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 studied the effects of the aminosteroid U-74389G (21-[4-(2, 6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)- triene-3,20-dione(2)-2-butenenedionate), a putative inhibitor of lipid peroxidation, which protects the rat myocardium after ischemia and reperfusion. Pentobarbital-anesthetized (50 mg/kg) rats were subjected to 60 min of occlusion of the left main coronary artery followed by 60 min of reperfusion. Myocardial ischemia/reperfusion produced a large cardiac necrosis (81 +/- 8.6% of the area at risk and 65 +/- 14.8% of the total left ventricle), polymorphonuclear infiltration in the jeopardized tissue (myeloperoxidase activity = 4.2 +/- 2.1 U X 10(-3)/g tissue in the area at risk and 7.0 +/- 3.6 U X 10(-3)/g tissue in the necrotic area), hydroxyl radical (OH.) formation (0.55 +/- 0.16 nmol/ml), increased plasma malonylaldehyde (40.2 +/- 3.9 nmol/ml) and lactate dehydrogenase (431 +/- 30 mIU/ml) and caused a decrease in the survival rate. Treatment with U-74389G (15 and 30 mg/kg i.v.) at the onset of reperfusion caused a reduction of necrotic area expressed as a percentage of either the area at risk (76 +/-7.4% with 15 mg/kg and 69 +/- 13.5% with 30 mg/kg; P < .05) or the total left ventricle (53 +/- 13.6% with 15 mg/kg and 46 +/- 16.8% with 30 mg/kg; P < .05). Treatment U-74389G reduced the myeloperoxidase activity, evaluated as an index of neutrophil infiltration, both in the area at risk (2.7 +/- 1.1 and 2.2 +/- 1.7 U X 10(-3)/g tissue with the doses of 15 and 30 mg/kg, respectively; P < .05) and in the necrotic area (4.3 +/- 2.4 and 3.8 +/- 2.9 U X 10(-3)/g tissue with 15 and 30 mg/kg, respectively; P < .05); decreased OH. formation (measured indirectly by the administration of the trapping agent salicylic acid); and analyzing the hydroxylation product 2,5-dihydroxybenzoic acid during reperfusion (0.35 +/- 0.12 and 0.32 +/- 0.15 nmol/ml with the doses of 15 and 30 mg/kg, respectively; P < .005). Treatment inhibited lipid peroxidation by blunting plasma malonylaldehyde (26.7 +/- 3.1 and 20.8 +/- 3.3 with the doses of 15 and 30 mg/kg, respectively; P < .001), prevented cellular disruption by reducing the increase of plasma lactate dehydrogenase (288.6 +/- 28 and 201.3 +/- 16 mIU/ml with the doses of 15 and 30 mg/kg, respectively; P < .001). Finally, U-74389G enhanced the survival rate evaluated at the end of the experiment (from 40 to 87%). These outcomes suggest that the drug may have potential for cardioprotective use in acute myocardial infarction.
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PMID:Protection of ischemic and reperfused rat myocardium by the nonglucocorticoid 21-aminosteroid U-74389G, a new inhibitor of lipid peroxidation. 861 38

Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.
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PMID:Effect of glibenclamide on ischemic canine myocardium with glucose infusion. 874 25

The present study covers both the effects of MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, and pentobarbital on cholinergic terminal damage and delayed neuronal death (DND) in ischemic gerbil. To study the above effects, in vivo microdialysis, immunohistochemical, and morphological techniques were used. MK-801 (3 mg/kg) or pentobarbital (50 mg/kg) were injected intraperitoneally 1 h or 30 min before 5 min ischemia, respectively. Each estimation was then carried out 4, 7, or 14 days after ischemia. Ischemia induced a significant decrease in acetylcholine (ACh) release and a disappearance of choline acetyltransferase (ChAT)-immunoreactivity in the hippocampus in addition to inducing DND. On day 4, MK-801 protected ischemia-induced DND in the hippocampal CA1 subfield. However, MK-801 had no effect against the decrease in ACh release in spite of protection of the decrease in ChAT-immunoreactivity. On day 7 and 14, no protective effect of MK-801 was observed in all estimations. It became clear that the mechanism of cholinergic terminal dysfunction is different from that involved in pyramidal cell death, i.e., excitative neurotoxicity induced by overabundant extracellular glutamate. Pentobarbital also provided protection against DND. However, protective effects of pentobarbital on the decrease in ACh release and the low ChAT-immunoreactivity were incomplete. Our present study indicated a limitation on the efficacy of NMDA receptor antagonist and barbiturate against cerebral ischemia.
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PMID:Effects of MK-801 and pentobarbital on cholinergic terminal damage and delayed neuronal death in the ischemic gerbil hippocampus. 920 99

OG-VI is a solution composed of 30 mM inosine, 30 mM sodium 5'-guanylate, 30 mM cytidine, 22.5 mM uridine, and 7.5 mM thymidine, expecting to use for total parenteral nutrition. We examined the effect of OG-VI on myocardial contractile dysfunction during reperfusion after ischemia (myocardial stunning) in dogs. Pentobarbital-anesthetized dogs were subjected to 20-min left anterior descending coronary artery ligation followed by 30-min reperfusion. Saline, OG-VI or its constituents [inosine and sodium 5'-guanylate mixture (IG), and cytidine, uridine, and thymidine mixture (CUT)], or 5-amino-4-imidazole carboxamide riboside (AICAr) was infused at 0.1 mL.kg-1.min-1, starting 30 min before the ischemia. The contractile function was determined by ultrasonometry and assessed as % segment shortening (%SS). %SS was markedly decreased by ischemia, and returned toward pre-ischemic level after reperfusion, although the recovery was incomplete. The %SS was almost completely recovered by OG-VI and IG, and to a lesser extent by AICAr; CUT was ineffective. In the presence of 1 mg.kg-1 of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, a selective adenosine A1 receptor antagonist), cardioprotective effect of OG-VI on stunned myocardium was still observed. In conclusion, infusion of OG-VI improved myocardial contractile dysfunction in stunned myocardium. This effect was more potent than its constituents and AICAr. Adenosine A1 receptors are not involved in the mechanism.
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PMID:Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture, OG-VI. 922 40

The nature of the delayed blood-brain barrier (BBB) opening that occurs in rats subjected to forebrain ischemia by the technique of two-vessel (carotid) occlusion plus hypovolemic hypotension (2VO ischemia) was probed by examining the simultaneous, trans-barrier movement of two hydrophilic, normally poorly permeative solutes of markedly different molecular size: sucrose (MW = 342) and inulin (MW approximately 5000). Pentobarbital-anesthetized, male, Sprague-Dawley rats (342-374 g) were subjected to 10 min of 2VO ischemia (tympanic temperature, 37.5-38.0 degrees C); 6 h later they were reanesthetized and, along with non-ischemic controls, injected i.v. with [14C]sucrose and [3H]inulin. Transfer constants (Kis) for blood-to-brain movement of the tracers and Vis (apparent initial volumes of tracer distribution) were determined for six brain regions by the multiple-time, graphical method (tracer circulation times from 3 to 30 min). Vis differed little or insignificantly between the two tracers, or between control and post-ischemic rats; the values did not suggest appreciable endothelial binding of either tracer that might lead to its uptake by adsorptive-phase endocytosis. In the controls, regional Kis +/- S.E.M. (nl g(-1) s(-1)) for inulin ranged from 0.18 +/- 0.04 to 0.31 +/- 0.09 and were significantly lower (P < 0.01) than Kis for sucrose (1.53 +/- 0.16-1.91 +/- 0.29). The Ki ratio (sucrose/inulin) across brain regions (mean, 6.6; S.E.M., 0.6) was much lower than would be expected according to the concept that movement of most organic non-electrolytes across the intact BBB occurs by dissolution in and diffusion through endothelial cell plasma membranes, at a rate proportional to the lipid solubility and diffusivity of the solute. This finding is interpreted as indicating that a portion of the transfer of sucrose and inulin occurred by a mechanism other than dissolution-diffusion (e.g., via pores or vesicles). In the post-ischemic rats, Kis for both tracers were elevated significantly (P < 0.01) in parietal cortex, striatum, hippocampus, and midbrain. The post-ischemic increases (delta Kis) in these regions were greater for sucrose (1.90-3.31 nl g(-1) s(-1)) than for inulin (0.80-1.33). Across brain regions the ratio between sucrose delta Ki and inulin delta Ki averaged 2.9 (S.E.M., 0.2), a value significantly greater than the ratio of 1 that would be expected were the BBB opening due to an enhancement of micropinocytosis and vesicular transport. The correspondence of the mean delta Ki ratio with the ratio of the free diffusion coefficients of the tracers (D(f, suc)/D(f, inu) = 2.9; water, 38 degrees C) suggests that the delayed opening of the BBB following 2VO ischemia involves the formation of trans- or paracellular, aqueous pores or channels.
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PMID:Evidence for pore-like opening of the blood-brain barrier following forebrain ischemia in rats. 924 60

The experiment reported was designed to investigate whether endothelin-1 (ET-1) contributes to vasospasm and poor perfusion during the reperfusion after prolonged ischemia in skeletal muscle. Male Sprague-Dawley rats weighting 100 to 120 g were anesthetized with Nembutal. The vascular isolated rat cremaster muscle, coupled with local interarterial infusion, was the model used in this study. The diameters of feeding arterioles and terminal arterioles were measured utilizing intravital microscopy. The number of terminal arterioles with temporary cessation of flow were counted in each cremaster. Group 1: ET-dose response (8 rats)--various concentrations of ET-1 (from 10(-8) M to 10(-5) M) were infused into the cremaster to test whether this muscle was responsive to the agent in a dose-dependent manner. Group 2: ET-antagonist response (12 rats)--PD-142893, 10(-4) M (ETab receptor antagonist) plus ET-1 10(-7) M were infused into the cremaster to test whether vasospasm caused by exogenous ET-1 could be prevented by pretreatment with this specific ETab receptor antagonist. Group 3: ischemia/reperfusion response (12 rats)--PD-142893, 10(-4) M was infused into the cremaster before ischemia (4 hr warm ischemia) and during reperfusion to test whether ETab receptor antagonism was effective in preventing the vasospasm associated with ischemia/reperfusion injury. The results from this study show that a mixed ETab endothelin antagonist, PD-142893, infused before ischemia and during reperfusion at a dose which virtually abolished the vasoconstriction produced by a high concentration of exogenous endothelin-1, had no effect on ischemia/reperfusion-induced vasoconstriction in this model. These results suggest that ET-1 probably does not contribute to the ischemia/reperfusion-induced vasoconstriction and poor reflow in rat skeletal muscle.
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PMID:Endothelin-1 does not contribute to ischemia/reperfusion-induced vasoconstriction in skeletal muscle. 927 7

Ischemic preconditioning is known to be mediated by several humoral factors, such as adenosine, norepinephrine, and bradykinin. We examined intracellular signal transduction of ischemic preconditioning following receptor stimulation. Alterations in the pH of the ischemic bed were monitored to assess the response of control and ischemic-preconditioned myocardium to glibenclamide and pertussis toxin. Pentobarbital-anesthetized open-chest dogs were subjected to 40 min of ligation of the left anterior descending coronary artery. Ischemic preconditioning was elicited by 25-min periods of coronary ligation followed by 5 min of reperfusion before a 40-min period of ligation. Glibenclamide (0.3 mg/kg)was given i.v. 20 min before the onset of ischemic preconditioning. Pertussis toxin (6-10 micrograms/kg) was given i.v. 3 days before the experiment. Tissue myocardial pH was measured by a glass micro-pH electrode. Ischemia for 5 min decreased myocardial pH and reperfusion returned it to the preischemic levels. Ischemia for 40 min decreased the myocardial pH from 7.43 +/- 0.06 to 6.43 +/- 0.08. Ischemic preconditioning significantly attenuated the decrease in myocardial pH (6.57 +/- 0.06) induced by 40 min of ischemia. Pretreatment with either glibenclamide or pertussis toxin completely abolished the effect of ischemic preconditioning on ischemic myocardial acidosis. Ischemic preconditioning can attenuate ischemia-induced myocardial acidosis in dogs, and this effect is mediated by activation of adenosine triphosphate-sensitive potassium channels and pertussis toxin-sensitive guanosine triphosphate-binding protein.
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PMID:Inhibitory effects of glibenclamide and pertussis toxin on the attenuation of ischemia-induced myocardial acidosis following ischemic preconditioning in dogs. 927 77

Splanchnic artery occlusion (SAO) results in a severe form of circulatory shock in which oxygen-derived free radicals play an important role. L-Propionyl carnitine (LPC), an endogenous ester that plays a crucial role in cellular fatty acid oxidation and metabolism, has been shown to exert a protective effect in myocardial ischemia/reperfusion injury. Our purpose was to investigate the effects of LPC in an SAO model of ischemia/reperfusion injury. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. An intravenous bolus of LPC (200 microg/kg) administered 2 min before reperfusion prolonged survival time (116+/-4 vs. 81+/-3 min in 1 mL/kg .9% NaCl vehicle, p < .01), increased survival rate (88 vs. 13.6%, p < .01), and attenuated the percent increase in hematocrits (27+/4% vs. 43+/-3%, p < .05), and the increases in tissue myeloperoxidase activity (1.76+/-.4 U/100 mg vs. 3.79+/-.2 U/100 mg, p < .05). In addition, LPC increased mean arterial blood pressures at 60 min (p < .05), 80 min (p < .05), 100 min (p < .05), and 120 min (p < .05) postreperfusion. Moreover, LPC markedly attenuated splanchnic artery endothelial dysfunction induced by SAO ischemia/reperfusion injury (maximal vasorelaxation to ACh, 74+/-2.7% vs. 57+/-1.9% in vehicle, p < .01). In this murine SAO model of ischemia/reperfusion injury, LPC affords significant protection that may be achieved through inhibiting leukocyte infiltration into intestinal tissue and preserving endothelial function, thereby decreasing microvascular permeability and maintaining tissue perfusion.
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PMID:L-propionyl carnitine, an endogenous ester in fatty acid metabolism, exerts anti-shock and endothelial protective effects in rat splanchnic ischemia-reperfusion injury. 952 30

Microvascular impairment observed during reperfusion following ischemia (IR) is a major determinant of the development of liver injury. Previous studies have shown that hyper-responsiveness to endothelin-1 (ET-1) contributes to microvascular dysfunction following a primarily inflammatory stress induced by endotoxin. The present study investigates whether a similar hypercontractile response to ET-1 occurs in the hepatic portal system of IR rats. Pentobarbital-anesthetized Sprague-Dawley rats underwent liver ischemia of the left and medial lobes for 60 min (IR: n = 8) or a sham operation (n = 8). Six hours after reperfusion, the liver was isolated and perfused through the portal vein. Baseline portal pressure (Pp), portal flow (Qp), and sinusoidal diameter (Ds) were measured before and 3 and 10 min after adding ET-1 (1 nM). In baseline, IR livers had a significantly greater Pp, portal resistance, and Ds than sham. ET-1 significantly increased Pp and portal resistance and significantly decreased Qp and Ds in IR and sham rats. However, these effects were significantly greater in IR. The results of the present study demonstrate that IR increases the porto-hepatic contractile response to ET-1, which may further sensitize the portal circulation to elevated ET-1 and may be a prominent contributor to the development of microvascular impairment following IR.
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PMID:Ischemia/reperfusion induces an increase in the hepatic portal vasoconstrictive response to endothelin-1. 1035 37

The purpose of this study was to determine the roles of cytosolic and ecto 5'-nucleotidase in myocardial ischemia-induced increases in interstitial fluid (ISF) adenosine. Pentobarbital anesthetized, open chest pigs were instrumented with two microdialysis fibers in the distally perfused bed of the left anterior descending (LAD) coronary artery to estimate ISF metabolites. Fibers in control hearts were perfused with standard Krebs buffer. In two additional groups, after collecting one dialysate sample with normal Krebs, fibers were perfused with buffer supplemented with either L-homocysteine thiolactone (5 mM) or the ecto 5'-nucleotidase inhibitor alpha, beta-methylene adenosine 5'-diphosphate (AOPCP, 5 mM). Hearts were then submitted to 60 minutes LAD occlusion and two hours reperfusion. Dialysate nucleosides and AMP were measured by high performance liquid chromatography. The local delivery of homocysteine did not alter preischemic dialysate adenosine concentration (0.30 +/- 0.04 microM) compared to pre-homocysteine infusion (0.39 +/- 0.04 microM) or control hearts (0.36 +/- 0.04 microM), but AOPCP significantly decreased preischemic dialysate adenosine levels (from 0.36 +/- 0.02 to 0.14 +/- 0.03 microM). During LAD occlusion both homocysteine and AOPCP reduced dialysate levels by approximately 50%. At 30 minutes ischemia dialysate adenosine concentrations were 19.47 +/- 2.72, 11.41 +/- 2.44, and 7.93 +/- 1.01 microM in control, homocysteine, and AOPCP hearts, respectively. AOPCP significantly increased dialysate AMP levels; at 60 minutes ischemia AMP levels were 6.22 +/- 2.97 microM in control hearts and 38.60 +/- 5.69 microM in AOPCP treated hearts. These results suggest that both cytosolic and ecto 5'-nucleotidase contribute to ischemia-induced increases in ISF adenosine in porcine myocardium.
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PMID:Evidence that cytosolic and ecto 5'-nucleotidases contribute equally to increased interstitial adenosine concentration during porcine myocardial ischemia. 1042 38


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