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

This review provides a summary and assessment of research involving renal prostaglandins. Arachidonic acid released from phospholipids is converted by prostaglandin cyclo-oxygenase in the kidney to PGF2, PGF2alpha, PGD2, and, possibly, to PGI2 and thromboxane A2. Production of PGE2 and PGF2alpha is predominately but not exclusively in the medulla, whereas degradative enzymes are present in both cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron. Urine prostaglandins probably reflect renal synthesis. PGE2 and endoperoxides stimulate and PGF2alpha and indomethacin inhibit renal renin synthesis. In response to ischemia, vasoconstriction, or angiotensin II the kidney increases prostaglandin synthesis to modulate renal vascular resistance. In conscious animals or man no role has been established for prostaglandins in the maintenance of basal renal blood flow or renal sodium excretion. PGE influences renal water excretion by inhibiting the action vasopressin. Despite conflicting data there is evidence that renal prostaglandins are involved either primarily or secondarily in many types of hypertension. Inhibitors of prostaglandin cyclooxygenase have been used with success in Bartter's syndrome. Conflicting results in many areas of investigation may be resolved by the use of more accurate and reliable assays, careful handling of samples, and the use of urine to further investigate renal prostaglandin synthesis.
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PMID:Prostaglandins and the kidney. 33 46

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
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PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78

Several lines of evidence indicate a role for elevated intracellular Ca2+ in mechanisms of cell killing induced by a wide variety of agents. Cardiac myocytes are susceptible to killing under various conditions, including ischemia and exposure to monensin. In order to delineate the Ca(2+)-dependent cell killing mechanism(s) to which cardiac myocytes are susceptible, we have investigated the mechanism by which they are killed by Ca2+ plus the divalent cation ionophore A23187. Evidence has been obtained for two Ca(2+)-mediated injury steps followed by a Na(+)-mediated step leading to cell death detected as membrane permeabilization to trypan blue dye. The first Ca(2+)-mediated step requires the presence of A23187 and low extracellular Ca2+ concentrations (1-100 microM) and is inhibited by Mn2+ and Ni2+ ions. The second Ca(2+)-dependent step requires extracellular Ca2+ concentrations in approximately the physiological range (greater than 1 mM), is not dependent on ionophore, and is not inhibited by Mn2+. Arachidonic acid release occurs during both Ca(2+)-mediated steps, but mostly during the second step. The second injury step is characterized by visible cell swelling and release of lactate dehydrogenase enzyme activity. The Na(+)-dependent step requires extracellular Na+ equal to or greater than half the physiological concentration (i.e., greater than or equal to 75 mM). Li+, which has a smaller ionic radius than Na+, can partially substitute for its in the Na(+)-dependent step, whereas K+, Cs+, Rb+, and NH4+ (which have larger ionic radii) cannot.
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PMID:Sodium- and calcium-dependent steps in the mechanism of neonatal rat cardiac myocyte killing by ionophores. II. The calcium-carrying ionophore, A23187. 152 52

Focal brain ischemia was induced in rats by inserting a silicone rubber cylinder attached to a nylon surgical thread from the common carotid artery into the middle cerebral artery bifurcation. Reperfusion was achieved by removing the cylinder. In the ischemic area, free fatty acids were measured. Arachidonic acid lipoxygenase metabolites: leukotriene C4 (LTC4), and cyclooxygenase metabolites: thromboxane B2 (TXB2), prostaglandin E2 (PGE2) and 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) were measured during ischemia and after reperfusion. There were five ischemia groups. The rats in these groups were killed 1, 2, 3, 4 or 6 hours after occlusion. In the reperfusion group, rats exposed to 1, 2, 3 and 4 hours of ischemia were killed 5, 4, 3 and 2 hours after reperfusion, respectively. The free fatty acids, which had increased due to occlusion, decreased after reperfusion from 1 hour of ischemia. With 2 or more hours of ischemia, however, the free fatty acids increased after reperfusion, indicating cell membrane destruction. Eicosanoids showed almost the same changes in all groups. The eicosanoid level was high only after 1 hour of ischemia and it stayed low if the ischemia time exceeded 2 hours and after reperfusion. Therefore, we suggested that eicosanoids are not a main cause of tissue damage in the ischemic area after 2 or more hours of ischemia.
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PMID:[Effect of occlusion and reperfusion on free fatty acid levels and eicosanoid metabolism in a rat model of focal ischemia]. 179 94

Isovolumically perfused control and chronic diabetic rat hearts were subjected to 20 min of global ischemia plus 30 min of reperfusion at preischemic flow rates. Recoveries of contractile function during reperfusion were similar in both groups. Addition of arachidonic acid produced profound postischemic dysfunction in nondiabetic hearts (isovolumic minute work = 19 +/- 8 vs. 86 +/- 10% of preischemic levels after 30 min), whereas arachidonic acid had no detrimental effect in diabetic hearts. Arachidonic acid also augmented endogenous prostacyclin release in control hearts (untreated 2.28 +/- 0.23 ng/ml; arachidonic acid 4.07 +/- 0.22 ng/ml) but failed to alter postischemic prostacyclin release in diabetic hearts. The arachidonic acid-induced postischemic dysfunction was significantly attenuated by coadministration of the oxygen free radical scavengers, superoxide dismutase plus catalase, but not by indomethacin. Thus arachidonic acid-induced dysfunction in normal hearts appears to be related, in part, to free radical production. The intrinsic capacity of the heart to synthesize prostacyclin as a result of ischemia and reperfusion does not appear to be impaired by diabetes. In contrast, the arachidonic acid-induced increase in prostacyclin following ischemia is blunted in the diabetic heart. Although chronic diabetic hearts showed increased tolerance to arachidonic acid-induced dysfunction during reperfusion, a defect in prostacyclin stimulation may place the diabetic at greater risk of complications of ischemic reperfusion in vivo by reducing the capacity to adequately respond to the aggregatory and vasospastic actions of increased circulating thromboxane consequent to myocardial ischemia and reperfusion.
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PMID:Arachidonic acid causes postischemic dysfunction in control but not diabetic hearts. 210 41

Isolated, ejecting rat hearts, perfused with Krebs-Henseleit buffer, were exposed to various periods of global ischemia. Arachidonic acid (AA) accumulated significantly in the ischemic heart when the duration of ischemia exceeded 45 min. During 30 min of reperfusion, tissue levels of AA raised steadily to values of 10.5, 17.7, and 63.1 nmol/g, after 30, 45, and 60 min of ischemia, respectively. During reperfusion, significant amounts of AA metabolite prostacyclin (determined as stable metabolite 6-ketoprostaglandin F1 alpha, by radioimmunoassay and high-performance liquid chromatography) were released after 30, 45, and 60 min of ischemia. Beside prostacyclin, only small amounts of thromboxane B2 could be found during reperfusion. In contrast to increasing amounts of AA in reperfused tissue, prostacyclin release was maximal during the first 5 min of reperfusion and declined rapidly thereafter. Relatively small proportions of the accumulated AA are converted into prostacyclin, i.e., less than 1%. When hearts were treated with mepacrine, AA accumulation was almost completely abolished during 60 min of ischemia. The cumulative release of prostacyclin was found to be reduced to 134 pmol/g during 30 min of subsequent reperfusion. A close, rectilinear correlation could be established between AA accumulation and cumulative prostacyclin release during reperfusion. It is likely, however, that the site of bulk AA accumulation and that of conversion of AA into eicosanoids does not coincide in the ischemic and reperfused heart because of the low conversion rates of AA into prostacyclin and the different time courses of AA accumulation and prostacyclin production after reinstallation of flow.
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PMID:Ischemia and reperfusion induced formation of eicosanoids in isolated rat hearts. 211 74

Arachidonic acid is liberated from damaged cell membranes during ischemia and is the source of vasoactive prostanoids. In this study, specific drugs that influence AA metabolism were investigated for their effects on brain edema and energy metabolites during ischemia. The agents tested were: methylprednisolone (phospholipase A2 inhibition), indomethacin (cyclooxygenase inhibitor), trapidil (TXA2 synthetase inhibitor), and OP-41483 (prostacyclin derivative). Cerebral ischemia was produced using bilateral common carotid artery occlusion in spontaneously hypertensive rats. Brain water content and concentrations of ATP, pyruvate, and lactate were determined 3 hr after occlusion. Compared with its vehicle, methylprednisolone significantly reduced water content and lactate concentration and maintained high levels of ATP. Indomethacin had no effect on brain water content nor metabolite levels. Trapidil decreased water content and lactate levels and increased levels of ATP and pyruvate. OP-41483 had no effect on water content and lactate, but maintained ATP and pyruvate at high levels. These results indicate that some of the AA metabolites may play an important role in the development of brain edema and in the impairment of energy metabolism.
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PMID:Role of arachidonic acid metabolism on ischemic brain edema and metabolism. 211 11

Using rat ventricular cells, we studied the actions of free fatty acids and their ability to modulate the ATP-sensitive K+ channel and to activate a new type of ATP-insensitive K+ channel previously identified in rat atrial cells. Perfusion of the cytoplasmic face of the membrane with unsaturated fatty acids (10-50 microM) such as arachidonic, linoleic, and eicosatrienoic acids inhibited the ATP-sensitive K+ channel almost completely; lysophospholipids also markedly inhibited this channel. Inhibition was due to decreases in the frequency and the burst duration of channel openings. Arachidonic acid activated the ATP-insensitive K+ channel with an outwardly rectifying property. Since the level of free fatty acids rises after longer periods of ischemia, we speculate that the ATP-insensitive K+ channel contributes to the late or secondary phase of extracellular K+ accumulation.
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PMID:Regulation of K+ channels in cardiac myocytes by free fatty acids. 211 11

We have observed that pial arteriolar dilation in response to hypercapnia and hypotension is abolished after cerebral ischemia in newborn pigs. We determined whether direct generation of activated oxygen on the brain surface (OX: xanthine oxidase, hypoxanthine, FeCl3, and FeSO4) or topical arachidonate altered pial arteriolar responsiveness in a manner similarly to cerebral ischemia. OX, which generated more brain surface superoxide than reperfusion after ischemia, dilated pial arterioles. This dilation was reversed within 10 min of the end of exposure. OX produced ultrastructural changes in pial vessel endothelium and appeared to cause intravascular aggregation of granulocytes. After OX, prostanoid-dependent pial arteriolar dilations in response to hypercapnia and hypotension were attenuated, whereas constrictor responses to norepinephrine and acetylcholine and dilator responses to prostaglandin E2 and isoproterenol were not affected. After OX, hypercapnia increased cortical periarachnoid cerebrospinal fluid prostanoids modestly, whereas acetylcholine produced the normal strong stimulation of prostanoid synthesis. Arachidonate (10(-4) M and 7 x 10(-4) M) also caused reversible pial arteriolar dilation but did not alter subsequent pial arteriolar responses. Therefore, although arachidonate did not mimic the effects of ischemia-reperfusion on pial arteriolar reactivity, OX produced alterations that are qualitatively similar, although quantitatively less, than those produced by ischemia.
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PMID:Activated oxygen and arachidonate effects on newborn cerebral arterioles. 212 Oct 51

Arachidonic acid metabolites have been implicated in the development of cerebral edema following ischemia. To define the time course of metabolite production, subtemporal craniectomies were performed on 60 male Sprague-Dawley rats (350-400 g). Thirty rats underwent middle cerebral artery occlusion while 30 rats underwent craniectomy alone. Five rats in each of two groups (middle cerebral artery occlusion and sham) were sacrificed at 15 minutes, 1 hour, 4 hours, 1 day, 3 days, and 6 days. The cerebral hemispheres were removed and divided in the midsagittal plane. Each hemisphere was immediately frozen in isopentane cooled in dry ice and stored at -70 degrees C. Tissue prostaglandins E2 and 6-keto F1 alpha, and leukotrienes (LT) B4 and C4 were measured by radioimmunoassay. Prostaglandin E2 and 6-keto prostaglandin F1 alpha were significantly elevated at 15 minutes in the middle cerebral artery occlusion hemispheres (p less than 0.05). Prostaglandins were not significantly elevated after 15 minutes. LT B4 and C4 were never significantly elevated. Meclofenamate, a nonsteroidal anti-inflammatory agent, was administered to 21 additional rats. Seven controls underwent middle cerebral artery occlusion alone, 7 were given intraperitoneal meclofenamate (20 mg/kg) 30 minutes prior to middle cerebral artery occlusion, and 7 underwent middle cerebral artery occlusion followed immediately by intraperitoneal meclofenamate (20 mg/kg). The animals were sacrificed at 15 minutes and similarly studied. There was a significant reduction of prostaglandin E2 and 6-keto prostaglandin F1 alpha following pretreatment with meclofenamate (p less than 0.01 and p less than 0.05). In pretreated rats, leukotrienes were not affected by meclofenamate. Similarly, prostaglandins and leukotrienes did not change when meclofenamate was administered after middle cerebral artery occlusion. We conclude that cyclo-oxygenase metabolite production begins within 15 minutes of middle cerebral artery occlusion. Treatment with meclofenamate prior to middle cerebral artery occlusion significantly reduced cyclooxygenase metabolite production, suggesting a protective effect of meclofenamate against ischemia-induced elevations of vasoactive prostaglandins implicated in the development of cerebral edema. Lipoxygenase metabolite production was not affected by middle cerebral artery occlusion or pharmacological intervention.
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PMID:Arachidonic acid metabolite production following focal cerebral ischemia: time course and effect of meclofenamate. 215 40


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