pathogenesis of ischemia/reperfusion lung injury and to determine whether pretreatment with an ET receptor antagonist prevents such injury. The left lung of Sprague-Dawley rats was subjected to 60 min of no-flow warm ischemia followed by 90 min of reperfusion. The plasma ET-1 concentration increased significantly after reperfusion compared with before and after ischemia (p < 0.05). Arterial oxygen tension was reduced, and the lung tissue wet/dry weight ratio increased in post-reperfusion lungs compared with both pre-ischemia and post-ischemia lungs. Histologic study showed pulmonary edema, hemorrhage, hyaline membrane formation, and a significant increase in lung tissue neutrophils after reperfusion. In addition, the expression of ET-1 mRNA was determined by Northern blot analysis. Although ischemia did not significantly alter ET-1 expression, reperfusion increased expression in the left lung markedly and in the right lung moderately. Pre-infusion of FR139317, an ETA receptor antagonist, prevented post-reperfusion damage to the lung. These results suggest that ET-1 contributes to the ischemia/reperfusion injury of the rat lung, mediated by an ETA receptor, and that an ETA receptor antagonist may inhibit ischemia/reperfusion lung injury.
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PMID:Contribution of endothelin-1 to warm ischemia/reperfusion injury of the rat lung. 852 Jul 82

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

Previously, we demonstrated that cerebral focal ischemic tissue exhibits a significant increase in immunoreactive endothelin (ET). Because increased ET might exacerbate the consequences of cerebral ischemia, we evaluated the effects of the orally active ETA/B receptor antagonist SB 217242 on middle cerebral artery occlusion (MCAO) in the spontaneously hypertensive rat (SHR). SHRs were treated b.i.d. with vehicle or with 3 or 15 mg/kg SB 217242 p.o. for 7 days. Permanent MCAO was performed on day 7 and animals were sacrificed on day 8. Forebrains were stained and the extent of cerebral (i.e., cortical) infarction was determined using image analysis. Hemispheric swelling (%), hemispheric infarct (%), and infarct volume (mm3) were quantitated for each animal. SB 217242 treatment produced a significant decrease in ischemic brain injury. Hemispheric infarction and infarct volume were reduced after the 15 mg/kg treatment (12.0 +/- 1.1% and 69 +/- 6 mm3) compared to vehicle (17.3 +/- 1.5% and 99 +/- 8 mm3) (p < 0.05). No significant effects on hemispheric swelling were observed. This is the first demonstration of an ET receptor antagonist exhibiting efficacy in cerebral focal ischemia. The fact that a 30% reduction in ischemic brain injury can be demonstrated after oral administration of SB 217242 suggests that ET antagonists may be of therapeutic utility in focal stroke.
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PMID:The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury. 858 28

The role of endogenous endothelins (ETs) in mediating postischemic hypoperfusion after transient global ischemia was investigated in halothane-anesthetized rats. Pretreatment with the broad spectrum ETA and ETB antagonist bosentan (17 mumol/kg) had minimal effect on postischemic hypoperfusion, as measured by hydrogen clearance, in the caudate nucleus and the parietal cortex during 3 h after bilateral common carotid artery occlusion with concomitant hemorrhagic hypotension (transient global ischemia). In cerebral blood flow (CBF) measured by [14C]iodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant hemorrhagic hypotension, bosentan treatment failed to alter CBF in any of the cerebral cortical regions examined. No changes in CBF, as measured by hydrogen clearance, were observed after transient bilateral common carotid artery occlusion. [14C]Iodoantipyrine autoradiography at 90 min post occlusion failed to demonstrate any increases in cerebral blood flow after transient bilateral common carotid artery occlusion in any of the 35 brain regions examined in anesthetized rats.
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PMID:Postischemic hypoperfusion in transient global ischemia: a role for endothelins? 858 34

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

This study attempted to define the role of endothelin (ET) in preconditioning. We previously showed that ET Is produced during myocardial ischemia and reperfusion. Because both preconditioning and ET act through protein kinase C, ET could play a role in preconditioning. Dogs were randomized to three groups subjected to 40 minutes of ischemia, with (groups A and B) or without (group C) preconditioning, followed by 4 hours of reperfusion. Groups A and C received saline infusions; group B received continuous infusions of the ETA-selective antagonist FR139317. Both preconditioned groups had smaller infarct sizes (group A, 7.9% +/- 2.5%; group B, 8.4% +/- 2.6%) than the nonpreconditioned group (group C, 16.2% +/- 3.3%). Administration of the ETA antagonist FR139317 did not alter infarct size. This study demonstrated that ETA-receptor blockade did not alter infarct size in preconditioned animals and suggests that endothelin does not play a significant role in this process.
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PMID:Endothelin-1 and myocardial preconditioning. 870 80

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

Effect of ETA-receptor antagonist, BQ123, on postischemic hypoperfusion in the presence or absence of nitric oxide synthetase inhibitor, N omega-nitro-L-arginine (NLA), was investigated in Mongolian gerbils. BQ123 given prior to ischemia reversed the early incomplete recovery of cerebral blood flow observed with NLA without affecting the late postischemic hypoperfusion. Additional postischemic administration of BQ123 also reversed (P < 0.01) the late postischemic hypoperfusion seen in NLA-, N omega-nitro-D-arginine methyl ester- or Ringer's-treated animals.
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PMID:Cerebral postischemic hypoperfusion is mediated by ETA receptors. 883 68

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


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