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)

Recent studies revealed an additive cardiodepressive effect of polymorphonuclear granulocytes (PMN) and thrombocytes in hearts exposed to a no-flow ischemia. To find out whether or not this is also true for isolated guinea pig hearts exposed to a low-flow ischemia, the current study was performed. PMN or thrombocytes, together or separately, were applied as a 1-min bolus (1,000/microl or 20,000/microl, respectively) during ischemia or in reperfusion in the presence of thrombin (0.3 U/ml perfusate). Recovery of external heart work and intracoronary cell retention were quantified in percent. Sole application of PMN or platelets during ischemia and reperfusion significantly compromised myocardial function, whereas coapplication of PMN and platelets did not exhibit any further cardiodepressive effect. Coapplication of cells almost prevented intracoronary platelet retention during ischemia and in reperfusion, as opposed to sole platelet application. Known blockers of endogenously released anti-platelet substances like nitric oxide, PGI(2) or adenosine did not mediate a further aggravation of myocardial dysfunction. The platelet-activating factor (PAF) antagonist WEB 2170 BS, however, significantly improved recovery of external heart work during ischemia and in reperfusion. This indicates that an additive cardiodepressive effect of PMN and platelets in working guinea pig hearts exposed to a low-flow ischemia, cannot be demonstrated, whereas PAF antagonists seem to be cardioprotective, under these conditions. Even addition of fibrinogen to the perfusate, did not show an additive cardiodepressive effect of coapplication of PMN and platelets.
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PMID:PMN/platelets coinfused in guinea pig hearts Exposed to low-flow ischemia have no additive cardiodepressive effect. 1463 Nov 4

Opioids have been shown to confer late preconditioning against ischemia/reperfusion injury in several species. However, it is unknown whether gender or aging affects opioid-induced cardioprotection. Isolated perfused hearts from Fischer 344 rats were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW373U86, a delta-opioid receptor agonist, was administered s.c. at varying doses (0.1, 0.33, 1.0 mg/kg) 24 h before (BW0.1, BW0.33 and BW1.0, respectively). In 12-week-old male (YM) rats, the recovery of LV developed pressure (LVDP) after ischemia/reperfusion improved significantly in BW0.33 and BW1.0, compared with the control (C). In 78-week-old male (OM) rats, the recovery of LV function after ischemia/reperfusion improved and the total release of CK and LDH during reperfusion was attenuated in BW1.0. In 12-week-old female (YF) rats, the recovery of LV function improved only in BW0.33 but not in BW0.1 and BW1.0. The cardioprotective effect afforded by BW373U86 was completely abolished by NS-398, a COX-2 selective inhibitor, in YM, YF, and OM, although NS-398 in itself did not affect myocardial ischemia/reperfusion injury. The levels of 6-keto-PGF(1alpha) (a stable metabolite of PGI(2)) in coronary effluent during reperfusion were higher in the BW373U86-pretreated group that showed cardioprotection than in C and this increase in PGI(2) production was also inhibited by NS-398 in YM, YF, and OM. In conclusion, BW373U86-induced late preconditioning can be observed in aged and female hearts. A COX-2-dependent increase in PGI(2) production is essential for BW373U86-induced late PC in both sexes and in both young and old rats.
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PMID:Gender and aging do not impair opioid-induced late preconditioning in rats. 1468 5

Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.
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PMID:Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses. 1469 82

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

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

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

Normal pregnancy is associated with significant changes in the neuronal and vascular control mechanisms of blood pressure (BP). Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria, and increased vascular resistance and BP. If untreated, PE leads to eclampsia with serious seizures and severe hypertension. However, the neurovascular mechanisms of hypertension in pregnancy and PE are unclear. Studies in animal models of hypertension in pregnancy suggest that inadequate cytotrophoblast invasion of uterine spiral arteries causes reduction in uteroplacental perfusion pressure leading to placental ischemia/hypoxia. Placental ischemia may promote the release of biologically active factors such as cytokines and reactive oxygen species. These circulating factors may increase the vascular permeability, cross the blood-brain barrier, and affect the sympathetic tone and the neuronal control mechanisms of BP. Placental factors could also cause endothelial cell dysfunction and inhibit nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), prostacyclin (PGI(2))-cyclic adenosine monophosphate (cAMP), and hyperpolarizing factor vascular relaxation pathways. Additionally, placental factors may induce endothelium-derived contracting factors such as endothelin, thromboxane and angiotensin II, which stimulate Ca(2+)-dependent vascular smooth muscle (VSM) contraction or increase protein kinase C activity and enhance myofilament sensitivity to intracellular free calcium concentration ([Ca(2+)](i)). The increased sympathetic tone combined with systemic decrease in endothelium-dependent vascular relaxation and enhanced VSM contraction may contribute to the increased vascular resistance and BP associated with PE. The hypertensive state in severe PE may weaken the blood-brain barrier and precipitate convulsions and cerebral hemorrhage. Careful monitoring of maternal neuronal, endothelial, and VSM function during pregnancy should circumvent the life-threatening neurovascular complications of PE-eclampsia.
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PMID:Neurovascular mechanisms of hypertension in pregnancy. 1671 96

This study was undertaken to examine the mechanism by which danaparoid sodium (DS), a heparinoid that contains mainly heparan sulfate, prevents reperfusion-induced hepatic damage in a rat model of ischemia/reperfusion (I/R)-induced liver injury. Administration of DS significantly reduced liver injury and inhibited the decrease in hepatic tissue blood flow in rats. DS attenuated hepatic I/R-induced increases in hepatic tissue levels of tumor necrosis factor (TNF) and myeloperoxidase (MPO) in vivo. In contrast, neither monocytic TNF production nor neutrophil activation was inhibited by DS in vitro. DS enhanced I/R-induced increases in levels of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory neurons, and of 6-ketoprostaglandin (PG) F (1a) , a stable metabolite of PGI (2) , in liver tissues. The therapeutic effects of DS were not seen in animals pretreated with capsazepine, an inhibitor of sensory neuron activation. The distribution of heparan sulfate in the perivascular area was significantly increased by DS administration in this rat model. DS significantly increased CGRP release from isolated rat dorsal root ganglion neurons (DRG) in vitro, while DX-9065a, a selective inhibitor of activated factor X, did not. DS enhanced anandamide-induced CGRP release from DRG in vitro. These observations strongly suggested that DS might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects of DS might be at least partly explained by its enhancement of sensory neuron activation, leading to the increase the endothelial production of PGI (2) .
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PMID:Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses. 1720 Jul 74

We recently demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons reduces spinal cord injury (SCI) by inhibiting neutrophil activation through an increase in the endothelial production of prostacyclin (PGI(2)). Carperitide, a synthetic alpha-human atrial natriuretic peptide (ANP), reduces ischemia/reperfusion (I/R)-induced tissue injury. However, its precise therapeutic mechanism(s) remains to be elucidated. In the present study, we examined whether ANP reduces I/R-induced spinal cord injury by enhancing sensory neuron activation using rats. ANP increased CGRP release and cellular cAMP levels in dorsal root ganglion neurons isolated from rats in vitro. The increase in CGRP release induced by ANP was reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation, or with (9S, 10S, 12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylic acid hexyl ester (KT5720), an inhibitor of protein kinase A (PKA), suggesting that ANP might increase CGRP release from sensory neurons by activating PKA through an increase in the cellular cAMP level. Spinal cord ischemia was induced in rats using a balloon catheter placed in the aorta. ANP reduced mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. ANP significantly enhanced I/R-induced increases in spinal cord tissue levels of CGRP and 6-keto-prostaglandin F(1alpha). a stable metabolite of PGI(2). ANP inhibited I/R-induced increases in spinal cord tissue levels of tumor necrosis factor and myeloperoxidase. Pretreatment with 4'-chloro-3-methoxycinnamanilide (SB366791), a specific vanilloid receptor-1 antagonist, and indomethacin reversed the effects of ANP. These results strongly suggest that ANP might reduce I/R-induced SCI in rats by inhibiting neutrophil activation through enhancement of sensory neuron activation.
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PMID:Atrial natriuretic peptide reduces ischemia/reperfusion-induced spinal cord injury in rats by enhancing sensory neuron activation. 1752 45


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