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 have previously shown that PGI2 and PGE2 have a synergistic role in restoring electrical transepithelial resistance (R) in ischemia-injured porcine ileum via the second messengers Ca2+ and cAMP. Because Ca2+ and cAMP stimulate Cl- secretion, we assessed the role of PG-induced Cl- secretion in recovery of R. Mucosa from porcine ileum subjected to ischemia for 45 min was mounted in Ussing chambers and bathed in indomethacin and Ringer solution. Addition of PGs stimulated a twofold increase in R, which was preceded by elevations in short-circuit current (increase of 25 microA/cm2). The PG-induced effect on R was partially inhibited with bumetanide, an inhibitor of Cl- secretion. The remaining elevations in R were similar in magnitude to those induced in ischemic tissues by amiloride, an inhibitor of Na+ absorption. Treatment with 10(-4) M 8-bromo-cGMP or 300 mosM mucosal urea resulted in elevations in R similar to those attained with PG treatment. PGs signal recovery of R via induction of Cl- secretion and inhibition of Na+ absorption, possibly by establishing a transmucosal osmotic gradient.
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PMID:Prostaglandin-induced recovery of barrier function in porcine ileum is triggered by chloride secretion. 988 75

Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
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PMID:EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits. 1051 71

The aim of this study was to assess whether cyclooxygenase (COX) inhibitors protect the endothelial function against the deleterious effect of ischemia and reperfusion. Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow, 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619, and the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation to SNP was unaffected in all groups. Pretreatment with 6-MNA, 30 microM, a COX-2 inhibitor with some activity on COX 1, diclofenac, 1 microM (COX-1 and -2), or 1-(7-carboxyheptyl) imidazole, 10 microM [thromboxane (TX) synthase inhibitor] but not indomethacin, 10 microM (COX-1 inhibitor) preserved the vasodilation induced by 5-HT after ischemia. Enzyme immunoassays indicated that all COX inhibitors decreased the concentration of TXB2 and 6-keto-PGF1alpha [stable metabolites of TXA2 and prostacyclin (PGI2), respectively] in coronary effluent during ischemia. Furthermore, indomethacin was the only one to abolish the concentration of PGE2 during ischemia and early reperfusion. No clear trend on ventricular postischemic recovery could be observed between treated and untreated groups under our experimental protocols. These data suggest that, under our conditions, 6-MNA, diclofenac, and 1-7-CHI, but not indomethacin, protect the endothelial function via a reduction in TX concentration. Disparities between COX inhibitors may be due to the complete abolition of PGE2 concentration during ischemia and reperfusion in the indomethacin group.
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PMID:Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. 1054 94

Experiments compared the hemispheric neural damage resulting from global hemispheric hypoxic ischemia (GHHI, ligation of right common carotid artery plus 35 min of 12% O2) in groups of anesthetized, male Long Evans rats, 9-10 weeks of age, kept at 37 degrees C, and previously given an intracerebroventricular (i.c.v., 2.5 microl) injection of 28 or 70 pmoles of PGE2, PGF2alpha or PGD2 or sterile saline (SS) 30 min beforehand. Mean arterial pressure (MAP), ipsilateral cortical capillary blood flow (CBF), colonic (Tc), ipsilateral (Tipsi) and contralateral (Tcontra), temporalis muscle temperatures were measured before, during and for 15 min after GHHI. Necrotic neural damage was assessed 7 days post-GHHI. All groups given GHHI + PGs showed increased ipsilateral hemispheric damage to GHHI especially due to enhanced neocortical damage, compared to the saline control group given the same insult. PGD2 was the most potent PG to cause further damage to the global insult. Tc, Tipsi, Tcontra and MAP increased following the i.c.v. injection of PGE2. I.c.v. PGF2alpha transiently decreased MAP, PGD2 tended to decrease cerebral blood flow and neither evoked changes in temperature compared to respective pre-injection control values. Results demonstrate increased neural damage to GHHI with prior i.c.v. PGE2, PGF2alpha or PGD2 administration.
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PMID:Temperature and hemodynamic changes associated with increased neural damage to global hemispheric hypoxic ischemia by prior prostaglandin E2, D2 and F2alpha administration. 1057 44

We investigated whether the stable prostacyclin analogue (OP-2507; OP) would ameliorate warm ischemia-related injury of the liver graft under conditions of a nonbeating heart. Thirty-six mongrel pigs were arranged into 3 groups of 6 pairs. Group 1 pigs underwent orthotopic liver transplantation from heart-beating donors (HBD). In group 2, animals received liver grafts from nonheart-beating donors (NHBD), defined as 30 min of cardiac arrest. Group 3 pigs received grafts from NHBD, but the donor had been pretreated with OP by intraportal infusion (2 microg/kg x min for 30 min immediately before the induction of cardiac arrest). The grafts were preserved at 4 degrees C in Euro-Collins solution in which OP was dissolved at 200 microg/l. Five-day survival rates after transplantation improved significantly in OP-treated animals (3/6, for group 3), compared with 0/6 for group 2 (P < 0.05, generalized Wilcoxon test). Five of 6 animals survived more than 5 days in the HBD group (group 1). Although the serum transaminase activities and bile production did not differ in the early phase of recirculation among the groups, there was a significant improvement in the hepatic microcirculatory environment in the surviving groups (groups 1 and 3). Analysis of arterial prostanoid levels showed a substantial suppression of PGE2 release by OP treatment following reperfusion. Our data indicate that a stable prostacyclin analogue can be clinically useful for expanding the donor pool by improving the quality of the liver graft.
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PMID:Efficacy of prostacyclin analogue (OP-2507) in viable hepatic grafts from pigs with non-beating hearts. 1127 Dec 2

Prostaglandins may influence cyclo-oxygenase (COX-2) and nitric oxide (NO) synthase activity, thus interfering with ischemia-induced neurotoxic processes. The prostaglandin synthetic derivative, latanoprost was tested in different in vivo and in vitro models of neuronal damage in order to study its influence on these processes. Ischemia was induced in rats by bilateral occlusion of the carotid arteries for 30 min. Latanoprost (0.01 mg x kg(-1)per die, i.p. for 3 days) or the ionotropic glutamate receptors antagonist, MK-801 (0.1 mg x kg(-1)per die, i.p. for 3 days) were equal in preventing lactate accumulation in retinal tissue of animals subjected to acute ischemia. Similar results were obtained in animals with retinal ischemia induced by increasing intraocular pressure to 120 mm Hg for 45 min. PGF2alpha, PGE2, latanoprost and acid of latanoprost (PhXA85) reduced the release of LDH from primary cultures of human retinal cells in vitro subjected to glutamate (10 microM) or hypoxia/re-oxygenation exposure. This effect was observed only at concentrations of 1-0.01 microM for PGF2alpha and PGE2, and of 0.1-0.001 microM for latanoprost (0.01 microM-0.1 nM for PhXA85). The COX-2 activity in cultured retinal cells exposed to glutamate was measured as PGE2 production when latanoprost was applied compared to arachidonic acid (AA) at different molar concentrations. The COX-2 activity was reduced by arachidonic acid (0.1-0.01 microM) as well as by latanoprost (0.1-0.001 microM) and PhXA85 (0.01-0.001 microM) in retinal cells exposed to glutamate. Inhibition of inducible NO synthase was also found with the same drug concentrations. These results suggest that latanoprost exerts a neuroprotective activity in vitro and in vivo. This effect seems to be present only at low concentrations of the drug. A negative feedback on neuronal COX-2 activity may be possibly involved.
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PMID:Latanoprost exerts neuroprotective activity in vitro and in vivo. 1127 75

16,16-Dimethyl-PGE2 (PGE2) may interact with one of four prostaglandin type E (EP) receptors, which signal via cAMP (via EP2 or EP4 receptors) or intracellular Ca(2+) (via EP1 receptors). Furthermore, EP3 receptors have several splice variants, which may signal via cAMP or intracellular Ca(2+). We sought to determine the PGE2 receptor interactions that mediate recovery of transmucosal resistance (R) in ischemia-injured porcine ileum. Porcine ileum was subjected to 45 min of ischemia, after which the mucosa was mounted in Ussing chambers. Tissues were pretreated with indomethacin (5 microM). Treatment with the EP1, EP2, EP3, and EP4 agonist PGE2 (1 microM) elevated R twofold and significantly increased tissue cAMP content, whereas the EP2 and EP4 agonist deoxy-PGE1 (1 microM) or the EP1 and EP3 agonist sulprostone (1 microM) had no effect. However, a combination of deoxy-PGE1 and sulprostone stimulated synergistic elevations in R and tissue cAMP content. Furthermore, treatment of tissues with deoxy-PGE1 and the Ca(2+) ionophore A-23187 stimulated synergistic increases in R and cAMP, indicating that PGE2 triggers recovery of R via EP receptor cross talk mechanisms involving cAMP and intracellular Ca(2+).
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PMID:PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum. 1144 18

Two isoenzymes of cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, COX-1 and COX-2, have been identified. COX-1 was proposed to regulate physiological functions, COX-2 to mediate pathophysiological reactions such as inflammation. In particular, it was suggested that maintenance of gastric mucosal integrity relies exclusively on COX-1. Recently, it was shown that a selective COX-1 inhibitor does not damage the mucosa in the healthy rat stomach, although mucosal prostaglandin formation is near-maximally suppressed. However, concurrent treatment with a COX-1 and a COX-2 inhibitor induces severe gastric damage. This indicates that in normal mucosa both COX-1 and COX-2 have to be inhibited to evoke ulcerogenic effects. In the acid-challenged rat stomach inhibition of COX-1 alone is associated with dose-dependent injury which is aggravated by additional inhibition of COX-2 activity or prevention of acid-induced up-regulation of COX-2 expression by dexamethasone. After acid exposure, COX-2 inhibitors cause substantial gastric injury when nitric oxide formation is suppressed or afferent nerves are defunctionalized. Ischemia-reperfusion of the gastric artery increases levels of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone aggravate ischemia-reperfusion-induced mucosal damage up to 4-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE2. Furthermore, the protective effects elicited by a mild irritant or intragastric peptone perfusion are antagonized by COX-2 inhibitors. Finally, COX-2 expression is increased in experimental ulcers. COX-2 inhibitors delay the healing of chronic gastric ulcers in experimental animals and decrease epithelial cell proliferation, angiogenesis and maturation of the granulation tissue to the same extent as non-steroidal anti-inflammatory drugs. These observations indicate that, in contrast to the initial concept, COX-2 plays an important role in gastric mucosal defense.
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PMID:Role of cyclooxygenase-2 in gastric mucosal defense. 1175 26

Kupffer cells (KCs), the resident macrophages of the liver, contribute prominently to liver injury by inflammatory mediators. Pre-conditioning with the atrial natriuretic peptide (ANP), known also as a regulator of macrophage functions, attenuates hepatic ischemia-reperfusion injury. Therefore, the aim of this study was to determine the presence of functional ANP receptors on isolated KCs and to investigate whether this hepatoprotective hormone influences the activation of KCs. KCs were isolated by collagenase/pronase digestion followed by elutrial centrifugation and cultured for 1 to 3 days. Intracellular cyclic guanosine 3'5'-monophosphate (cGMP) concentrations were measured by radioimmunoassay after treating the cells with sodium nitroprusside or ANP. KCs were stimulated with bacterial lipopolysaccharide in the presence or absence of ANP, and inflammatory mediators were determined. Phagocytosis was assayed using Coumarin-labeled latex particles and flow cytometric analysis. Treatment of KCs with ANP but not with sodium nitroprusside resulted in a significant elevation of intracellular cGMP levels indicating functional type A natriuretic peptide receptors (NPR-As). ANP significantly reduced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) secretion, paralleled by an increased cell-associated TNFalpha. LPS-induced TNFalpha mRNA expression was not affected. ANP significantly increased phagocytotic activity of KCs via NPR-A. No effect of ANP on LPS-activated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 protein levels, iNOS mRNA expression, nitric oxide, and PGE2-production was observed. We demonstrated functional cGMP-dependent ANP receptors in isolated rat KCs. ANP reduced TNFalpha release possibly by influencing post-translational processing of TNFalpha in LPS-activated KCs. In addition, we demonstrated that ANP enhances phagocytosis in KCs. These effects may contribute to the hepatoprotective actions of ANP.
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PMID:The atrial natriuretic peptide as a regulator of Kupffer cell functions. 1202 55

Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolism of arachidonic acid into prostanoids. Although it is constitutively expressed in brain neurons, the inducible isoform (COX-2) is also upregulated in pathological conditions such as seizures, ischemia or some degenerative diseases. To assess whether COX-2 is regulated after stress, we have used adult male Wistar rats, some of which were immobilized during 6 h. An increase in PGE2 concentration occurs in brain cortex after 2-6 h of the onset of stress as well as an enhancement of COX-2 protein. Immunohistochemical studies indicate that COX-2 is expressed in the cortex and hippocampus after stress in cells with morphology of neurons. Administration of PDTC (150 mg/kg), an inhibitor of the transcription factor NF-kappaB or MK-801 (0.2 mg/kg), an N-methyl-D-aspartate receptor blocker, prevents both stress-induced increase in COX-2 activity and protein levels, suggesting an implication of these factors in the mechanism by which stress induces COX-2 in brain. To assess if COX-2 accounts for the oxidative status seen in brain after stress, a group of animals were i.p. injected with NS-398, a specific COX-2 inhibitor 1 h prior to the onset of stress. NS-398 (5 mg/kg) decreases stress-induced malondialdehyde accumulation in cortex as well as prevents the stress-induced oxidation of glutathione. Finally, NS-398 reduced Ca2+-independent inducible nitric oxide synthase (iNOS, NOS-2) activity and lowered the stress-induced accumulation of NO metabolite levels in cortex. These effects of NS-398 seem to be due to the specific inhibition of COX-2, since it has no effect on stress-induced corticosterone release, glutamate release, and NF-kappaB activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.
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PMID:Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain. 1278 18


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