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)

Arachidonic acid metabolites are believed to be important mediators of tissue injury during reperfusion after cerebral ischemia. To determine whether inhibiting the oxygen-dependent metabolism of arachidonic acid would reduce reperfusion injury, we administered the mixed cyclooxygenase-lipoxygenase inhibitor BW755C (3-amino-1-[m(trifluoromethyl)phenyl]-2-pyrazoline) near the time of reperfusion in a rat model of temporary focal ischemia. The duration of ischemia + reperfusion was 2 hours + 22 hours, 3 hours + 3 hours, or 3 hours + 21 hours. The effects of drug or saline treatment on infarct volume, blood-brain barrier permeability, and blood flow were determined. Cortical blood flow was monitored with laser Doppler flowmetry and blood-brain barrier permeability was evaluated by the Evans blue dye method. Infarct volume was determined in all groups by computerized image analysis of Nissl-stained sections. We found that BW755C treatment significantly attenuated delayed postischemic hypoperfusion in the 3 + 3 group (p < 0.05) and reduced the volume of Evans blue dye staining in the cortex (p < 0.01) and basal ganglia (p < 0.05). Hemispheric swelling was reduced in all treatment groups (p < 0.01), as was total infarct volume in the ischemic hemisphere (p < 0.05). These results support the hypothesis that arachidonic acid metabolites contribute to acute postischemic reperfusion injury and suggest that using a mixed cyclooxygenase-lipoxygenase inhibitor as an adjunct to thrombolytic or revascularization therapy could lengthen the ischemia time after which reperfusion is beneficial.
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PMID:Attenuation of postischemic brain hypoperfusion and reperfusion injury by the cyclooxygenase-lipoxygenase inhibitor BW755C. 778 58

Microvascular dysfunction is a prominent feature of the lung injury associated with intestinal reperfusion (IR). This study examines the hypothesis that IR induces pulmonary thromboxane A2 (TxA2) release, which contributes to pulmonary microvascular dysfunction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IR). Sham-operated animals served as controls (SHAM). Following IR or SHAM, the lungs were perfused in vitro with a modified Krebs buffer and ventilated with room air. Eicosanoid levels within the pulmonary venous effluent and bronchoalveolar lavage (BAL) fluid were determined (TxB2, 6-keto-PGF1a, and PGE2). Pulmonary artery pressure (PAP) was measured continuously and expressed as change from baseline in mm Hg. The dominant eicosanoid generated by the lungs in response to IR was TxB2. TxB2 levels in the pulmonary venous effluent of IR lungs were 75% greater than controls (P = 0.005). Similarly, TxB2 levels in the BAL were more than 2.5 times controls (P = 0.001). The change in PAP of lungs from IR animals was significantly greater than that of controls (4.1 +/- 1.5 vs 0.3 +/- 0.54 mm Hg, IR vs SHAM, P = 0.01). The increased PAP associated with IR lungs was prevented by cyclooxygenase inhibition with indomethacin (-1.28 +/- 0.29 mm Hg, P < 0.05) and thromboxane synthetase inhibition with imidazole (-1.75 +/- 0.95 mm Hg, P < 0.05). These experiments support the hypothesis that IR up-regulates endogenous pulmonary TxA2 release. Furthermore, the local release of TxA2 by the lung may contribute to the microvascular dysfunction characteristic of IR-induced lung injury.
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PMID:Pulmonary thromboxane release following intestinal reperfusion. 779 27

The endothelium influences local vascular tone by releasing endothelium-derived relaxing factors such as nitric oxide, prostacyclin and a putative hyperpolarizing factor. In isolated ophthalmic arteries and the perfused eye, all endothelial factors importantly contribute to vascular regulation. In larger ophthalmic vessels, this is due to their effects on vascular smooth muscle cells; in smaller vessels, pericytes can be influenced as well. Contracting factors formed include peptide endothelin-1 and cyclooxygenase products, such as thromboxane A2 and prostaglandin H2. In the peripheral circulation endothelial dysfunction occurs under pathological conditions, both in conduit arteries and the microcirculation. An imbalance of endothelium-derived relaxing and contracting factors could be important for the development of vascular ophthalmic complications like hypertension, diabetes, arteriolosclerosis and retinal ischemia. Endothelial dysfunction may also contribute to vasospastic events in retinal migraine and some forms of low tension glaucoma associated with Raynaud phenomenon and migraine.
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PMID:The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology? 780 Dec 20

In this study Mongolian gerbils were submitted to a normothermic bilateral carotid ligation lasting 5 min. A noncompetitive antagonist of NMDA receptors, MK-801, 0.8 mg/kg, was injected i.p. 30 min before ischemia, or the ganglioside GM1, 30 mg/kg, was given i.p. for 3 days, twice a day. The morphology of the hippocampal CA1 neurones and the brain content of cyclooxygenase metabolites of arachidonic acid: prostaglandin 6-keto PGF1 alpha and thromboxane Tx B2 were studied. Untreated ischemia induced the accumulation in brain of the 6-keto PGF1 alpha and Tx B2 immunoreactive materials, and resulted in a lesion of 70% of CA1 neurones. In the MK-801- and GM1-pretreated groups the postischemic levels of Tx B2 were significantly decreased. However MK-801 and GM1 did not prevent damage to the CA1 neurones in gerbils normothermic after ischemia, whereas a partial neuroprotection was observed in hypothermic, MK-801 treated gerbils. The results of this study indicate that NMDA receptors may participate in the mechanism of postischemic release of eicosanoids in brain. They also confirm a potential modulatory role of gangliosides. These results are discussed in terms of the involvement of cyclooxygenase metabolites of arachidonic acid in the mechanism of a selective delayed neuronal damage to the hippocampus CA1 after ischemia.
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PMID:Effects of MK-801 and ganglioside GM1 on postischemic prostanoid release and hippocampal lesion in gerbil brain. 788 81

We examined the effects of endothelium-dependent responses on coronary perfusion pressure (CPP) in isolated, blood-perfused neonatal pig hearts under conditions of controlled coronary flow. Baseline CPP was increased 8%-21% by the cyclooxygenase inhibitor indomethacin (10-100 microM), and 30%-92% by NG-monomethyl-L-arginine (L-NMMA, 10-100 microM), an inhibitor of nitric oxide (NO) synthase, suggesting that both prostaglandin and nitric oxide synthesis contribute to basal coronary tone. Both acetylcholine (ACh) and bradykinin (BK) decreased CPP. These effects were enhanced by preconstriction with endothelin-1. L-NMMA markedly attenuated BK-induced coronary vasodilation and converted the ACh response to constriction, indicating a significant role for NO release in these responses. After 1 h of total, global normothermic ischemia and 45 min of reperfusion, vasoconstrictor responses to endothelin-1 and ACh were enhanced, while BK-induced dilation was significantly reduced. L-Arginine supplementation during reperfusion did not restore vasodilatory responses to ACh or BK. The magnitude of L-NMMA-induced coronary vasoconstriction during reperfusion was similar to that observed without ischemia-reperfusion. Coronary vasodilation in response to sodium nitroprusside, a NO precursor that causes endothelium-independent vasodilation by directly activating smooth muscle guanylate cyclase, was unaffected by ischemia-reperfusion. We conclude that NO production in the neonatal coronary circulation contributes to both basal tone and the response to ACh and BK. After ischemia-reperfusion, basal NO production and smooth muscle relaxation mediated by guanylate cyclase are intact, whereas agonist-stimulated dilation is significantly impaired.
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PMID:Endothelium-dependent regulation of coronary tone in the neonatal pig. 797 31

Activation of the cerebral arachidonate (AA) cascade is one of the major causes of edema and tissue injury in cerebral ischemia, particularly after reperfusion. The cascade produces toxic oxygen radicals responsible for peroxidative neurodegeneration and synthesizes, the potent edematous inducer, leukotrienes. The present study was undertaken to evaluate the effect of MCl-186 (3-methyl-1-phenyl-pyrazolin-5-one), a radical scavenger and antioxidant which has beneficial anti-ischemic actions, on the cerebral AA cascade. Postischemic treatment with MCl-186 (1.0 and 3.0 mg/kg i.v.) significantly inhibited the aggravation of cortical edema seen 60 min after recirculation following 30 min of ischemia in gerbils. An antilipoxygenase agent, FPL-55712 (7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2- hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, monosodium salt; 10 mg/kg i.v.) or AA-861 ((2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinon e; 60 mg/kg i.p.) was also effective in this model; however, indomethacin (4 mg/kg i.p.), a cyclooxygenase inhibitor, was ineffective. Concomitant treatment with MCl-186 (0.1-3.0 mg/kg i.v.) remarkably inhibited the swelling observed 24 hr after cortical infusion of AA (80 micrograms) in rats. Similarly, antilipoxygenase agents clearly inhibited the AA-induced edema. Furthermore, postischemic treatment with MCl-186 (0.3-3.0 mg/kg i.v.) inhibited the facilitation of cerebral leukotriene synthesis seen 15 min after recirculation following 30 min of ischemia in gerbils. These findings suggest that the site of action of MCl-186 as an anti-ischemic agent may be closely associated with the cerebral AA cascade, especially the lipoxygenase system, activated by ischemia-reperfusion.
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PMID:Effects of an antistroke agent MCl-186 on cerebral arachidonate cascade. 799 77

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.
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PMID:[Possible significance of free oxygen radicals for reperfusion injury]. 815 62

Recent published studies indicate that the cyclooxygenase inhibitor meclofenamate can abolish preconditioning. Unpublished preliminary data from this laboratory suggest that meclofenamate may be blocking cardiac ATP-sensitive potassium channels (KATP channels), which may also mediate preconditioning. The purpose of the present study was to determine whether meclofenamate is a cardiac KATP channel blocker and it can abolish the anti-ischemic activity of the KATP channel opener cromakalim. This concept was tested initially in an isolated rat heart model of 25 min of ischemia and 30 min of reperfusion. Meclofenamate, in a concentration (5 microM) that did not cause proischemic effects alone, abolished the protective effect of cromakalim, as measured by recovery of contractile function, lactate dehydrogenase release and contracture formation. The preischemic coronary dilating activity of cromakalim was not attenuated by meclofenamate. The cyclooxygenase inhibitors indomethacin and SQ 29,109 had no effect on the cardioprotection afforded by cromakalim. Concentration-response curves for the ability of cromakalim to increase time to contracture during ischemia in rat hearts were generated alone or in the presence of 5 or 10 microM meclofenamate. Cromakalim increased the time to contracture with an EC25 of approximately 3 microM. Meclofenamate appeared to block this effect in a manner that was not surmountable by 100 microM cromakalim. Studies in guinea pig hearts showed that meclofenamate had no effect on action potential duration or effective refractory period when given alone. Meclofenamate attenuated the action potential duration shortening effects of cromakalim in this model. Thus, meclofenamate blocked the cardioprotective effects of cromakalim and this effect was not related to cyclooxygenase inhibition. Meclofenamate appears to be a cardiac KATP channel blocker.
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PMID:The cardioprotective and electrophysiological effects of cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism. 818 22

Mesenteric ischemia of short duration (5-10 min) can stimulate A delta- and C-fiber afferent nerve endings in the viscera to reflexly activate the cardiovascular system. The mechanism of activation of abdominal visceral afferents is probably multifactorial and may involve prostaglandins (PGs), which have been shown to directly stimulate and/or sensitive visceral afferents when administered exogenously. We hypothesized that brief visceral ischemia is accompanied by release of PGI2 and PGE2 into the interstitium, where these cyclooxygenase products could stimulate or sensitize visceral afferent nerve endings. Accordingly, we measured immunoreactive PGE2 (iPGE2) and 6-keto-PGF1 alpha (i6-keto-PGF1 alpha), the stable metabolite of PGI2, in lymph draining the ischemic viscera as well as in portal venous blood. An intestinal lymph duct distal to the lymph node was cannulated in pentobarbital sodium-anesthetized cats. Lymph and plasma iPGE2 and i6-keto-PGF1 alpha concentrations were measured by radioimmunoassay before, during, and immediately after a 5- to 10-min occlusion of the descending aorta. The i6-keto-PGF1 alpha concentration increased significantly (P < 0.001) in portal venous plasma (61 +/- 12 to 107 +/- 18 pg/0.1 ml; n = 14) but not in lymph (148 +/- 30 to 159 +/- 24 pg/0.1 ml; n = 16). In contrast, iPGE2 concentration was significantly (P < 0.01) elevated in both venous plasma (156 +/- 16 to 207 +/- 26 pg/0.1 ml; n = 19) and lymph (520 +/- 48 to 590 +/- 52 pg/0.1 ml; n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Brief mesenteric ischemia increases PGE2, but not PGI2, in intestinal lymph of cats. 820 52

Eicosanoids were discovered as "prostaglandins" in the mid-1930s. The discovery that eicosanoids were ubiquitous in mammalian cells and that nonsteroidal anti-inflammatory drugs worked by inhibiting enzymes that synthesized these chemicals heralded their extensive investigation in all fields of biology. Precursor fatty acids (arachidonic acids) are stored in cell phospholipids, acted on by two enzymes (cyclooxygenase and lipooxygenase) that yield prostaglandins, thromboxane, prostacyclin, and leukotrienes. Knowledge of their biochemical processes continue to unfold, but it is now believed that eicosanoids are part of a larger group of agents termed phospholipid mediators. Eicosanoids are intimately involved with cardiovascular function as well as central and peripheral vascular disease processes and ischemia. In the gastrointestinal tract, these potent lipids not only participate in many normal functions (eg, acid secretion and motility) but also in disease states (eg, inflammatory bowel disease and peptic ulcer disease). In shocklike states of sepsis and/or endotoxemia, eicosanoids have assumed a major role in many events that occur. Recently, discoveries have demonstrated that platelet-activating and tumor necrosis factors exert their effects in part through eicosanoids. The future will demonstrate these compounds to be critical not only in intracellular (molecular) events but also in the effects they produce that are far from the source of origin.
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PMID:Eicosanoids. Critical agents in the physiological process and cellular injury. 823 81


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