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)

Ischemia and reperfusion have been shown to cause damage to the endothelium as well as to the cardiac myocyte. Although the vasodilator response has been shown to be impaired following ischemia and reperfusion, the effect of a short period of global ischemia on the contractile response of the coronary vasculature is not clear. In the present study, coronary vasoconstriction in response to U46619, PGF2 alpha, 5-HT, and KCl was found to be depressed for at least 15 min following 15 min of in vitro global ischemia in rats hearts. Vasodilator blockers or inactivators were used in an effort to restore this depressed coronary response. Indomethacin (5 microM) was used to block production of vasodilator prostaglandins, L-NAME (30 microM) to block production of nitric oxide (NO), and adenosine deaminase (2.4 units/ml of coronary flow) to inactivate adenosine. None of these agents restored the normal coronary constrictor response following ischemia. When superoxide dismutase and catalase (both 20 micrograms/ml of coronary flow) were infused for 5 min before and after ischemia, the coronary response recovered more than 100% of its preischemic value by 15 min of reperfusion, but still remained depressed at 5 min reperfusion. These data suggest that free radicals produced during ischemia and/or reperfusion may be at least partly responsible for this temporary "stunning" of the coronary vasculature. Since the impaired contractile response was still present at 5 min reperfusion when the buffer was supplemented with oxygen radical scavengers, another mechanism must also be involved in this "stunning" process.
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PMID:Effects of short term ischemia and reperfusion on coronary vascular reactivity and myocardial function. 747 69

Indomethacin, a prostaglandin synthetase inhibitor, is an effective tocolytic agent that may have adverse fetal side effects such as constriction of the ductus arteriosus, pulmonary hypertension, and reduced urine production. We describe an unusual neonatal complication following 6 days of tocolysis with indomethacin. A 22-year-old gravida 5, para 3104 was admitted at 25 weeks of gestation in labor. Attempts to stop labor using magnesium sulfate and terbutaline failed. The contractions stopped following the administration of indomethacin, which was continued for 6 days. On day 7, due to contractions and vaginal bleeding, she underwent a classic cesarean section. The female newborn, weighting 1044 g, did well for 2 days, when she developed pneumoperitoneum. On laparotomy, an isolated midileal perforation was found, with otherwise normal-appearing bowel. Isolated intestinal perforation has been described in premature neonates who were treated with indomethacin for patent ductus arteriosus. This complication is caused by splanchnic ischemia secondary to the loss of the vasodilatory effect of prostaglandins. This case indicates that this rare but serious complication may also follow intrauterine exposure to indomethacin.
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PMID:Isolated small bowel perforation following intrauterine treatment with indomethacin. 794 25

Myocardial ischemia and reperfusion can evoke excitation of cardiac vagal nerve endings and activation of a cardiogenic depressor reflex (Bezold-Jarisch effect). We postulate that oxygen-derived free radicals, which are known to be produced during prolonged ischemia and reperfusion, contribute to this afferent excitation. We recorded activity from 47 chemosensitive vagal afferent fibers in 31 rats; the endings of these fibers were located in the left ventricle. Chemosensitive endings were identified with topical applications of capsaicin (10 micrograms) to the surface of the heart. Reactivity of the endings to oxygen-derived free radicals was assessed by topical application of H2O2 (3 to 9 mumol). Activity of the vagal fibers was recorded during 30 minutes of occlusion of the left anterior descending coronary artery (LAD) and 10 minutes of subsequent reperfusion. The activity of chemosensitive endings within the ischemic zone increased in the first 2 minutes of LAD occlusion from 2.2 +/- 0.4 to 4.3 +/- 0.9 impulses per second (107 +/- 30% increase, P < .05). This increased activity waned after 3 to 5 minutes of occlusion. Endings outside the ischemic zone did not increase, their activity at the beginning of ischemia. Reperfusion caused a rapid elevation of activity only in chemosensitive fibers whose endings were found to respond to topical H2O2. The reperfusion-sensitive endings were located both within and outside the ischemic zone of the left ventricle. Indomethacin (5 mg/kg i.v., 20 minutes before occlusion) effectively prevented activation of chemosensitive afferent endings at the beginning of LAD occlusion regardless of their sensitivity to H2O2 but had no effect on the activation at reperfusion.
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PMID:Activation of cardiac vagal afferents in ischemia and reperfusion. Prostaglandins versus oxygen-derived free radicals. 815 37

Indomethacin (IND), widely used in premature infants to effect nonoperative closure of patent ductus arteriosus (PDA), has been implicated in gastrointestinal tract (GI) perforations and necrotizing enterocolitis (NEC). The vasoactive effects of IND could simultaneously affect regional blood flow distribution, specifically a decrease in intestinal blood flow. This study determined blood pressure (BP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR) and regional blood flows (mL/min/g) at baseline, 15, 60, and 120 minutes after intravenous infusion of IND (0.4 mg/kg) in three groups: preterm piglets delivered 7 to 10 days before term; 1- to 2-day-old piglets; and 7- to 14-day-old piglets. IND did not significantly affect hemodynamic parameters (BP, HR, CO, TPR) or regional blood flows to the heart, central nervous system, kidney or GI tract in the premature animals. In 1- to 2-day-old animals, a significant increase in BP and TPR occurred at 120 minutes, with significant decreases in blood flow to the GI tract in the esophagus, stomach, and rectosigmoid. In the 7- to 14-day group CO significantly decreased while TPR increased. Significant decreases in blood flow occurred throughout the GI tract, most pronounced in the small intestine and colon, essentially due to decreased mucosal blood flow. Our study indicates that indomethacin can cause selective GI tract mucosal ischemia, and that the effect is increased in the more developed animal. This effect on mucosal blood flow suggests the GI tract disturbances seen after IND administration are due to an ischemic injury to mucosa previously affected by ischemia-reperfusion injury from other stresses.
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PMID:Indomethacin-induced blood flow distribution in premature and full-term piglets. 826 8

Several attempts have been undertaken to reduce the severity of ischemic myocardial injury by exogenous administration of eicosanoids and by modification of endogenous eicosanoid production. The present study investigates whether defibrotide, a compound that stimulates endogenous prostacyclin (PGI2), has a beneficial effect in experimental ischemic myocardial injury. Anesthetized, open-chest minipigs were subjected to 1 h of coronary artery occlusion, followed by 3 h of reperfusion. Defibrotide (32 mg/kg x h) or its vehicle were infused i.v. throughout the experiment. Defibrotide increased cardiac PGI2 formation 3- to 4-fold greater than control (P < .05). Thromboxane levels remained unchanged. Irreversible ischemic injury, as identified by negative tetrazolium staining, amounted to 44 +/- 6% of the area at risk in pigs receiving vehicle but was reduced to 23 +/- 4% by defibrotide (P < .05). This reduced tissue injury in defibrotide-treated pigs was associated with improved functional recovery (left ventricular pressure, + dP/dtmax), during early reperfusion. Recovery did not occur in vehicle-treated pigs. Collagen (2 micrograms/ml)-induced platelet aggregation ex vivo was increased in vehicle-treated pigs during ischemia and reperfusion, but not in animals treated with defibrotide. Polymorphonuclear neutrophil leukocyte accumulation in the ischemic border zone was reduced from 59 +/- 17 cells/mm2 in vehicle-treated pigs to 17 +/- 9 cells/mm2 by defibrotide (P < .05). Pretreatment of the animals with indomethacin (3 mg/kg) prevented the reduction of infarct size and polymorphonuclear neutrophil leukocyte infiltration by defibrotide. Indomethacin increased infarct size in vehicle- and defibrotide-treated pigs by 71 and 59%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of endogenous prostacyclin protects the reperfused pig myocardium from ischemic injury. 842 39

D-myo-Inositol-1,2,6-triphosphate (IP3) has been shown to reduce edema and progressive ischemia following experimental skin burns. The mechanism(s) are not identified but could be related to antiinflammatory effects of the agent. In the present ex vivo study we compared the effects of IP3 with those of saline and indomethacin on eicosanoid formation by normal and burned rat skin. In burned skin IP 3 treatment reduced the release of thromboxane B2 (TXB2) (P < 0.01) and leukotriene B4 (LTB 4) (P < 0.05) but there was only a weak trend for less prostaglandin E (PGE) compared to burned control animals receiving saline. Indomethacin reduced the release of TXB2 (P < 0.01), and PGE (P < 0.001), but not LTB 4 from burned skin compared to skin from saline-treated burned animals. In non-burned skin IP 3 increased the release of PGE (P < 0.01) and LTB 4 (P < 0.01), but did not significantly influence TXB2 accumulation in the incubation fluid compared to the saline-treated group. Indomethacin reduced the release of TXB2 (P < 0.001) and PGE (P < 0.001), but increased LTB 4 (P < 0.001) in normal skin compared to the saline-treated group. In conclusion, IP 3 inhibited the release of TXB2 and LTB 4 from burned skin ex vivo, but increased PGE and LTB 4 release from normal skin. These results suggest that the mode of action of IP 3 differs from that of nonsteroidal antiinflammatory drugs. The effects of IP 3 on the arachidonic acid cascade also seem to differ in burned versus normal skin.
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PMID:Effects of D-myo-Inositol-1,2,6-triphosphate on eicosanoid formation in burned skin. 860 94

The effect of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate), a new cyclooxygenase inhibitor, on experimental brain edema was studied. In vitro, KBT-3022 (100 microM) and its metabolite desethyl KBT-3022 (10 and 100 microM), but neither acetylsalicylic acid nor indomethacin, inhibited arachidonic acid-induced swelling of guinea pig cortical slices. KBT-3022 (3-100 microM) and desethyl KBT-3022 (3-30 microM), but neither acetylsalicylic acid nor indomethacin, inhibited lipid peroxidation in guinea pig brain homogenate. In vivo, oral administration of KBT-3022 (1, 3 and 10 mg/kg) and indomethacin (10 and 30 mg/kg), but not acetylsalicylic acid, prevented brain edema induced by bilateral carotid occlusion and recirculation in gerbils. Indomethacin then prevented postischemic hyperthermia, but not KBT-3022. KBT-3022 (10 mg/kg) and indomethacin (30 mg/kg) inhibited lactate accumulation in gerbil brain after ischemia and recirculation. These results suggest that KBT-3022 prevents development of both cytotoxic edema in vitro and vasogenic edema in vivo.
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PMID:Effect of KBT-3022, a new cyclooxygenase inhibitor, on experimental brain edema in vitro and in vivo. 866 54

We tested the hypothesis that gram-negative bacteremia (GNB) and brief (30 min) reductions in the hepatic O2 supply by low-flow ischemia differentially modulate tumor necrosis factor-alpha (TNF-alpha) gene expression owing to sequence-specific activation of cyclooxygenase vs. complement (C) pathways. Buffer-perfused Sprague-Dawley rat livers (n = 82) were studied over 180 min after intraportal 10(9) live E. coli serotype 055:B5 (EC) or 0.9% NaCl (NS) at t = 0. Compared with EC and NS controls receiving constant-flow perfusion, sequential GNB and ischemia/reperfusion (I/R) were studied in EC + 30 I/R and NS + 30 I/R livers, in which 30 min of ischemia (I) beginning 0.5 h after EC or NS was followed by 120 min of reperfusion (R). This sequence was reversed in 30 I/R + EC and 30 I/R + NS groups. Bacterial clearance, bioactive and antigenic TNF-alpha, prostaglandin E2 (PGE2), and hepatic O2 uptake and performance were serially assessed. Venous TNF-alpha increased in EC controls to peak at 155 +/- 29 U/ml after 180 min (P < 0.001 vs. NS controls) as did hepatic TNF-alpha mRNA. Both TNF-alpha transcripts and protein levels were markedly attenuated in EC + 30 I/R (P < 0.001 vs. EC) despite equivalent EC clearance by Kupffer cells. Indomethacin (10(-5) M) decreased I/R-induced PGE2 secretion and restored TNF-alpha to control levels. In contrast, TNF-alpha levels in 30 I/R + EC perfusates exceeded those of EC + 30 I/R livers (P < 0.05) and were indistinguishable from EC controls. Allopurinol pretreatment but not heat inactivation of C or infusion of soluble human complement receptor type 1 inhibited TNF-alpha production in 30 I/R + EC organs. These results identify a novel sequence-dependent interaction whereby hepatic O2 deprivation after GNB downregulates TNF-alpha via generation of cyclooxygenase metabolites, whereas ischemia preceding GNB increases cytokine expression via reactive O2 species but not C activation.
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PMID:Bidirectional effects of hepatic ischemia/reperfusion on E. coli-induced TNF-alpha gene expression. 876 13

Capillary endothelial cells are critical targets in both ischemia and reperfusion of the brain. Arachidonic acids and oxygen free radicals have been shown to cause disruption of blood-brain barrier (BBB) by destruction of capillary endothelial cell membrane. However, the exact mechanism of BBB breakdown by cerebral ischemia/reperfusion remains undetermined. The aim of the present study is to clarify the mechanism of intracellular calcium ion ([Ca2+]i) change in brain capillary endothelial cells under anoxia/reoxygenation. Brains capillary endothelial cells were isolated from ten male Sprague-Dawley rats by a two step enzymatic process. [Ca2+]i was measured by means of a confocal laser scanning microscope using Indo 1-A/M as a calcium indicator. The endothelial cells were subjected to anoxia and reoxygenization under different conditions. [Ca2+]i increased gradually during anoxia and slightly decreased after reoxygenation. Indomethacin and SOD suppressed the elevation of [Ca2+]i during anoxia. NG-nitro-L-arginine methyl ester and catalase moderately suppressed the elevation, however nifedipine did not suppress it at all. In this model, rapid [Ca2+]i change was not observed during the reoxygenation phase. The results indicate that the anoxia induced elevation of [Ca2+]i in the brain capillary endothelial cells depends on superoxide and peroxynitrite generation.
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PMID:The role of calcium ion in anoxia/reoxygenation damage of cultured brain capillary endothelial cells. 941 62

The aim of the study was to investigate the time course of neutrophil activation after skeletal muscle ischemia in humans and to assess the effect of xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. In patients undergoing tourniquet ischemia of the upper limb, polymorphonuclear neutrophils (PMN) were simultaneously isolated from antecubital vein blood of both the contralateral control arm and the tourniquet arm. PMN-superoxide production (PMN-SOP) was determined by a cytochrome C reduction assay, PMN-myeloperoxidase activity (PMN-MPO) by guaiacol oxidation and serum PMN-elastase concentration by an enzyme immunoassay. At 60 min after release of the tourniquet, significant increases of PMN-SOP, PMN-MPO, and serum elastase concentrations were observed in tourniquet arms as compared with control arms (p < .05). Allopurinol (300 mg orally, 12 and 2 h before ischemia) significantly inhibited the increase of PMN-SOP, PMN-MPO, and serum elastase (p < .05). Indomethacin (50 mg orally, 2 h before ischemia) prevented increased PMN-MPO and serum elastase, but prevented increased PMN-SOP only when neutrophils were incubated in the presence of their autologous plasma. These findings suggest that ischemia/reperfusion of human skeletal muscle involves both xanthine oxidase-dependent oxygen free radicals and cyclooxygenase metabolites. These pathways could activate circulating neutrophils which potentially inflict local and remote endothelial injury.
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PMID:Neutrophil activation after skeletal muscle ischemia in humans. 946 69


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