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

The effects of anti-inflammatory steroids and BW-755C (both of which inhibit the formation of prostaglandins and leukotrienes) were studied in ischemia-induced edema and necrosis of the rabbit ear utilizing an occlusion reperfusion model. The results were compared with cyclooxygenase inhibitors which selectively block the synthesis of prostaglandins without affecting leukotriene production. Significant inhibition of the progression of necrosis was observed with both methyl prednisolone and BW-755C. The cyclooxygenase inhibitors, naproxen and low-dose indomethacin had no effect on the progression of ear necrosis. By contrast, high-dose indomethacin significantly inhibited edema but accelerated the progression of necrosis.
 ...
PMID:Salvage of ischemic rabbit ear by BW-755C and steroids, but not by indomethacin. 310 60

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.
 ...
PMID:Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism. 312 73

To determine the relative importance of arachidonic acid pathway products on vulnerability to ventricular fibrillation (VF), we examined the effects of synthesis inhibitors and a receptor blocker acting in the cyclooxygenase (C) and lipoxygenase (L) pathways on VF thresholds in a feline model of coronary occlusion. Thresholds for the induction of VF wer measured before and after a 5-minute coronary occlusion in drug-treated animals and control subjects. Animals were treated with BW755c, a dual L and C inhibitor, CGS-8515, and L inhibitor, FPL-55712, a leukotriene receptor blocker, or sulfinpyrazone, a C inhibitor. BW755c, CGS-8515, and FPL-55712 all prevented an otherwise significant fall in VF threshold during coronary occlusion (p less than 0.01) independent of an effect on effective refractory period, heart rate, or blood pressure. In contrast, sulfinpyrazone, the only compound devoid of an effect on the L pathway, did not protect against an occlusion-related fall in VF threshold. BW755c and CGS-8515 inhibited the synthesis of L and C metabolites coincident with their protection against VF (p less than 0.01). We conclude that agents that antagonize the effects of L products protect against enhanced ventricular vulnerability during acute ischemia, whereas C inhibition alone may not afford this protection.
 ...
PMID:Modulation of arachidonic acid metabolites and vulnerability to ventricular fibrillation during myocardial ischemia in the cat. 314 41

The time-dependent release of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), thromboxane (Tx) B2, and 6-keto-PGF1 alpha (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE2, PGF2 alpha, 6-keto, and Tx were: 253 +/- 75, 953 +/- 300, 650 +/- 200, and 550 +/- 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15-60 min of the reflow at which time levels of PGE2, PGF2 alpha, 6-keto, and Tx, as compared with the preischemic baseline, rose approximately 8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF2 alpha/6-keto and PGE2/6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from approximately 1 to approximately 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Time course of release in vivo of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TxB2 into the brain extracellular space after 15 min of complete global ischemia in the presence and absence of cyclooxygenase inhibition. 314 90

Superior mesenteric artery occlusion leads to mesenteric ischemia, activation of arachidonic acid metabolism and release of endotoxins into the systemic circulation. The effect of leukotriene and prostaglandin antagonists on hemodynamic response and survival of rats after superior mesenteric artery (SMA) occlusion was investigated. The animals were divided into five groups: in group 1 (n = 105) the SMA was clamped for 2 h and mortality assessed after 24 h. Group 2 animals (n = 20) were pretreated with 5 mg/kg indomethacin and the SMA clamped similarly to group 1, group 3 animals (n = 15) were pretreated with 5 mg/kg Voltaren, group 4 animals (n = 20) received 20 mg/kg BW 755C before mesenteric artery occlusion, and group 5 animals (n = 50) were pretreated with 100 mg diethylcarbamazine. The blood pressure and pulse response as well as histologic appearance of the bowel 1 h after declamping was similar in all five groups. The mortality rate after 24 h was 34% in the control group, 36% with indomethacin treatment, 36% with voltaren, 47% with BW 755C and 40% with diethylcarbamazine. The mortality rate in all the treated groups was not significantly different from the control group. Plasma thromboxane B2 levels were inhibited significantly by indomethacin and Voltaren and to a lesser extent by BW 755C. There was a paradoxical rise in thromboxane B2 following diethylcarbamazine treatment. It is concluded that inhibition of the cyclooxygenase and/or the lipoxygenase pathways of arachidonic acid did not alter the hemodynamic response and mortality following 2 h of acute superior mesenteric artery occlusion.
 ...
PMID:Effect of prostaglandin and leukotriene antagonists in acute mesenteric artery occlusion. 314 80

It remains uncertain whether platelet activation in ischemic stroke is contributory or secondary to brain ischemia. The efficacy of aspirin (ASA) in stroke prevention suggests that platelet activation contributes to the occurrence of stroke. On the other hand, platelet activation may be simply a generalized consequence of cerebral ischemic damage. To examine this issue, plasma levels of the platelet specific proteins beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were measured in fifty-eight patients with various defined types of acute ischemic strokes. beta-TG was a broader indicator of platelet activation than PF4. Compared with an age-matched control group, thromboembolic and cardioembolic stroke patients had significantly elevated beta-TG levels (p less than 0.001). Also, beta-TG levels in these stroke categories were significantly higher in samples drawn within the first week after the event than in those drawn later (p less than 0.001). In contrast, beta-TG levels in lacunar stroke patients and in most TIA patients were normal. beta-TG levels did not correlate with the volume of cerebral infarction as measured by planimetry from CT scans. Moreover, beta-TG levels in patients on chronic ASA therapy at the time of stroke did not differ from those in patients of the same diagnostic categories not taking aspirin. These data indicate that platelet activation may be important in some, but not all, subtypes of ischemic stroke and that platelet activation can occur in stroke even though the platelet cyclooxygenase pathway is suppressed.
 ...
PMID:Enhanced in vivo platelet activation in subtypes of ischemic stroke. 316 Dec 20

The purpose of our experiment was to examine whether the cyclooxygenase inhibitor indomethacin ameliorates neuronal injury in the gerbil hippocampal CA1 sector following 5 minutes of forebrain ischemia. Thirty minutes before bilateral carotid artery occlusion, Mongolian gerbils were injected intraperitoneally with 1 (n = 10), 2 (n = 10), 5 (n = 12), or 10 (n = 7) mg/kg of indomethacin. Seven days after occlusion, the gerbils were perfusion-fixed and neuronal density in the hippocampal CA1 sector was assessed. The mean +/- SEM neuronal density in nine unoperated normal gerbils was 307 +/- 9/mm, in 10 untreated ischemic gerbils 55 +/- 21/mm, and in seven vehicle-treated ischemic gerbils 15 +/- 9/mm. The mean +/- SEM neuronal density in ischemic gerbils treated with 1, 2, 5, or 10 mg/kg indomethacin was 132 +/- 28/mm, 154 +/- 29/mm, 176 +/- 30/mm, and 136 +/- 39/mm, respectively. Indomethacin at any dose significantly ameliorated ischemic neuronal damage in the gerbil hippocampal CA1 sector.
 ...
PMID:Indomethacin ameliorates ischemic neuronal damage in the gerbil hippocampal CA1 sector. 318 24

Six anesthetized dogs treated with indomethacin, prostacyclin (PGI2), and heparin were compared with 7 anesthetized controls (ischemia without treatment) to determine whether cyclooxygenase inhibition would lead to enhanced granulocyte accumulation because of preferential formation of lipoxygenase products. Cortical somatosensory evoked response, [14C]iodoantipyrine autoradiographic blood flow, and 111In-labelled granulocyte accumulation were compared 4 hours after a 60-minute exposure to multifocal brain ischemia. Treatment with indomethacin, PGI2, and heparin eliminated neuron-disabling brain blood flows without altering early postischemic granulocyte accumulation. Granulocyte accumulation after 4 hours of reperfusion was not significantly different in control and treated dogs. The final amplitude of the cortical somatosensory evoked response in the treated group averaged 38.0 +/- 13.6% (mean +/- SEM) of the corresponding baseline value compared with 21.0 +/- 4.6% in the control group, but this difference was not significant.
 ...
PMID:Indomethacin, prostacyclin, and heparin improve postischemic cerebral blood flow without affecting early postischemic granulocyte accumulation. 329 33

We found recently that exogenously administered PGD2, PGE1 and PGI2 showed a protective effect against cerebral hypoxia/ischemia in mice. In the present study, to find out whether these PGs play a pathophysiological role in cerebral hypoxia/ischemia, we examined a possible role of PGs in the development of adaptive protection against cerebral hypoxia/ischemia. Mice were pretreated with a sublethal dose of KCN, hypoxic gas mixture and electroshock 10-120 min before tests. Ten to thirty min after pretreatment with a sublethal dose of KCN, mice proved to be significantly protected against cerebral hypoxia/anoxia in all models studied: KCN-induced anoxia, normobaric hypoxia and decapitation-induced gasping. Similar results were observed when hypoxic gas and electroshock were used as pretreatments. These facts indicate that the protective effect does not depend on how cerebral hypoxia/anoxia is induced but on the substances formed in the brain after hypoxia/anoxia as well as electroshock. Brain concentrations of cyclooxygenase products markedly increased subsequent to hypoxia/anoxia as well as electroshock. The increase in PGs formation as well as resistance to hypoxia was prevented by pretreatment with indomethacin. These findings suggest that endogenously formed PGs at least including the three PGs, PGD2, PGE1 and prostacyclin in mouse brain during or after hypoxia/ischemia are responsible for the increase of resistance to hypoxia/ischemia.
 ...
PMID:A possible role of endogenously formed cerebral prostaglandins in the development of adaptive protection against cerebral hypoxia/ischemia in mice. 344 51

The present studies show that ischemia and reperfusion cause severe injury without evidence of generation of large amounts of reactive oxygen. Calculations show that it is necessary that amounts of reactive oxygen several orders of magnitude greater than that measured during ischemia-reflow injury be generated intracellularly by redox-cycling compounds such as diquat or by direct oxidants such as t-butyl hydroperoxide before endogenous cellular antioxidant systems in ischemia-reperfused rat liver or canine heart are overwhelmed. Thus, our data are incompatible with the hypothesis that oxygen radicals cause ischemia-reflow injury by lipid peroxidation or tissue thiol oxidation as postulated in Figure 1. How might one reconcile these results with the important experiments documenting protection against ischemia-reflow injury by treatment with antioxidants, antioxidant enzymes, allopurinol, cyclooxygenase/lipoxygenase inhibitors, cobra venom factor, and antisera against leukocytes (Table 1)? It seems most likely that the small amounts of reactive oxygen that can be generated in a reduced, acidic environment, such as occurs in tissue ischemia, could only be playing a catalytic function and not producing a massive oxidative attack on tissue membranes. Thus, future studies might best be directed at the catalytic function of superoxide/hydrogen peroxide in modulating the availability of substances such as lipoxygenase and cyclooxygenase products and of endothelium-derived relaxing factor during ischemia-reflow injury.
 ...
PMID:No evidence for reactive oxygen damage in ischemia-reflow injury. 345 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>