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

Reperfusion of ischemic brain is associated with production of thromboxane A2 (TXA2), a proaggregatory vasoconstrictor. We used an animal model of transient forebrain ischemia to study the effects of 1-benzylimidazole (1-BI), a selective inhibitor of thromboxane synthase, upon cerebral eicosanoid levels and cerebral blood flow. Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. The mean +/- SEM brain level of TXB2, the stable metabolite of TXA2, determined after 60 minutes of reperfusion was 101 +/- 20 pg/mg brain protein in five ischemic control rats. Infusion of 10 micrograms/g 1-BI reduced mean +/- SEM cerebral TXB2 concentration to 11 +/- 3 pg/mg brain protein in five rats (p less than or equal to 0.002). Mean +/- SEM hemispheric cerebral blood flow measured in four ischemic control rats after 60 minutes of reperfusion was 42 +/- 9 ml/100 g brain/min compared with 104 +/- 13 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.001). Mean +/- SEM hippocampal blood flow in four ischemic control rats after 60 minutes of reperfusion was 51 +/- 14 ml/100 g brain/min compared with 125 +/- 25 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.04). We conclude that selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA2 concentrations and elevating cerebral blood flow.
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PMID:Effect of thromboxane synthase inhibition on eicosanoid levels and blood flow in ischemic rat brain. 271 3

Pretreatment with the thromboxane synthase inhibitor OKY-046 but not the cyclo-oxygenase inhibitor ibuprofen protects against ischemia-induced acute tubular necrosis. However, ibuprofen together with the vasodilating agent prostaglandin E1 is protective. This suggests that a high prostaglandin to thromboxane ratio is the major factor operative in preventing tubular necrosis, the subject of this study. Rats that had unilateral nephrectomy (n = 60) with the exception of rats that had sham operations (n = 8) underwent 45 minutes of left renal pedicle clamping. Thirty minutes before the operation, the rats received either a saline solution or a thromboxane synthase inhibitor that was given intravenously. The inhibitors OKY-046 (2 milligrams per kilogram, n = 10), UK38485 (1 milligram per kilogram, n = 9) and U63357A (10 milligrams per kilogram, n = 10) were given as a single bolus while the inhibitor CGS13080 (0.1 milligram per kilogram, n = 9, and 1.0 milligram per kilogram, n = 7) was given by constant infusion and continued for 60 minutes after reperfusion. With saline solution therapy, five minutes after reperfusion, thromboxane B2 increased from 154 to 2,537 picograms per milliliter (p less than 0.00001) and 6-keto-prostaglandin F1 alpha increased from 51 to 266 picograms per milliliter (p less than 0.004). At 24 hours, the creatinine level increased from 0.5 to 2.8 milligrams per deciliter (p less than 0.00001). Only OKY-046 yielded a creatinine level at 24 hours of 1.2 milligrams per deciliter, a value lower than that for those in the saline solution control group (p less than 0.002). Furthermore, OKY-046 led to the highest prostaglandin to thromboxane ratio (p less than 0.035). The five other ratios which occurred after drug therapy were inversely related to the decrease in the creatinine value (r = -0.93, p less than 0.02). Histologically, OKY-046 was the only thromboxane synthase inhibitor to prevent acute tubular necrosis (p less than 0.05). Results show that a high prostaglandin to thromboxane ratio protects against acute tubular necrosis.
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PMID:A high plasma prostaglandin to thromboxane ratio protects against renal ischemia. 367 99

The vasodilatation induced by acetylcholine (ACh) in a rabbit isolated perfused kidney was abolished when the tissue was exposed to cold ischemia for 72 h in Euro-Collins (EC) solution. This vasodilatation is due to the release of endothelium-derived relaxing factor (EDRF) from renal vasculature as evidenced by the attenuation following methylene blue pretreatment. When kidneys were preserved in EC solution containing UK 38485, a thromboxane synthase inhibitor, or nicardipine, a calcium channel blocker, ACh-induced vasodilatation persisted after 72 h of cold ischemia. These results were taken as evidence of tissue protective activity of UK 38485 and nicardipine and have promising implications for cadaveric kidney transplantation.
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PMID:The endothelium-derived relaxing factor-mediated acetylcholine response of the arterial perfusion pressure after cold storage of the isolated rabbit kidney. 762 84

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that may suppress regional cerebral blood flow (rCBF) during postischemic hypoperfusion. This study was undertaken to determine if rCBF could be elevated by postischemic treatment with a TXA2 receptor antagonist, SQ29,548, given alone or in combination with 1-benzylimidazole (1-BI), a thromboxane synthase inhibitor. Wistar rats were subjected to 30 min of reversible forebrain ischemia and treated with SQ29,548 or an SQ29,548/1-BI combination during 60 min of reperfusion. Cerebral TXB2, the stable metabolite of TXA2, was 1.33 +/- 0.91 ng mg brain protein-1 in animals treated with SQ29,548 and exposed to ischemia, compared to 1.15 +/- 0.32 in ischemic controls (p = NS). Administration of SQ29,548/20 mg kg-1 1-BI reduced cerebral TXB2 to 0.20 +/- 0.25 (p < or = 0.01). Regional CBF was depressed significantly in ischemic controls compared to sham-ischemic animals (p < or = 0.01 in all regions except for p < or = 0.05 in diencephalon) and was not altered by treatment with SQ29,548. Rats given the SQ29,548/1-BI combination showed an overall increase in rCBF that did not reach statistical significance when compared to ischemic controls. However, rCBF in hippocampus and diencephalon of animals given the drug combination was significantly greater than in rats treated with SQ29,548 alone (p < or = 0.05).
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PMID:Thromboxane receptor antagonism and synthase inhibition in cerebral ischemia. 846 80

There are multiple causes of liver graft nonfunction in the early post-transplant period. Since a severe microcirculatory disturbance based on ischemia-reperfusion liver injury is considered to be the main underlying pathophysiology, it is suspected that various vasoactive substances are liberated after reperfusion of the graft. In order to investigate this matter, we conducted an experimental study with pig liver allotransplantation. Two groups of animals received donor grafts with or without thromboxane synthase inhibitor (sodium ozagrel), 1.25 mg/ kg body weight intravenously, given at the time of liver harvesting. All of the recipient animals in the treatment group (n = 10) survived longer than 7 days whereas three of ten animals in the control group died within 7 days. Serum lactate dehydrogenase (LDH) in the recipient serum at 1 h after reperfusion was significantly lower in the treatment group (915.1 +/- 167.3 U/l) than in the control group (1264.4 +/- 134.7 U/l). Serum thromboxane B2 (2261.7 +/- 1055.7 pg/ml) and endothelin-1 (6.3 +/- 2.2 pg/ml) after reperfusion in the treatment group were significantly lower than those in the control group (4220.0 +/- 1711.0 pg/ml and 11.2 +/- 3.1 pg/ml, respectively). Although serum angiotensin II after reperfusion tended to be lower in the treatment group than in the controls serum renin activity was less than 3 ng/ml in both groups of animals. There were no differences in the plasma endotoxin levels between the two groups. We conclude that the administration of sodium ozagrel to the donor animals provided better graft function in recipients than no such treatment. We speculate that the inhibition of thromboxane A2 production suppresses the liberation of other vasoconstrictive substances, preventing microcirculatory disturbance and, thereby, contributing to improved graft function after liver transplantation.
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PMID:Liberation of vasoactive substances and its prevention with thromboxane A2 synthase inhibitor in pig liver transplantation. 874 15

The effects of FPL-55712 (leukotriene receptor antagonist) and OKY-046 (thromboxane synthase inhibitor) were studied on ischemic and reperfused myocardium using in vivo and in vitro rat heart paradigms. The in vivo studies included production of regional ischemia by coronary artery ligation for 72 h followed by reperfusion. Macroscopic methods using nitro blue tetrazolium (NBT) staining were employed to measure infarct size. For in vitro studies, isolated rat hearts were perfused by Langendorff's technique. Regional ischemia was produced for 60 min followed by reperfusion. Coronary outflow and creatine phosphokinase (CPK) release in the coronary effluent were measured. Both these parameters showed a correlation with the duration of reperfusion. In isolated heart studies, FPL-55712 reduced CPK release and improved coronary outflow significantly, whereas OKY-046 did not show any beneficial effect. In intact heart studies, FPL-55712 did not reduce the infarct size, whereas OKY-046 decreased the myocardial infarct to a significant extent. The present study demonstrates a definite involvement of leukotrienes and thromboxanes in reperfusion injury. Inability of FPL-55712 to reduce infarct size may be due to the very short half-life of the drug. Lack of efficacy of OKY-046 in isolated studies suggests the involvement of platelet-derived thromboxanes in the reperfusion injury as these are not available in isolated heart preparations.
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PMID:Role of eicosanoid inhibition of ischemia reperfusion injury: intact and isolated rat heart studies. 922 47

Lipid inflammatory mediators are thought to play a critical role in the pathogenesis of vascular injury. Among the events which might cause the synthesis of eicosanoids in blood vessels is activation of the complement. To evaluate how complement might influence eicosanoid metabolism, we investigated endothelial cells exposed to xenoreactive antibodies and complement, as might occur in rejecting xenografts where severe vascular injury is a typical feature. While resting porcine aortic endothelial cells released only prostaglandin (PG) I2, endothelial cells stimulated with xenoreactive antibodies and complement released PGE2 and thromboxane A2 (TXA2), in addition to increased amounts of PGI2. This alteration in eicosanoid metabolism was associated with induction of cyclooxygenase (Cox)-2 and thromboxane synthase, but not Cox-1. Unlike results seen in other systems, the upregulation of Cox-2 and the subsequent release of eicosanoids by endothelial cells was not directly induced by complement but rather required production of IL-1alpha, which acted on endothelial cells as an autocrine factor. Since eicosanoids have a potent effect on inflammation, vascular tone and platelet aggregation, we postulated that the abnormalities in eicosanoid release induced by xenoreactive antibodies and complement might provide one explanation for the vascular injury, focal ischemia, and thrombosis observed in acute vascular rejection and other vasculitides mediated by complement.
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PMID:Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2. 927 32

Hepatic injury after hepatic stress is caused by several mechanisms, including inflammatory reaction and microcirculatory disturbance. Levels of thromboxane, a vasoconstrictive eicosanoid, have been shown to increase in systemic circulation after different types of hepatic stress such as endotoxemia, hepatic ischemia-reperfusion, hepatectomy, liver transplantation, hemorrhagic shock and resuscitation, hepatic cirrhosis, and alcoholic liver injury. The production of thromboxane from the liver is also enhanced under these stresses, which may act on the liver in an autocrine or a paracrine fashion. Kupffer cells, resident hepatic macrophages, may be a major source of stress-induced thromboxane, although other cell types in the liver such as sinusoidal endothelial cells and hepatocytes may also produce this eicosanoid. Thromboxane induces hepatic damage through vasoconstriction, platelet aggregation, induction of leukocyte adhesion, up-regulation of proinflammatory cytokines, and induction of other vasoconstrictor release. In this regard, administration of cyclooxygenase inhibitor, specific thromboxane synthase inhibitor, and specific thromboxane receptor antagonists has been shown to protect from severe hepatic injury elicited by these hepatic stresses. Furthermore, blockade of Kupffer cell function by administration of gadolinium chloride showed salutary effects in preventing hepatic damage in bile duct ligation models. This review article summarizes the recent knowledge of the role of thromboxane in various types of hepatic stress and the effects of thromboxane inhibitors in these models.
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PMID:Role of thromboxane in producing hepatic injury during hepatic stress. 1610 91

Retinal blood flow in human diabetics has been reported to follow a biphasic time course in which an initial period of reduced flow and ischemia is often followed by a hyperemic and angiogenic phase in which flow can exceed normal levels. The purpose of the present study is to investigate the mechanisms of the initial decrease in flow, since early interventions could provide the most effective treatment strategies. C57BL/6 mice were injected with streptozotocin (STZ) at 12 weeks of age and remained hyperglycemic until data were gathered 4 or 8 weeks later. Experimental measurements included retinal arteriolar red blood cell velocity and arteriolar diameters, with the diameters measured prior to and following an intravenous injection of the thromboxane synthase inhibitor ozagrel (100 mg/kg). Arterioles leading out of the optic disk constricted significantly at 4 weeks post-STZ (p<0.001) compared to age-matched controls, but not at 8 weeks post-STZ. Calculations of retinal blood flow indicated a 45% decrease at 4 weeks post-STZ, but only a 26% decrease by 8 weeks. Not all arterioles constricted equally in response to STZ; the most substantial constrictions were present in arterioles that were more closely arranged with countercurrent venules leading back into the optic disk. Injection of ozagrel provided significant dilation of constricted retinal arterioles. In addition, the pattern of dilation was consistent with the sites of the most severe constriction, i.e., ozagrel-induced dilation in the STZ mice occurred to the greatest extent in the arterioles more closely paired with the venules draining the microvascular bed. In summary, STZ induces a biphasic alteration in retinal blood flow in mice, in which thromboxane contributes to the initial reduction in blood flow at 4 weeks. Moreover, the thromboxane-induced arteriolar constriction is dependent on the proximity of the retinal arterioles to countercurrent venules.
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PMID:Ozagrel attenuates early streptozotocin-induced constriction of arterioles in the mouse retina. 1826 22


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