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

Hypoxic-ischemic insults caused by placental insufficiency in perinatal life are today considered a major cause for neuronal injury and impaired postnatal development. A major consequence of placental insufficiency and ischemia is the change in metabolism of arachidonic acid and its oxidation products. A burst of postischemic production of prostaglandins, unequivocally shown in many systems, is documented in the fetal rabbit brain as well as in placenta tissue soon after vascular restriction. PGE2, a most abundant prostaglandin of the fetal brain, is particularly elevated. Similarly, thromboxane B2 and 6-keto PGF1 alpha, the stable metabolites of thromboxane A2 and prostacyclin, are both increased over the control values. However, after 48 h of restriction, the levels of these eicosanoids are restored to near-normal values. The metabolic machinery responsible for the conversion of arachidonic acid into eicosanoids in brain and placenta tissues appears to be impaired following a period of placental insufficiency. This inhibition can be accounted for by excessive production of eicosanoids and also by formation of an endogenous inhibitor or free radicals. Studies are in progress to test these possibilities.
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PMID:Ischemia stress and arachidonic acid metabolites in the fetal brain. 277 99

Vasoactive arachidonic acid metabolites are postulated to play a role in the pathogenesis of cerebral ischemia. In order to characterize the local generation of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in transient ischemia with reperfusion, Mongolian gerbils were studied for regional cerebral blood flow (CBF), using the hydrogen clearance technique, and for cerebral levels of the thromboxane metabolite TXB2, and prostaglandins 6-keto-PGF1 alpha and PGE2, as well as the leukotriene LTB4. The gerbils were anesthetized with pentobarbital, and half of the animals were pretreated with the cyclooxygenase inhibitor indomethacin. All received 10 or 20 minutes of dense forebrain ischemia followed by reperfusion of 10 minutes, 50 minutes, or 100 minutes. A separate control group received no ischemic lesion. Regional CBF decreased significantly from 23.7 +/- 2.6 to 4.3 +/- 1.7 cc/100 gm/min during ischemia (p less than 0.01). Reperfusion resulted in initially normal flows (22.5 +/- 5.1 cc/100 gm/min) followed by a progressive hypoperfusion (11.3 +/- 2.7 cc/100 gm/min). All metabolites showed parallel significant (p less than 0.05) increases after transient ischemia and reperfusion compared to baseline levels (values (in pg/mg protein) were: TXB2 45.5 +/- 7.1 vs 23.3 +/- 3.6; 6-keto-PGF1 alpha 262.8 +/- 47.9 vs 175.8 +/- 26.8; PGE2 256.5 +/- 35.6 vs 112.5 +/- 11.2; and LTB4 37.8 +/- 4.6 vs 24.6 +/- 6). These levels were all significantly decreased (p less than 0.05) by pretreatment with indomethacin except for the leukotriene LTB4, which was increased. Transient cerebral ischemia results in a reperfusion abnormality and the local generation of cyclooxygenase products, which are reduced by pretreatment with indomethacin; however, cyclooxygenase inhibition may result in increased substrate availability for the lipoxygenase system. Studies of such an interaction may lead to new understandings of the pharmacological modification of detrimental vascular changes after transient cerebral ischemia.
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PMID:Development of cyclooxygenase and lipoxygenase metabolites of arachidonic acid after transient cerebral ischemia. 300 Dec 48

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

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.
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PMID:Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism. 312 73

Myocardial reperfusion after prolonged periods of ischemia may result in the acceleration and exacerbation of ventricular injury. This is associated with intramitochondrial calcium overload and gross alterations in ultrastructure. Prostaglandins (PGs) (e.g., PGE2, PGE2 alpha, thromboxane A2, PGl2) are synthesized by the heart during myocardial infarction, and cardiotoxic influences of arachidonate on contractile recovery with enhanced efflux of enzymes occur after reperfusion. Accumulation of arachidonic acid in early ischemia indicates degradation of phospholipids as structural components of myocyte membranes. One major cause for reperfusion-induced exacerbation of ischemic damage is a free radical-induced peroxidation of lipids with cellular disruption. On reperfusion, both vasoconstrictive and dilator PGs are released from platelets, myocytes, and endothelium, and flushed downstream. This may cause additional vasoconstriction in the microcirculation of normally and/or hypoperfused cardiac regions. Locally released vasodilating PGs can improve cardiac perfusion and prevent plugging of blood elements, thereby antagonizing cell destruction during flow restoration. Several drugs are available that modify blood cell and myocyte arachidonate metabolism, and may favor synthesis of dilating and antiaggregatory PGs.
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PMID:Role of arachidonic acid metabolites in cardiac ischemia and reperfusion injury. 314 Feb 23

The rabbit epigastric free flap was used to investigate the effect of prostacyclin and drugs modifying its synthesis in vivo on microvascular blood flow. Prostacyclin and its analogue carbacyclin caused an increase in flow with a maximal twofold increase at approximately 6.5 and 250 ng/ml, respectively, in the flap. Thromboxane synthetase inhibitors such as dazoxiben hydrochloride, UK-38,485, 7-IHA, and imidazole (up to 7 X 10(-4) M in the flap) as well as the prostaglandins 6-oxo-PGF1 alpha and PGE2 (up to 3.7 and 9.2 ng/ml, respectively, in the flap) all failed to modify the control flow rate in the cutaneous microcirculation. It is concluded that the vasodilatory properties of prostacyclin and carbacyclin, together with their known platelet antiaggregatory properties, warrant further study in problem areas of microsurgery such as flap ischemia. The use of thromboxane synthetase inhibitors had no demonstrable effect on the normal flap, and their effect on the ischemic flap remains to be investigated.
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PMID:Pharmacologic modification of blood flow in the rabbit microvasculature with prostacyclin and related drugs. 315 1

Vasodepressor prostanoids have been suggested to regulate renal hemodynamics after nephrotoxic injury and thus protect the kidney against the effects of prolonged ischemia. This study assessed whether changes in two microvascular vasodilator prostanoids would correlate with changes seen in renal hemodynamics in rabbits with nephrotoxic renal injury produced by either uranyl nitrate or mercuric chloride. Rabbits were killed at 3, 24, and 72 h after the nephrotoxin injections and 6-ketoprostaglandin (PG) F1 alpha and PGE2 synthesis was measured in vitro in isolated renal microvessels. At the end of 24 h, synthesis of both prostanoids was significantly increased in all nephrotoxin-treated animals, an observation not noted at the end of 3 h. At 72 h, 6-keto-PGF1 alpha production remained elevated. Pretreatment with mepacrine blocked the increased prostanoid production seen in uranyl nitrate-treated animals. Thus, renal microvascular vasodilator prostanoid biosynthesis is increased 24-72 h after nephrotoxin administration. These data suggest that the biosynthesis of prostacyclin and PGE2 may contribute to the maintenance of renal blood flow in the first few days after acute renal injury and further suggest that a mechanism for this increase may be stimulation of phospholipase A2.
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PMID:Alterations in rabbit renal microvascular prostanoid synthesis in acute renal failure. 336 78

Cerebral ischemia was induced in unanesthetized gerbils using bilateral carotid artery ligations. The effects of 20 min of global ischemia on the concentrations of prostaglandin F2 alpha (PGF2 alpha), PGE2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 were determined after 0-24 h of reperfusion. Ischemia had little effect on eicosanoid production, but significant increases were observed by 5 min of reperfusion, with maximal levels reached by 15 min of reperfusion. PGF2 alpha was the most concentrated prostaglandin in postischemic brain, whereas PGE2 was most concentrated in control cerebra. Pretreatment with anesthetic doses of pentobarbital supported increased accumulation of PGF2 alpha in postischemic cerebra, increased accumulation of 6-keto-PGF1 alpha during the ischemic episode, and decreased accumulation of PGE2 at 120 min of reperfusion. It appears that the protective effects of barbiturate anesthesia are not expressed by the reduced accumulation of the above eicosanoids.
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PMID:Effects of cerebral ischemia and reperfusion on prostanoid accumulation in unanesthetized and pentobarbital-treated gerbils. 339 20

The postischemic production of PGE2, PGD2, 6-keto-PGF1 alpha, and TXB2 in brain tissue was studied in Mongolian gerbils using tissue extraction as well as a new ex vivo method. This new method permits the study of prostaglandin synthesis in slices from discrete areas of the brain (cortex, hippocampus, striatum, hypothalamus). Gerbils were sacrificed at 0, 5, and 30 minutes, and 4 and 24 hours after a 15-minute occlusion of both carotid arteries. Apart from 6-keto-PGF1 alpha, tissue prostaglandins determined by the extraction method were significantly increased 3 and 30 minutes after reperfusion. The most pronounced changes found by the ex vivo method were increased productions of PGD2 immediately after reperfusion (285% in cortex, 215% in hypothalamus) and PGE2 (350% in hippocampus, 320% in striatum) 4 hours after reperfusion. At 24 hours after reperfusion PGE2 and PGD2 synthesis were significantly decreased by 23-70% of the values obtained from sham-operated controls. Thromboxane increased slightly in all areas after recirculation and subsequently decreased to values below the control level in striatum. The results obtained by ex vivo incubation of tissue slices demonstrate that ischemia and subsequent recirculation cause site-, time-, and PG-specific changes of tissue eicosanoid production.
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PMID:Postischemic production of eicosanoids in gerbil brain. 346 70

Ischemia was induced for 25 min in the spinal cord of rabbits followed by a long term period of recirculation. At various time points of recirculation (5, 30 min, 4, 18 hr and 1 wk) slices were taken from the ischemic region and incubated for 45 min in Krebs-Ringer solution. The levels of the eicosanoids, PGE2, PGD2, PGF2 alpha, TXB2, 6-keto-PGF1 alpha and 5-HETE accumulated in the incubation medium were measured by radioimmunoassay. TXB2, release was found to be increased at an early (5 min) and late (1 wk) period of reperfusion. A seven-fold increase in the release of 5-HETE was found 5 min after reperfusion that tended to stay elevated at 18 hr and 1 week of recirculation. PGI2 synthetase activity decreased by 40% at 30 min, with return to normal at later time points. The ratio of TXA2/PGI2 was significantly higher than control at 30 min and 1 wk. The synthesis of PGE2, PGD2 and PGF2 alpha was maintained at normal levels throughout the complete course of reperfusion. No changes in eicosanoid synthesis were noted in remote spinal cord regions. The significant increase of TXA2 synthesis at 5 min and 1 wk of reperfusion may point to a role of this arachidonate metabolite in the acute events and in the later stages of neurological dysfunction. The enhanced release of 5-HETE, a metabolite of 5-HETE, suggest an enhanced formation of leukotriene B4 and peptide leukotrienes and a potential role for these 5-lipoxygerase metabolites of arachidonate in ischemia injury to the brain and the spinal cord.
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PMID:Increased thromboxane A2 and 5-HETE production following spinal cord ischemia in the rabbit. 347 67


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