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)

The anti-ischemic effects of nafazatrom (10 mg/kg intraduodenally) have been studied in a canine model of myocardial infarction. Nafazatrom was given 30 min before and 2 h after occlusion of the left anterior descending coronary artery (LAD). Effects were compared with those after intravenous indomethacin (10 mg/kg) treatment. Infarct size was measured at 6 h of coronary occlusion by postmortem tetrazolium staining. Myocardial ischemia was reduced after nafazatrom administration, whether related to total left ventricle (18 +/- 3.3 vs. 30.7 +/- 4.8%; p less than 0.05) or to the LAD vessel area at risk for infarction (51.4 +/- 4.0 vs. 82.5 +/- 4.5%; p less than 0.01). Salvage with nafazatrom occurred in the subepicardial and endomural tissues without lateral protection. Indomethacin had no effects on infarction. The LAD occlusion-induced hemodynamic consequences were reduced at 15 min by nafazatrom and remained unchanged by indomethacin. During the following experimental course, no differences were noted between the groups. At 6 h, blood flow in the nonoccluded circumflex artery increased by 12.6 +/- 3.2 ml/min (p less than 0.05) following nafazatrom treatment. Thus, nafazatrom reduced ischemia by a mechanism unrelated to changes in hemodynamics. Most likely, this was due to 5-lipoxygenase inhibition. This may shift arachidonic acid metabolism to cyclooxygenase products and prevent release of deleterious lipoxygenase products by neutrophils during ischemic injury.
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PMID:Effects of nafazatrom and indomethacin on experimental myocardial ischemia in the anesthetized dog. 241 12

Myocardial ischemia was induced in perfused paced isovolumic left heart preparation of the rabbit by reducing, for a period of 40 min, the flow rate from 20 ml/min to 0.2 ml/min (severe model) and to 1 ml/min (moderate model). The relationship between prostaglandin biosynthesis and cardiac ischemic damage was evaluated in the two experimental models. The results obtained indicate that the total amount of 6-keto-PGF1 alpha generated increases with the severity of the ischemia, particularly during the 20 min of reperfusion (moderate model 81.8 +/- 13.7 ng: severe model 375 +/- 102 ng). The inhibition of the prostaglandin synthesis, prostaglandin-E2, and 6-keto-prostaglandin-F1 alpha (PGE2 and 6-keto-PGF1 alpha levels below the detection limits) by Aspirin (20 micrograms/ml) and Indomethacin (1 microgram/ml) in moderate myocardial ischemia was correlated with greater increments in resting diastolic tension (nearly 100% and 40%, respectively). This phenomenon was also associated to a further decrease on cardiac contractility and increase on coronary perfusion pressure upon reperfusion. On the contrary drugs which stimulated prostaglandin generation in myocardial tissue, such as Defibrotide (400 micrograms/ml), completely protected the organ from ischemia. U-60257 (3 micrograms/ml) and FPL-55712 (2 micrograms/ml), compounds, which respectively inhibits biosynthesis and the effects of leukotrienes, displayed a beneficial activity on this moderate model of ischemia. The present data suggests that the deleterious effect of nonsteroidal antiinflammatory drugs in low flow myocardial ischemia and reperfusion damage may be associated with removal of PGI2 and PGE2 from ischemic myocardium.
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PMID:Nonsteroidal antiinflammatory drugs aggravate acute myocardial ischemia in the perfused rabbit heart: a role for prostacyclin. 246 44

The role of PGF2 alpha in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring PGF2 alpha levels in superior mesenteric vein, right ventricle, aorta, and femoral vein during superior mesenteric artery occlusion-induced shock by comparing the circulatory effects of exogenous PGF2 alpha injected into either the superior mesenteric or the femoral vein and by inhibiting of prostanoid synthesis with indomethacin. Release of the superior mesenteric artery occlusion caused a dramatic decrease in mean arterial blood pressure; an increase in mean portal venous pressure, and more than fivefold increases in plasma PGF2 alpha levels in superior mesenteric vein, right ventricle, and aorta. In spite of the decreased mean arterial blood pressure, postocclusion blood flow in the mesenteric artery did not fall below preocclusion values. Indomethacin in itself, significantly reduced plasma PGF2 alpha levels as well as intestinal blood flow and increased mean arterial blood pressure in animals without superior mesenteric artery occlusion. Furthermore, indomethacin attenuated the magnitude of postocclusion hypotension and completely prevented PGF2 alpha production during superior mesenteric artery occlusion shock. Exogenous PGF2 alpha 10 micrograms/kg injected into the superior mesenteric or femoral vein produced hypotension or hypertension, respectively. When PGF2 alpha was injected into the superior mesenteric vein, the plasma level of PGF2 alpha in the aorta was similar to that observed during superior mesenteric artery occlusion shock, whereas PGF2 alpha injected into the femoral vein gave a significantly higher concentration. Pulmonary metabolism of PGF2 alpha was significantly reduced in shock. The present results suggest that PGF2 alpha released by intestinal tissues might play an important role in shock caused by intestinal ischemia.
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PMID:Role of PGF2 alpha in the superior mesenteric artery-induced shock. 258 97

Using the middle cerebral artery occlusion model in cats, we evaluated the possible role of the cyclooxygenase pathway in alterations of local cerebral blood flow and the development of cortical edema following prolonged ischemia or recirculation. We divided 57 cats into three groups, and each cat received saline (control), indomethacin, or the free radical scavenger ONO-3144. Each group was subdivided into prolonged ischemia (4 hours of occlusion: PI) and recirculation (2 hours of occlusion followed by 2 hours of recirculation: RC) subgroups. We compared local cerebral blood flow and cortical specific gravity between the PI and RC subgroups of the control and drug-treated groups. In the PI subgroup, indomethacin did not influence the time course of local cerebral blood flow but significantly worsened the decrease in cortical specific gravity. On the other hand, indomethacin significantly improved postischemic hypoperfusion and ameliorated the decrease in cortical specific gravity in the RC subgroup. The effects of ONO-3144 were similar to those of indomethacin, except that ONO-3144 did not affect cortical specific gravity in the PI subgroup. Indomethacin inhibits cyclooxygenase activity, whereas ONO-3144 scavenges the oxygen-centered radical released in the conversion of prostaglandin G2 to prostaglandin H2. Thus, prostaglandins do not seem to play a major role in the occurrence of brain edema due to prolonged regional ischemia. By contrast, oxygen-centered radicals released from the cyclooxygenase pathway appear to be at least partially responsible for the occurrence of recirculation-induced edema and postischemic hypoperfusion.
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PMID:Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats. 272 47

The role of prostanoids in respiratory failure during circulatory shock of intestinal origin was investigated in anesthetized, non-ventilated dogs by measuring PGF2 alpha thromboxane B2 (TXB2) and 6-keto prostaglandin F1 alpha (PGF1 alpha) in arterial and mixed venous (right ventricle) blood samples during superior mesenteric artery occlusion-induced (SMAO) shock. Release of the SMAO caused a dramatic decrease in mean arterial blood pressure (MABP), arterial and mixed venous pO2, hyperventilation and a more than 2 fold increase in levels of prostanoid studied within 5 min. At the same time, arterial and mixed venous pCO2 and pH remained unchanged. Thereafter, 6-keto PGF1 alpha concentration decreased so that at 60 min post release it was not significantly different from that of control values. PGF2 alpha and TXB2 levels rose continuously during shock. Respiratory failure which occurred after declamping was characterized by low pO2 and oxygen saturation and hyperventilation throughout the experiment. Pulmonary metabolism of PGF2 alpha was significantly reduced in shock. Indomethacin significantly attenuated the magnitude of postocclusion hypotension and respiratory failure, furthermore reduced prostanoid production. The present results suggest that PGF2 alpha and thromboxane A2 released by intestinal tissues might play an important role in the development of respiratory failure in shock caused by intestinal ischemia.
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PMID:Role of prostanoids in respiratory failure during circulatory shock of intestinal origin in dogs. 278 Jul 63

Indomethacin can reduce the microvascular permeability induced by repeated ischemia. In this investigation the influence of histamine H1 and H2 receptor blockers was studied for comparison with indomethacin. Application of 60 mmHg pressure to the hamster cheek pouch for 5 min was repeated eight times, with 10-min restitution intervals. Altered permeability was evaluated with use of FITC-dextran and intravital microscopy. Progressive efflux of FITC-dextran was observed in the control group. When either diphenhydramine or indomethacin was used alone, a few spots of extravasated dye were seen. Combination of diphenhydramine with either indomethacin or cimetidine reduced the extravasation. Furthermore, the spots appeared significantly later than in the controls, and some faded. Increase in the efflux of macromolecules due to repeated ischemia seems to be mediated via H1 and H2 receptors in conjunction with other receptors and/or amines e.g. prostaglandins.
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PMID:The effect of antihistamines and indomethacin on microvascular permeability changes due to repeated pressure-induced local ischemia. 289 58

We studied the effect of intracoronary leukotriene B4, C4, D4 and E4 (0.1-3 micrograms) on coronary artery blood flow and resistance in anesthetized pigs. Conventional hemodynamics were measured, and the peripheral electrocardiogram was obtained in lead II. Thromboxane B2 and 6-keto-prostaglandin F1 alpha (as breakdown products of thromboxane and prostacyclin, respectively) were measured during the influence of leukotrienes on the heart. All leukotrienes except B4 reduced coronary flow. Peak reduction was produced by 3 micrograms of each eicosanoid: C4 = 96 +/- 4%+; D4 = 98 +/- 2%+; E4 = 82 +/- 8%+. Coronary resistance increased after the same dose B4 = 65 +/- 18%; C4 = 225 +/- 94% (P less than 0.01); D4 = 442 +/- 118%+; E4 = 110 +/- 43% (+ = P less than 0.001). Increase in filling pressure and heart rate but blood pressure reduction and diminution in left ventricular d P/dtmax were observed with leukotriene C4, D4 and E4. The S-T segments of the electrocardiogram were elevated, thus indicating myocardial ischemia during the blood flow reduction. Indomethacin (5 mg/kg i.v.) had no effects on the leukotriene-induced hemodynamic sequelae. Thromboxane B2 concentration in coronary sinus blood plasma increased by 132-176% (P less than 0.05) at peak leukotriene effects on blood flow. Thus, leukotriene C4, D4, and E4 are vasoconstrictors in the situ porcine heart. Leukotriene B4, however, exerts no hemodynamic effects. The electrocardiographic ischemia and changes in hemodynamics indicate actions on coronary resistance and myocardial depression. These eicosanoids may contribute to cardiac dysfunction and vasospasm in coronary artery disease.
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PMID:Leukotrienes on porcine hemodynamics and prostanoid release. 299 76

The authors have previously reported a model of ischemic bowel necrosis produced in the rat by synthetic platelet-activating factor (PAF) or a combination of PAF and bacterial endotoxin. Because rat platelets are refractory to PAF and thromboemboli were not found in the mesenteric or intestinal microvasculature, they suspected that secondary mediators were involved in the pathogenesis of bowel necrosis. They have found the following lipoxygenase products of arachidonic acid, especially leukotrienes (LT), probably played an important role in the pathogenesis of bowel necrosis, because diethylcarbamazine (an inhibitor for LTA synthesis) and FPL55712 (LT antagonist) ameliorated, and at times completely prevented, the lesions. NDGA (a nonspecific lipoxygenase inhibitor) was less effective, probably because of its additional effect on cyclooxygenase inhibition. Verapamil, a calcium channel blocker, ameliorated the disease. Thromboxane A2, a potent vasoconstrictor, was probably not responsible for the ischemia of the gastrointestinal tract. This is suggested by the ineffectiveness of OKY-046 in preventing bowel necrosis. Prostaglandin (PG) E1 infusion often prevented the bowel necrosis, which suggested beneficial effects of vasodilating PGs, probably released as a defense mechanisms. Indomethacin aggravated the disease, probably by inhibiting PG release and shifting the metabolic pathway toward the lipoxygenase pathway. Antihistamine and antiserotonin had no effect, which suggested that these mediators were not involved in the pathogenesis of bowel necrosis. Shock produced by PAF was probably not the only cause of bowel necrosis, because reversal of the hypotension did not always prevent the development of bowel necrosis. Hemoconcentration (increased vasopermeability) and leukopenia induced by PAF did not correlate with the development or severity of bowel necrosis.
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PMID:Platelet-activating factor-induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis. 308 Aug 95

This study was carried out to investigate the possible contribution of endogenous prostaglandin (PG) production to failure of contractile recovery following reperfusion of hypoperfused isolated rat hearts. A 90% reduction in coronary flow rate for 60 min resulted in a time-dependent depression of contractile force and an elevation in resting tension. Reperfusion produced a slight (approximately 11%) recovery of contractile force, whereas resting tension remained elevated. Reperfusion was a potent stimulus for PG (as assessed by 6 keto-PGF1 alpha) release and resulted in levels that were significantly higher than those observed prior to ischemia. When PG synthesis was inhibited by the nonsteroidal anti-inflammatory drugs ibuprofen, indomethacin, or acetylsalicylic acid (ASA), recovery of ventricular contractility on reperfusion was significantly higher than that seen in the absence of drugs. Ibuprofen was the most effective, producing an average recovery of 70% (P less than 0.05 from control). Indomethacin and ASA produced approximately a 40% (P less than 0.05) and 35% (P less than 0.05) recovery of contractile force, respectively. The improved recovery in contractility was significantly depressed by the addition of low concentrations of prostacyclin (PGI2) and PGF2 alpha, whereas PGE2 and 6 keto-PGF1 alpha, the hydrolysis product of PGI2, were ineffective. The effects on resting tension were inconsistent. PG release during reperfusion was unrelated either to the length of the initial period of reduced coronary flow or the degree of contractile recovery; it was attenuated either by a reduction in or by an elevation of Ca concentration. These results indicate that endogenous PGs mediate, at least in part, reperfusion-associated failure of ventricular function.
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PMID:Contribution of prostaglandins to reperfusion-induced ventricular failure in isolated rat hearts. 308 30

The effects of mannitol, nimodipine, and indomethacin on ischemic neuronal injury were examined in 45 rats divided equally into nine groups subjected to 10 minutes of forebrain ischemia. Of two control groups, one received maintenance fluids while the other received a normal saline bolus. In the remaining seven groups, mannitol, nimodipine, and indomethacin were administered singly or in combination 5 minutes before forebrain ischemia. Seven days after ischemia, the brains were perfusion-fixed, sectioned coronally into 2.8-mm slices, and stained with hematoxylin and eosin. Ischemic neurons were directly counted on predetermined regions of standardized serial sections. Considerable amelioration of ischemic injury (ischemic neurons/total neurons) was observed with mannitol (ischemic injury, 7 +/- 5% in the hippocampal CA1/CA2 sectors and 28 +/- 17% in the CA3 sector). This is in contrast to control values of 64 +/- 11% and 80 +/- 6%, respectively, and those obtained in the normal saline group of 70 +/- 10% and 59 +/- 13%, respectively. The beneficial effect with nimodipine reached significance in only the hippocampal CA3 sector (ischemic injury, 35 +/- 21%). Indomethacin showed no significant benefit. Combining the agents resulted in significantly reduced neuronal injury compared with control groups, although the effect was not greater than that achieved with mannitol alone. The degree of ischemic injury was least when all three agents were used in combination (ischemic injury, 12 +/- 12% in the hippocampal CA1/CA2 sectors and 4 +/- 4% in the CA3 sector). Our data support the concept that successfully blocking the ischemic cascade with a single, diversely acting agent or multiple agents will evoke the best beneficial response.
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PMID:Effect of mannitol, nimodipine, and indomethacin singly or in combination on cerebral ischemia in rats. 312 27


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