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

Mucosal arachidonic acid metabolism was examined after 3 h of ischemia and 1 h of reperfusion in isolated ileal segments in the dog. The cyclooxygenase products thromboxane B2, 6-ketoprostaglandin F1 alpha, and prostaglandin E2 increased by 365%, 97%, and 158%, respectively, after ischemia and reperfusion but were not altered after 3 h of ischemia alone. The potent chemotactic lipoxygenase product leukotriene B4 (LTB4) increased by 687% after ischemia and reperfusion and was not affected by ischemia without reperfusion. In addition, tissue production of the thiol ether leukotrienes (LTC4, LTD4, and LTE4) increased threefold after ischemia and reperfusion. Quantitation of regionally isomeric hydroxy acids produced from arachidonate revealed a 300% increase in 12-hydroxyeicosatetraenoate (12-HETE) after intestinal ischemia and reperfusion without a change in other isomers (15-HETE and 5-HETE). Stereochemical analysis of 12-HETE demonstrated exclusive synthesis of the S-enantiomer. A significant and time-dependent decrease in intestinal blood flow also occurred during reperfusion. Administration of the dual cyclooxygenase-lipoxygenase synthesis inhibitor BW755C (1 mg/kg ia) did not alter time-dependent decreases in blood flow and failed to inhibit eicosanoid synthesis. Histologic examinations of intestinal samples revealed significant mucosal damage associated with ischemia alone and ischemia after reperfusion. This study indicates that intestinal ischemia-reperfusion injury is associated with dramatic alterations in mucosal production of vasoactive eicosanoids and with changes in blood flow that occur during reperfusion but not during ischemia alone. These events may be involved in the pathology characteristic of this injury.
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PMID:Mucosal arachidonate metabolism and intestinal ischemia-reperfusion injury. 250 53

The oxygenation of arachidonic acid by lipoxygenases results in the formation of HPETEs (hydroperoxyeicosatetraenoic acids), the first products of the LOX pathway. These compounds are short lived and are catabolised into various families of more stable compounds of which the HETEs, hepoxilins, lipoxins and leukotrienes have been identified so far. The development of new techniques have helped to identify and understand the structures of various HPETEs and only recently the biological effects of HPETEs and their various catabolites are being unraveled. Although lipoxygenases are ubiquitous, not all tissues possess the same spectrum of lipoxygenase enzymes. Hence different HPETEs can be formed in different tissues. Recent studies have revealed that HPETEs or products derived from them possess a diversity of important biological properties including the regulation of electrolyte flux and eicosanoid and corticosterone syntheses, release of histamine, regulation of oocyte maturation and release of various reproductive hormones. HPETEs appear to be involved in some pathological conditions viz, skin psoriasis, Clarkson's disease, nerve injury and spinal cord ischemia. These novel eicosanoids are associated with the release of insulin as well as renin. Recently HPETEs have been suggested to act as second messengers in the Aplysia sensory neurons and its catabolite, hepoxilin, has been demonstrated to have effects on mammalian hippocampal neurons. The purpose of this review is to provide a brief summary of the formation of the HPETEs and the various families of compounds derived from them as well as the various types of biological activities for these products described so far.
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PMID:Biosynthesis, catabolism, and biological properties of HPETEs, hydroperoxide derivatives of arachidonic acid. 251 25

Results of our consecutive study on the pathogenic mechanism underlying ischemic brain edema are summarized in this paper. Pertinent findings are as follows: (1) there is a close correlation between the influxes of water and sodium following ischemia; (2) the edema fluid can be regarded as the ultrafiltrate of serum; (3) there is a significant increase in the brain content of HETEs following ischemia; (4) the lipoxygenase activity of brain microvessels is increased following ischemia; (5) the lipoxygenase activity as well as the Na+, K+-ATPase activity of brain microvessels are enhanced by a hydroperoxide, 15-HPETE; (6) inhibition of Na+, K+-ATPase of brain microvessels by intraarterial infusion of ouabain resulted in a significant decrease in edema formation; and (7) not the cyclooxygenase, but the lipoxygenase pathway seems to be involved in the enhancement of microvessel Na+, K+-ATPase. Lipoxygenase(s) and Na+-K+-ATPase of brain microvessels, the activities of which are enhanced by an increased level of free radicals and/or hydroperoxides, may play a significant role in the occurrence of ischemic brain edema.
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PMID:The role of free radicals and eicosanoids in the pathogenetic mechanism underlying ischemic brain edema. 266 83

The precise role of eicosanoids in the development of myocardial injury during ischemia and reperfusion is still a matter of debate. Enhanced local production of these bioactive compounds appears to be a common response to tissue injury. Most likely, the cardiac tissue has the capacity to generate prostaglandins, thromboxanes as well as leukotrienes. Prostacyclin (PGI2) is the major eicosanoid produced by the jeopardized myocardium. In addition, at sites of tissue injury activation of platelets and infiltrating leukocytes results in the formation of considerable amounts of thromboxanes and leukotrienes. The production of eicosanoids requires prior release of arachidonic acid (AA) from phospholipids. Both ischemia and reperfusion are associated with a rise in the tissue level of AA. The absence of a proportional relationship between the tissue level of AA and the amounts of PGI2 produced suggests that the sites of AA accumulation and PGI2 formation are different. It is conceivable that AA accumulation is mainly confined to myocytes, whereas the capacity to synthesize PGI2 mainly resides in vascular cells. Both beneficial and detrimental effects of eicosanoids on cardiac tissue have been described. Prostaglandins act as vasodilators. Besides, some of the prostaglandins, especially PGI2, are thought to possess cyto-protective properties. Thromboxanes and leukotrienes may impede blood supply by increasing smooth muscle tone. Besides, leukotrienes augment vascular permeability. Experimental studies, designed to evaluate the effect of pharmacological agents, like PGI2-analogues and lipoxygenase and cyclo-oxygenase inhibitors, indicate that eicosanoids influence the outcome of myocardial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Significance of myocardial eicosanoid production. 267 62

Regional changes in the amount of free fatty acids, polyphosphoinositides, and water content in the cerebral cortex were examined using a middle cerebral artery occlusion model of rats. The amount of various free fatty acids increased as polyphosphoinositides decreased during 3 and 6 hours of ischemia in the occluded middle cerebral artery territory. After 3 hours of reperfusion following 3 hours of ischemia, free fatty acids partially recovered while polyphosphoinositides did not. Water content increased significantly after 3 and 6 hours of ischemia, and a further increase was found after 3 hours of reperfusion following 3 hours of ischemia. The change of polyenoic fatty acids in this occluded middle cerebral artery territory was much smaller than that in the case of decapitation ischemia, although the amounts of polyphosphoinositides and monoenoic and saturated fatty acids showed almost identical changes in both cases, probably because polyenoic fatty acids may be washed out and/or peroxidatively consumed in the middle cerebral artery occlusion model due to its residual blood flow. Changes in the area surrounding the occluded middle cerebral artery territory were similar to the above results, although less dramatic. However, there was no change in free fatty acids, polyphosphoinositides, and water content in the contralateral cortex. A novel free radical scavenger (MCI-186), which prevents both nonenzymatic peroxidation and lipoxygenase activity in vitro, markedly attenuated the ischemic and postischemic brain swelling. These results suggest that free radical mechanisms may be involved in ischemic and postischemic brain edema.
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PMID:Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. 283 36

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

Cardiac myolysis was observed in guinea pigs sensitized with vesicular stomatitis virus (VSV), following challenge with this antigen. The phenomenon developed within 1 h of challenge, appearing as islands in the myocardium. The speed and focal nature of the damage point to obstruction of blood flow as a cause of the myolysis. The myolysis was not a toxic effect of the virus itself, but probably a consequence of cardiac anaphylaxis. It occurred only after challenge, and was abolished in 71% of the animals by pretreatment with a mixture of the lipoxygenase-cyclooxygenase inhibitor, BW755C and H1 histamine receptor antagonist, diphenhydramine. Treatment with BW755C alone before challenge prevented myolysis from developing in 46% of the animals. Challenge in vitro with VSV to the perfused, spontaneously beating, sensitized isolated guinea pig heart increased sulfidopeptide-leukotriene (LTC4, LTD4, LTE4) production from undetectable levels (0.5 ng LTD4-equivalent/heart/15' to 13 ng LTD4-equivalent/heart/15'. At the same time, there were derangements in cardiac rate, contractility and coronary outflow typical of cardiac anaphylaxis. The reduction in coronary outflow rate during cardiac anaphylaxis is due largely to the powerful vasoconstrictor effect of LT, as well as perhaps platelet-activating-factor. Thus it is speculated that there is a causal relationship between LT release, vasoconstriction, ischemia and myolysis in the heart, following VSV challenge to sensitized guinea pigs.
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PMID:Immunological challenge with virus initiates leukotriene C4 production in the heart and induces cardiomyolysis in guinea pigs. 302 94

Arachidonic acid is metabolized to leukotriene (LT) B4, C4, D4, and E4 by lipoxygenase. LTB4 is a chemotactic agent while LTC4 and LTD4 stimulate smooth muscle fibers to contract. Mesenteric vessels have the capacity to release leukotrienes. The possibility that leukotrienes might be responsible for or contribute to mesenteric ischemia during mesenteric low flow, embolism, and thrombosis prompted us to investigate their action on mesenteric vessels. LTB4, C4, and D4 were applied topically on small bowel mesentery of 22 Sprague-Dawley rats in sequentially increasing concentrations. Mesenteric arterioles with diameters of 8-20 microns were observed through a microscope and vessel diameters were measured using a video shear monitor. LTB4 had no effect on diameter, but doses as low as 3 X 10(-8) M induced white blood cell adherence to venular endothelium, reflecting the potent chemotactic properties of this compound. LTC4 and D4 had no effect on systemic blood pressure or white blood cell adherence. Applications of 6.4 X 10(-9), 3.2 X 10(-8), and 6.4 X 10(-8) M LTC4 decreased mesenteric arteriolar diameter to 85.3* +/- 4.7% (mean +/- SD), 75.7* +/- 7.5%, and 66.8* +/- 6.1% of baseline, and 4 X 10(-9), 2 X 10(-8), and 4 X 10(-8) M LTD4 decreased diameter to 84.9* +/- 6.1%, 75.1* +/- 4.2%, and 64.1* +/- 5% of baseline, respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of leukotrienes B4, C4, and D4 on rat mesenteric microcirculation. 303 80

The authors have previously reported a model of ischemic bowel necrosis produced in the rat by synthetic platelet-activating factor (PAF) or a combination of PAF and bacterial endotoxin. Because rat platelets are refractory to PAF and thromboemboli were not found in the mesenteric or intestinal microvasculature, they suspected that secondary mediators were involved in the pathogenesis of bowel necrosis. They have found the following lipoxygenase products of arachidonic acid, especially leukotrienes (LT), probably played an important role in the pathogenesis of bowel necrosis, because diethylcarbamazine (an inhibitor for LTA synthesis) and FPL55712 (LT antagonist) ameliorated, and at times completely prevented, the lesions. NDGA (a nonspecific lipoxygenase inhibitor) was less effective, probably because of its additional effect on cyclooxygenase inhibition. Verapamil, a calcium channel blocker, ameliorated the disease. Thromboxane A2, a potent vasoconstrictor, was probably not responsible for the ischemia of the gastrointestinal tract. This is suggested by the ineffectiveness of OKY-046 in preventing bowel necrosis. Prostaglandin (PG) E1 infusion often prevented the bowel necrosis, which suggested beneficial effects of vasodilating PGs, probably released as a defense mechanisms. Indomethacin aggravated the disease, probably by inhibiting PG release and shifting the metabolic pathway toward the lipoxygenase pathway. Antihistamine and antiserotonin had no effect, which suggested that these mediators were not involved in the pathogenesis of bowel necrosis. Shock produced by PAF was probably not the only cause of bowel necrosis, because reversal of the hypotension did not always prevent the development of bowel necrosis. Hemoconcentration (increased vasopermeability) and leukopenia induced by PAF did not correlate with the development or severity of bowel necrosis.
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PMID:Platelet-activating factor-induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis. 308 Aug 95

Although it is known that arachidonic acid accumulates in the ischemic myocardium and that cardiac prostaglandin formation from the precursor arachidonic acid is altered during disease states, the role of arachidonic acid in the myocyte itself is not yet clear. Using isolated Ca-tolerant adult rat heart muscle cells, we were able to study cardiac metabolism of arachidonic acid without the effects induced by endothelial or other non-muscle tissue. Myocytes rapidly incorporate arachidonic acid as well as other fatty acids into their lipid pools, the predominant acceptor being the triacylglycerols at an extracellular fatty acid concentration of 20 microM. As exogenous arachidonic acid is decreased, the distribution pattern shifts to favor phospholipid esterification. Cardiocyte prostaglandin production from arachidonic acid added to the incubation medium was limited (less than 1% conversion of added arachidonic acid) and lipoxygenase pathway activity was not detected. Oxidation rates of arachidonic acid were 3-fold lower than for palmitic acid, indicating that it is of secondary importance in energy-yielding reactions. Our results suggest that arachidonic acid serves primarily as a structural component of myocardial membranes and that its release during ischemia would permit its use as a substrate for prostaglandin production by coronary vascular tissue.
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PMID:The role of arachidonic acid in rat heart cell metabolism. 311 4


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