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

We studied the effect of arachidonic acid on function and CPK release of normal, ischemic and reperfused isolated rat hearts. Under control conditions arachidonate (10 micrograms/ml) produced a transient inotropic effect which gradually reversed during a 90 minute perfusion. Creatinephosphokinase (CPK) release was augmented by arachidonic acid, particularly under high flow (pre-ischemia and reperfusion) conditions. Recovery of contractility following reperfusion of ischemic myocardium was significantly depressed by arachidonic acid. Vitamin E (100 ng/ml) an antioxidant and free radical scavenger, reduced the enzyme leakage and enhanced recovery of contractility of reperfused myocardium. It also prevented the depression in contractility during control perfusion. Similar protective effects were observed by perfusing the heart with reduced calcium but not by nifedipine; a calcium channel blocker, indomethacin; a prostaglandin synthesis inhibitor or nordihydroguarietic acid; a lipoxygenase inhibitor. Arachidonic acid also inhibited membrane Na+/K+-ATPase although it is unlikely that this property mediated its cardiotoxic influence since it was not prevented by vitamin E. In addition, we observed that arachidonic acid increased the coronary resistance of isolated hearts, probably through enhanced calcium influx as this constriction was reduced by low calcium as well as by nifedipine. Thus, arachidonic acid possesses distinct properties. Its cardiotoxic influence is likely mediated by free radical generation.
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PMID:Toxic properties of arachidonic acid on normal, ischemic and reperfused hearts. Indirect evidence for free radical involvement. 392 Jun 82

To know the mechanism underlying ischemic brain edema, a time-course analysis of the eicosanoid synthetic capacity of brain microvessels was carried out using unilateral, middle cerebral artery (MCA)-occluded rats. Concomitant with the development of brain edema the synthetic capacity of all products, including cyclooxygenase and lipoxygenase products, increased significantly. Next the effects of 15-hydroperoxyarachidonic acid (15-HPAA) on the synthetic capacity of microvessels were examined. The drug caused a generalized increase of each product, the profile of which was similar to that obtained with ischemic hemispheres, although the ratios of each product differed somewhat among them. The enhanced synthesis of eicosanoids by 15-HPAA was markedly suppressed by radical scavengers such as alpha-tocopherol, hydroquinone, and 1,2-bis(nicotineamide)-propane. Furthermore, the evolution of brain edema was virtually suppressed by the systemic administration of 1,2-bis(nicotineamide)-propane. The above result suggests that the enzyme activity of the arachidonic acid (AA) cascade of microvessels is stimulated by its own products. Such a mechanism will form a vicious cycle that accelerates the accumulation of free radicals within microvessels and thus may play a role in the progressing disruption of the blood-brain barrier (BBB) following ischemia.
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PMID:Alterations of the eicosanoid synthetic capacity of rat brain microvessels following ischemia: relevance to ischemic brain edema. 396 37

Using the rat middle cerebral artery occlusion model, alterations in the eicosanoid synthetic capacity of brain microvessels following ischemia were studied by radiochromatography. Brain microvessels of normal rats predominantly produced hydroxyacids with relatively small amounts of PGD2 and PGE2 from exogenous arachidonic acid. Confirmation that hydroxyacids and prostaglandins were products respectively of lipoxygenase(s) and cyclooxygenase was obtained by experiments using indomethacin and eicosatetraynoic acid. The eicosanoid synthetic capacity of the brain microvessel, especially of hydroxyacids, was significantly enhanced 24 and 72 hours after the onset of ischemia. Because this is the phase of maximum edema in the present model, enhanced eicosanoid production in the brain microvessel may be involved in the mechanisms that underly ischemic brain edema.
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PMID:Ischemic brain edema following occlusion of the middle cerebral artery in the rat. II: Alteration of the eicosanoid synthesis profile of brain microvessels. 396 53

The effects of oral nafazatrom pretreatment (10 mg/kg, twice a day, for 10 days) on myocardial ischemia were studied in the rabbit heart during 6-h occlusion of the left anterior descending coronary artery (LAD). The tension-time index (TTI), hemodynamics, and ischemia size were determined (Evan's blue-triphenyltetrazolium chloride staining with planimetry). In drug-vehicle controls, left ventricular (LV) and peripheral pressures and LV dP/dtmax decreased, while heart rate, end-diastolic pressure, the TTI, and electrocardiographic ST segments increased. Hemodynamics were nearly unaltered in the nafazatrom-pretreated animals, except for a heart rate elevation during the initial phase of LAD occlusion. In drug-treated hearts, 45 +/- 6% of the LAD perfusion region at risk was ischemic, showing a patchy distribution. In vehicle controls, 82 +/- 4% (p less than 0.02 vs. nafazatrom pretreatment) of the LAD-perfused myocardial regions was transmurally ischemic, showing a uniform pattern. Thus, nafazatrom pretreatment prevented most hemodynamic changes following LAD occlusion in the rabbit heart. Significant amounts of the muscle remained normoxic within the nonperfused arterial regions. These results indicate that the inhibition of lipoxygenase enzymes by nafazatrom may delay the development of ischemic damage to the heart following acute coronary artery occlusion.
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PMID:Reduction of acute myocardial ischemia in rabbit hearts by nafazatrom. 620 Jul 22

Administration of leukotrienes to cardiac tissue produces contractile depression and coronary artery constriction [5,8], thus making it possible that these substances mediate cardiac dysfunction under pathologic conditions. Up to now no studies have been performed to determine whether cardiac tissue has the inherent ability to produce leukotrienes. The present study was therefore carried out to ascertain whether isolated hearts perfused with saline buffer devoid of any blood constituents can produce leukotrienes under a variety of pharmacologic and pathologic situations. No leukotriene (LT) C4 was detected under control conditions or from hearts subjected to global ischemia and reperfusion or hypoxia and reoxygenation. A23187, a Ca2+ ionophore markedly stimulated LTC4 release. This effect was prevented by nordihydroguaiaretic acid, a selective lipoxygenase inhibitor. The addition of arachidonate as substrate had no effect on LTC4 release. In an attempt to divert arachidonate to LTC4 production, indomethacin, a cyclo-oxygenase inhibitor was added before arachidonate. No LTC4-like immunoreactivity was found in these experiments. These studies suggest that a lipoxygenase pathway for leukotriene production is present either in the coronary vasculature or myocardium. It was stimulated only by Ca2+ ionophore, probably indicating a requirement for high amounts of intracellular Ca2+.
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PMID:Calcium-ionophore stimulated release of leukotriene C4-like immunoreactive material from cardiac tissue. 644 Sep 98

Ischemia ultimately leads to loss of thermodynamic order in all cells. During ischemia and reperfusion, the influx of Ca2+ ions appears to initiate a number of cell processes, the reversal of which depends on the re-establishment and maintenance of adequate organ perfusion and high energy metabolism. Promising therapeutic approaches for accomplishing these goals include substrate augmentation, inhibition of calcium-activated injury, membrane stabilization, manipulation of the cycloxygenase and lipoxygenase reactions, and the use of free radical scavengers.
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PMID:Physiology of resuscitation. 644 2

The effect of nafazatrom, a new antithrombotic agent, was studied in a canine model of regional myocardial ischemia. Nafazatrom was administered 1 mg/kg intravenously every 6 h for 48 h. After 24 h of drug or placebo administration, animals underwent 90 min of occlusion of the proximal left circumflex coronary artery followed by gradual reperfusion over a period of 30 min. Twenty-four hours later, the animals were sacrificed and infarct size was determined by histochemical staining with triphenyltetrazolium chloride. Nafazatrom-treated animals had a significant reduction in infarct size expressed as a percent of the anatomical area at risk for infarction: 21 +/- 5% in the treated group vs. 41 +/- 5% in the control group (X +/- S.E.M., P less than 0.05). Histological examination confirmed the gross results of postmortem histochemical staining. Salvage of ischemically jeopardized tissue appeared to be unrelated to myocardial oxygen demand as there were no hemodynamic differences between groups. The beneficial effects of nafazatrom are presumably related to a limitation of autolytic processes on the heart during and after ischemia as a result of the drug's ability to inhibit lipoxygenase and to prevent the enzymatic degradation of prostacyclin.
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PMID:Beneficial effects of nafazatrom on ischemic reperfused myocardium. 647 19

Leukotriene D4 (1--20 micrograms/kg i.a.) administered to conscious spontaneously hypertensive rats (SHR) and WKY rats caused acute elevation of blood pressure in both groups, but only in SHR a prolonged hypotensive period followed the hypertensive event. SHR rats had tachycardia during the hypertensive phase and relative bradycardia during the hypotensive phase which was more pronounced and prolonged than in WKY rats. In SHR rats only, plasma epinephrine and norepinephrine were elevated (6- and 3-fold, respectively) at the peak of the hypertensive period. Pretreatment of SHR rats with indomethacin (5 mg/kg) potentiated the LTD4-induced pressor response and shortened the hypotensive-bradycardic effect of LTD4. This same biphasic, dose-dependent response to LTD4 (1--20 micrograms/kg i.v.) was present in pithed SHR rats. Therefore, a direct action of LTD4 on vascular smooth muscle and heart is suggested. In all WKY rats and some SHR rats, a bradycardic effect of LTD4 resulted from sinus bradycardia, whereas in pithed SHR rats impaired conduction varying from transient second degree atrioventricular block to complete heart block was observed. Electrocardiographic signs of ischemia were seen only in LTD4-injected, pithed SHR rats. These results suggest fundamental differences between SHR and WKY rats in regard to their sensitivity to lipoxygenase products.
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PMID:Leukotriene D4: cardiovascular and sympathetic effects in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. 689 89

Ischemic brain insults are accompanied by several metabolic alterations. In the present review, the adverse reactions, which might be important for the outcome of these insults, are those related to phospholipid and polyunsaturated fatty acid metabolism triggered by the disturbed calcium ion homeostasis in combination with energy depletion following ischemia. The conditions lead to an activation of phospholipases and to a decreased rate of phospholipid resynthesis with a concomitant increase in the concentration of free fatty acids, in particular arachidonic acid. During the recirculation phase, when oxygen supply is reestablished, the polyunsaturated arachidonic acid serves as substrate in the cyclo-oxygenase and lipoxygenase pathways leading to the formation of hydroxy-and hydroperoxy fatty acids, prostaglandins and possibly also leukotrienes. These substances have adverse effects on the integrity of cell membranes, irreversibly altering the functional properties of the cells, and also vasomodulator properties influencing the effectiveness of the reperfusion of the brain.
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PMID:Ischemic brain injury: the importance of calcium, lipolytic activities, and free fatty acids. 704 18

There is widespread interest in the neurotoxicity of the endogenous excitatory amino acid neurotransmitter glutamate. Excessive glutamate release or accumulation leads to neuronal injury or death in a variety of experimental models of ischemia, anoxia and hypoglycemia. This injury appears to be caused by overactivation of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors since a variety of competitive and uncompetitive NMDA antagonists can attenuate this process, sometimes in a dramatic fashion. Given the clinical context in which this form of neuronal injury occurs, it would be desirable if we could identify agents that blocked NMDA toxicity, after initial receptor binding and ion channel fluxes had transpired. Because NMDA receptor activation initiates the arachidonic acid cascade, we have recently looked at whether the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) can reduce NMDA neurotoxicity in vitro. In the concentration range 1-30 microM, NDGA diminished the death of cultured rodent hippocampal neurons produced by 100 microM NMDA. When 30 microM NDGA was present both before and after NMDA exposure, death declined by over 50%. NDGA did not block NMDA-induced inward currents in voltage-clamped neurons, so the drug is not a direct NMDA receptor antagonist. It also had no effect on the elevation in intracellular calcium produced by NMDA exposure. It is likely that NDGA acts at a site(s) distal to the NMDA receptor and the neuronal membrane to limit NMDA toxicity. We are hopeful that strategies for limiting excitotoxicity, which halt destructive intracellular events, can be developed for use in human neurological diseases linked to excessive stimulation of glutamate receptors.
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PMID:Nordihydroguaiaretic acid attenuates NMDA neurotoxicity--action beyond the receptor. 750 52


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