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)

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.
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PMID:Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. 905 Aug 95

Cathepsin A-like enzyme released from human platelets by thrombin hydrolyzed at the highest rate Cbz-Phe-Ala, Cbz-Phe-Met and Cbz-Phe-Leu, did not require activators and was inhibited by DFP, DCI and mercurial compounds (mersalyl acid, PCMS, PCMB and HgCl2). The optimum activity of secreted enzyme was at pH 5.0-6.0. Cbz-Glu-Tyr was also hydrolyzed at lower pH with optimum at pH 3.5. These enzymatic properties are the same as those of cathepsin A solubilized from whole platelets and purified from other mammalian cells and tissues. High specific activity of secreted cathepsin A, and a broad pH range of activity may have a significance in extracellular proteolysis in local sites of ischemia. Large portion of cathepsin A-like activity was not secretable by high concentration of thrombin and was sedimented with platelet aggregates. No activity of lysosomal carboxypeptidases B and prolylcarboxypeptidase was detectable in supernatants and pellets of thrombin-stimulated platelets.
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PMID:Cathepsin A-like activity in thrombin-activated human platelets. Substrate specificity, pH dependence, and inhibitory profile. 921 30

Proteases as well as alterations in intracellular calcium have important roles in hepatic preservation-reperfusion injury, and increased calpain activity recently has been demonstrated in liver allografts. Experiments were designed to evaluate (i) hepatic cytosolic calpain activity during different periods of cold ischemia (CI), rewarming, or reperfusion, and (ii) effects of inhibition of calpain on liver graft function using the isolated perfused rat liver and arterialized orthotopic liver transplantation models. Calpain activity was assayed using the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl coumarin (AMC) and expressed as mean +/- SD pmol AMC released/min per mg of cytosolic protein. Calpain activity rose significantly after 24 hr of CI in University of Wisconsin solution and further increased with longer preservation. Activity also increased within 30 min of rewarming, peaking at 120 min. Increased durations of CI preceding rewarming resulted in significantly higher activity (P < 0.01). Calpain activity increased rapidly upon reperfusion and was significantly enhanced by previous CI (P < 0.01). Calpain inhibition with Cbz-Val-Phe methyl ester significantly decreased aspartate aminotransferase released in the isolated perfused rat liver perfusate (P < 0.05). Duration of survival after orthotopic liver transplantation using livers cold-preserved for 40 hr was also significantly increased (P < 0.05) with calpain inhibitor. In conclusion, calpain proteases are activated during each phase of transplantation and are likely to play an important role in the mechanisms of preservation-reperfusion injury.
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PMID:Calpain is a mediator of preservation-reperfusion injury in rat liver transplantation. 925 86

The purpose of this study was to evaluate whether the synthetic adrenocorticotropin-(4-9) (ACTH-(4-9)) analogue ORG 2766, HMet(O2)-Glu-His-Phe-D-Lys-Phe-OH, which has been shown to have beneficial effects on both the recovery from experimentally induced lesions of the central nervous system and peripheral nerve degeneration, has a protective effect on focal ischemic neuronal damage. The NMDA receptor antagonist dizolcipine (MK-801), a very potent neuroprotective drug, was used as positive reference compound. Isoflurane-anesthetized rats had the middle cerebral artery occluded using either an intravasal or an extravasal technique, because pilot experiments had shown differences in the severity of ischemia for the two middle cerebral artery occlusion techniques. MK-801, 500 microg kg(-1) min(-1), or saline was administered i.v. 30 min after occlusion of the middle cerebral artery. In the ACTH-(4-9) analogue/saline group, 10 and 150 microg/kg of the analogue, or saline was injected s.c. both directly after and 24 h after occlusion. The ACTH-(4-9) analogue treatment had no effect on the infarction volume in either model of middle cerebral artery occlusion, whereas MK-801 caused a significant reduction in the volume of cortical infarction in both models. We conclude that, although ORG 2766 is known to enhance the recovery from experimentally induced lesions of the central nervous system through a neurotrophic action and has proven to have significant beneficial effects on peripheral nerve regeneration, it did not prevent ischemic neuronal damage after intravasal or extravasal middle cerebral artery occlusion in rats. The results with MK-801, which caused significant reductions in the volume of cortical infarction in both models of middle cerebral artery occlusion, with clearly the largest reduction in the intravasal middle cerebral artery occlusion model, again indicate that there are differences in the severity of the cerebral ischemia which the two models produce in the rat brain.
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PMID:The effect of the adrenocorticotropin-(4-9) analogue, ORG 2766, and of dizolcipine (MK-801) on infarct volume in rat brain. 965 55

Mexiletine is a class I antiarrhythmic drug with neuroprotective effects in models of brain ischemia attributable to inhibition of brain sodium channels. We compared effects of R-mexiletine on wild-type and mutant rat brain (rbIIA) and heart (rh1) sodium channel alpha-subunits transiently expressed in tsA-201 cells. R-mexiletine induced tonic and frequency-dependent block and bound with a 26-fold (brain) or 35-fold (heart) higher affinity to inactivated sodium channels. Affinities of both resting and inactivated channels for R-mexiletine block were approximately 2-fold higher for heart than for brain channels. Mutations in transmembrane segment IVS6 of heart (rhF1762A) and brain (rbF1764A and rbY1771A) channels, which reduce block by other local anesthetics, reduced high-affinity block of inactivated channels and frequency-dependent block of open channels by R-mexiletine and abolished the difference in affinity between brain and heart sodium channels. Unlike previous local anesthetics studied, the strongest effect was observed for mutation rbY1771A. Comparison of mutations of the homologous phenylalanine residue in brain and heart channels showed striking differences in the effects of the mutations. rbF1764A reduced drug block by slowing R-mexiletine binding to inactivated channels, whereas rhF1762A reduced block by increasing the rate of dissociation from inactivated and resting channels. Thus, rbF1764/rhF1762 is a critical determinant of affinity and tissue-specific differences in mexiletine block of brain and heart sodium channels, but its role in drug interaction differs in these two channel isoforms.
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PMID:Differential interaction of R-mexiletine with the local anesthetic receptor site on brain and heart sodium channel alpha-subunits. 1057 51

In rats and rabbits, endogenous opioid peptides participate in ischemic preconditioning. However, it is not known which endogenous opioid(s) can trigger cardioprotection. We examined preconditioning-induced and opioid-induced limitation of cell death in isolated, calcium-tolerant, adult rabbit cardiomyocytes. Cells were subjected to simulated ischemia by pelleting and normothermic hypoxic incubation. Preconditioning was elicited with 15 min of simulated ischemia followed by 15 min of resuspension and reoxygenation. All cells underwent 180 min of simulated ischemia. Cell death was assessed by trypan blue permeability. Morphine protected cells, as did preconditioning; naloxone blocked the preconditioning-induced protection. Exogenous Met5-enkephalin (ME) induced protection, but exogenous beta-endorphin did not. ME-induced protection was blocked by the delta-selective antagonist naltrindole. Additionally, two other proenkephalin products, Leu5-enkephalin and Met5-enkephalin-Arg-Phe, provided protection equipotent to ME. These data suggest that one or more proenkephalin products interact with delta-opioid receptors to endogenously trigger opioid-mediated protection.
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PMID:Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta-opioid receptors. 1060 Aug 67

To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A2 receptor (A2R), we investigated the effects of adenosine and YT-146, selective A2A receptor (A2AR) agonist, on I/R-induced liver injury in rats. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil elastase release from isolated neutrophils by about 35% in vitro. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the endotoxin-stimulated TNF-alpha production by monocytes to less than 50% of the control. Although ZM241385, a selective A2AR antagonist, significantly enhanced the fMLP-induced neutrophil elastase release in isolated neutrophils in vitro, this agent did not affect the endotoxin-stimulated TNF-alpha production by monocytes. Male Wistar rats were subjected to complete ischemia of median and left lobes of liver for 60 min and the subsequent reperfusion. Serum levels of transaminases increased over time after hepatic I/R, peaking at 12 hrs after reperfusion. Intravenous infusion of Adenosine (1 and 10 mg/kg/hr) and YT-146 (0.1 and 1 mg/kg/hr) significantly inhibited the I/R-induced increases in serum transaminase levels 12 hrs after reperfusion. The I/R-induced decrease in hepatic tissue blood flow was significantly inhibited by adenosine and YT-146. Hepatic levels of TNF-alpha, cytokine-induced neutrophil chemoattractant (a member of interleukin-8), and myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by administration of adenosine and YT-146. However, ZM241385 did not reduce the I/R-induced liver injury and it inhibited neither the decrease in hepatic tissue blood flow, nor the indicators of leukocyte activation. These findings suggest that adenosine may reduce I/R-induced liver injury mainly by inhibiting hepatic TNF-alpha production via A2AR, thereby reducing neutrophil activation.
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PMID:[Adenosine reduces ischemia/reperfusion-induced liver injury by inhibiting leukocyte activation]. 1062 74

Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to 4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0. 7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/-0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0. 1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100 micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3) N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium-intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3) N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.
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PMID:Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. 1064 26

We have previously shown that PGE(2) enhances recovery of transmucosal resistance (R) in ischemia-injured porcine ileum via a mechanism involving chloride secretion. Because the tyrosine kinase inhibitor genistein amplifies cAMP-induced Cl(-) secretion, we postulated that genistein would augment PGE(2)-induced recovery of R. Porcine ileum subjected to 45 min of ischemia was mounted in Ussing chambers, and R and mucosal-to-serosal fluxes of [(3)H]N-formyl-methionyl-leucyl phenylalanine (FMLP) and [(3)H]mannitol were monitored as indicators of recovery of barrier function. Treatment with genistein (10(-4) M) and PGE(2) (10(-6) M) resulted in synergistic elevations in R and additive reductions in mucosal-to-serosal fluxes of [(3)H]FMLP and [(3)H]mannitol, whereas treatment with genistein alone had no effect. Treatment of injured tissues with genistein and either 8-bromo-cAMP (10(-4) M) or cGMP (10(-4) M) resulted in synergistic increases in R. However, treatment of tissues with genistein and the protein kinase C (PKC) agonist phorbol myristate acetate (10(-5)-10(-6) M) had no effect on R. Genistein augments recovery of R in the presence of cAMP or cGMP but not in the presence of PKC agonists.
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PMID:Genistein augments prostaglandin-induced recovery of barrier function in ischemia-injured porcine ileum. 1066 44

Recent studies have demonstrated that three membrane-permeant A(1) receptor antagonists reduced infarct size in a model of ischemia followed by brief reperfusion. However, it was not determined whether cardioprotection was mediated by nonspecific intracellular effects of these highly lipophilic drugs and whether the antagonists only delayed myocardial necrosis without affecting the ultimate infarct size. In the present study, closed-chest dogs were subjected to 90 min of left anterior descending coronary artery occlusion and 72 h of reperfusion and received either a nonmembrane-permeant adenosine receptor blocker that is devoid of direct intracellular effects and is 6-fold selective for the A(1) receptor [1, 3-dipropyl-8-p-sulfophenylxanthine (DPSPX); n = 11] or vehicle (n = 12). DPSPX was administered as three 200-mg boluses 60 min before and 30 and 120 min after reperfusion. The area of necrosis was determined histologically and expressed as a percentage of the area at risk. Baseline predictors of infarct size were similar in the two groups. The ratio of the area of necrosis to the area at risk was less in the DPSPX group (17.8 +/- 4.3% versus 35.0 +/- 1.9%; P =. 012), and DPSPX improved regional ventricular function. Under both basal and stimulated (formyl-Met-Leu-Phe) conditions, suspensions of human neutrophils generated extracellular adenosine levels (approximately 50 nM) sufficient to activate A(1) receptors. Moreover, both DPSPX and 1,3-dipropyl-8-cyclopentylxanthine, a selective A(1) receptor antagonist, significantly reduced the chemoattractant response of neutrophils to formyl-Met-Leu-Phe. We conclude that blockade of A(1) adenosine receptors attenuates myocardial ischemic/reperfusion injury, possibly in part by decreasing the chemoattractant response of neutrophils.
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PMID:Sustained reduction in myocardial reperfusion injury with an adenosine receptor antagonist: possible role of the neutrophil chemoattractant response. 1068 6


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