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)

We previously reported that nitric oxide (NO) derived from endothelial NO synthase (NOS) increased endothelial prostacyclin (PGI(2)) production in rats subjected to hepatic ischemia-reperfusion (I/R). The present study was undertaken to determine whether neutrophil elastase (NE) decreases endothelial production of PGI(2), thereby contributing to the development of I/R-induced liver injury by decreasing hepatic tissue blood flow in rats. Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), were transiently increased and peaked at 1 h after reperfusion, followed by a gradual decrease until 3 h after reperfusion. Sivelestat sodium hydrochloride and L-658,758, two NE inhibitors, reduced I/R-induced liver injury. These substances inhibited the decreases in hepatic tissue levels of 6-keto-PGF(1alpha) at 2 and 3 h after reperfusion but did not affect the levels at 1 h after reperfusion. These NE inhibitors significantly increased hepatic tissue blood flow from 1 to 3 h after reperfusion. Both hepatic I/R-induced increases in the accumulation of neutrophils and the microvascular permeability were inhibited by these two NE inhibitors. Protective effects induced by the two NE inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin. Administration of iloprost, a stable derivative of PGI(2), produced effects similar to those induced by NE inhibitors. These observations strongly suggest that NE might play a critical role in the development of I/R-induced liver injury by decreasing endothelial production of NO and PGI(2), leading to a decrease in hepatic tissue blood flow resulting from inhibition of vasodilation and induction of activated neutrophil-induced microvascular injury.
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PMID:Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. 1524 60

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the anti-thrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI(2)), and PGE(2) were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF(1alpha) levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE(2) levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp(49)-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of ilo-prost, a stable analog of PGI(2), and PGE(2) produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE(2) 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE(2) and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-alpha is capable of inducing COX-2, inhibition of TNF-alpha production by AT might inhibit COX-2-mediated PGE(2) production. These effects induced by AT might contribute to its anti-inflammatory activity.
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PMID:Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1. 1535 51

PGF(2)-like compounds are formed in abundance in vivo by the free radical-induced peroxidation of arachidonic acid, independent of the cyclooxygenase enzyme. These compounds are collectively referred to as F(2)-isoprostanes because of their structural similarity to cyclooxygenase-derived PGF(2alpha). Certain findings suggest a potential role for isoprostanes as mediators of some of the adverse sequelae of ischemia-reperfusion injury to kidney. Recent evidence also suggests a potentially important role for isoprostanes in the pathogenesis of hepatorenal syndrome. Cell culture studies suggest that cisplatin-induced LLC-PK1 cell injury may be attended by increased isoprostane production through a mechanism involving thiol depletion. Another area in which a role for free radical-induced lipid peroxidation and F(2)-isoprostanes has been suggested is in the pathogenesis of ciclosporin (CSA)-induced renal toxicity. A recent study also suggests that enhanced formation renal F(2)-isoprostanes may be relevant to the progressive reduction in renal blood flow demonstrable in aging kidneys. This emerging evidence suggests that further studies are warranted to determine the importance of F(2)-isoprostanes in human renal diseases characterized by renal vasoconstriction, such as renal ischemia, hepatorenal syndrome, renal senescence and toxic nephropathies.
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PMID:F2-isoprostanes and the kidney. 1561 48

The production of peroxynitrite (ONOO(-)) in the endothelium decreases NO bioavailability, decreases vasorelaxation and changes vascular tone. ONOO(-) can also influence the production of prostacyclin-another vasorelaxant. We used a nanotechnological approach (nanosensors) to elucidate the release of NO, O(2)(-), and ONOO(-) in endothelium and their effect on production of prostanoids. The basal ONOO(-) concentration near the endothelium (3-5 microm) varied from 1 to 50 nmol/L and maximal calcium ionophore stimulated ONOO(-), did not exceed 900 nmol/L. The highest ONOO(-) concentrations were produced in ischemia/reperfusion atherosclerosis, diabetes, aging and vary among different racial groups (higher in Blacks than in Whites). ONOO(-) decreased PGI(2) activity with IC(50) approximately 150 nmol/L for 8 min reaction time, but has no effect of short reaction time. Prostaglandin E(1) decreased NO, O(2)(-), and ONOO(-) by limiting Ca(2+) flux into endothelium, decreased edema and vasoconstriction during ischemia/reperfusion. In endothelium (HUVEC's) of Black's the ONOO(-) concentrations were high 750+/-50 nmol/L while the lowest concentrations of vasorelaxants were 275+/-25 nmol/L of NO, 150+/-15 pb/100 microg protein of 6-keto-PGF(1)(alpha) as compared to White's (420+/-30 and 470+/- nmol/L for ONOO(-) and NO respectively and 280+/-20 pg/100 mg protein for 6-keto-PGF(1)(alpha)).
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PMID:Role of peroxynitrite in the process of vascular tone regulation by nitric oxide and prostanoids--a nanotechnological approach. 1562 93

Arachidonic acid (AA) and its vasoactive metabolites have been implicated in the pathogenesis of brain damage induced by cerebral ischemia. The membrane AA concentrations can be reduced by changes in dietary fatty acid intake. The purpose of the present study was to investigate the effects of chronic ethyl docosahexaenoate (E-DHA) administration on the generation of eicosanoids of AA metabolism during the period of reperfusion after ischemia in gerbils. Weanling male gerbils were orally pretreated with either E-DHA (100, 200 mg/kg) or vehicle, once a day, for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 10 min. E-DHA (200 mg/kg) pretreatment significantly decreased the content of brain lipid AA at the termination of treatment, prevented postischemic impaired regional cerebral blood flow (rCBF) and reduced the levels of brain prostaglandin (PG) PGF(2alpha) and 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), as well as leukotriene (LT) LTB(4) and LTC(4) at 30 and 60 min of reperfusion compared with the vehicle, which was well associated with the attenuated cerebral edema in the E-DHA-treated brain after 48 h of reperfusion. These data suggest that the E-DHA (200 mg/kg) pretreatment reduces the postischemic eicosanoid productions, which may be due to its reduction of the brain lipid AA content.
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PMID:Chronic administration of ethyl docosahexaenoate reduces gerbil brain eicosanoid productions following ischemia and reperfusion. 1609 34

Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8-12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8-iso-PGF(2alpha)), an indicator of oxidative damage, and prostaglandin F(2alpha) metabolite (15-keto-dihydro-PGF(2alpha)), an indicator of cyclooxygenase-2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S-100beta. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8-iso-PGF(2alpha) are greater after more extended periods of ischemia. PBN (alpha-phenyl-N-tert-butyl nitrone), a so-called spin-trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8-iso-PGF(2alpha) concentration is decreased during reperfusion. Use of water-soluble sulfonated PBN (S-PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.
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PMID:Circulatory arrest as a model for studies of global ischemic injury and neuroprotection. 1617 25

We examined the roles of cyclooxygenase (COX) isozymes, prostaglandins (PGs), and their receptors in the mucosal defense against ischemia/reperfusion (I/R)-induced gastric lesions in mice. Male C57BL/6 mice, including wild-type animals and those lacking prostaglandin E(2) (EP)1, EP3, or prostaglandin I(2) (IP) receptors, were used after 18 h of fasting. Under urethane anesthesia, the celiac artery was clamped (ischemia) for 30 min, and then reperfusion was achieved for 60 min through the removal of the clamp, and the stomach was examined for lesions. I/R produced hemorrhagic gastric lesions in wild-type mice. The severity of lesions was significantly increased by pretreatment with indomethacin (a nonselective COX inhibitor) and rofecoxib (a selective COX-2 inhibitor) but not 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560; a selective COX-1 inhibitor). The expression of COX-2 mRNA was up-regulated in the stomach following I/R but not by sham operation or ischemia alone. The ulcerogenic response was markedly aggravated in IP receptor knockout mice but not those lacking EP1 or EP3 receptors. I/R increased the levels of 6-keto-PGF(1alpha) and PGE(2) in the stomach of wild-type mice, and this response was attenuated by indomethacin and rofecoxib but not SC-560. Pretreatment of wild-type mice with iloprost, a prostacyclin (PGI(2)) analog, significantly prevented the I/R-induced gastric lesions in the absence and presence of indomethacin or rofecoxib. PGE(2) also reduced the severity of I/R-induced gastric lesions, yet the effect was much less pronounced than that of iloprost. These results suggest that endogenous PGs derived from COX-2 play a crucial role in gastric mucosal defense during I/R, and this action is mainly mediated by PGI(2) through the activation of IP receptors.
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PMID:Roles of cyclooxygenase-2 and prostacyclin/IP receptors in mucosal defense against ischemia/reperfusion injury in mouse stomach. 1623 16

We recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP), a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/R-induced liver injury in wild type mice (CGRP+/+) and congenitally alphaCGRP-deficient mice (CGRP-/-). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF(1alpha), a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP-/-. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+, although it showed neither of these therapeutic effects in CGRP-/-. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA). AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.
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PMID:Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation. 1667 69

Possible mechanisms for testicular focal necrosis induced by human chorionic gonadotropin (hCG) were examined in Fischer 344 rats. A single s.c. injection of 2000 IU/kg hCG produced focal necrosis 2 days later in testicular tissues such as the seminiferous tubules in the frontal lower part of the testis (FLPT) of 11-week-old F344/Jcl rats. This hCG-induced necrosis was suppressed by an oral treatment (concomitant or delayed by 3 hr) with cyclooxygenase inhibitors (indomethacin, rofecoxib) or prostaglandin (PG) receptor blocker (AA-2414). Focal necrosis was also induced by intratesticular injection of PGF(2alpha) or PGE(2) with this necrosis suppressed by previous oral treatment with AA-2414, and the PGF(2) level in the testis increased 4 hr after hCG treatment. These findings suggested that de novo synthesis of PGs beginning at 3-4 hr was responsible for induction of necrosis. No necrosis was induced by hCG in the Leydig cell-devoid testis produced by ethane dimethanesulfonate treatment. Necrosis of spontaneously-induced Leydig cell tumor mass was also induced by hCG, suggesting that Leydig cells are responsible for induction of necrosis. An injection of dye into the testicular artery and laser Doppler flowmetry revealed a continuous reduction of blood flow at the FLPT at 6-48 hr after hCG treatment; contrary to this, the upper part showed an early recovery from the reduced flow. From these results, the mechanism of the hCG-induced necrosis was concluded to be: 1) hCG stimulates Leydig cells to synthesize PGs de novo; 2) PGs induce the intratesticular arteries to contract in the FLPT; and 3) obstruction of blood flow (ischemia) for more than 12 hr induced focal necrosis in the testis.
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PMID:Possible mechanism for testicular focal necrosis induced by hCG in rats. 1707 84

The objective is to investigate the outcome of transplantation using kidney grafts from donors after cardiac death (DCDs) with a total ischemia time (TIT) longer than 24 h. All 373 kidneys were procured from DCDs. They were procured using the in-situ regional cooling technique. Grafts were classified into two groups according to TIT. Fifty-three grafts had a TIT longer than 24 h (group 1), and the other 320 grafts (group 2) were less than 24 h. The numbers of never functioning grafts (PGF) were 3 in group 1 (5.7%) and 17 in group 2 (5.3%), a nonsignificant difference. Graft survival rates at 3, 5 and 10 years posttransplant were 84.9%, 73.0% and 64.1% in group 1, and 76.3%, 69.9% and 57.1% in group 2, which demonstrate no significant difference. The significant risk factors for graft failure were donor age, serum creatinine level on hospitalization and WIT. However, TIT longer than 24 h was not employed. Multivariate logistic regression indicated that only WIT was associated with an increase in the risk of PGF. Our results demonstrate that kidneys from DCDs, even if their TIT is more than 24 h, should be considered a worthwhile source of renal grafts.
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PMID:Should we discard the graft? Analysis of the renal grafts with a total ischemia time of more than 24 hours donated after cardiac death. 1784 27


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