Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
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The cardiotoxic potential of the phenothiazine neuroleptic thioridazine and five of its metabolites, including two stereoisomeric forms of thioridazine 5-sulfoxide (ring sulfoxide), was characterized in the isolated perfused rat heart. Hearts from male Sprague-Dawley rats were perfused using a modified Langendorff technique. After a 30-min control period, hearts were perfused for 30 min with 15 or 30 microM thioridazine, racemic and isomeric forms of thioridazine 5-sulfoxide, or thioridazine 2-sulfoxide. Thioridazine disulfoxide, thioridazine 2-sulfone, and desmethylthioridazine 2-sulfoxide were perfused at 15 microM. Thioridazine (15 microM) severely reduced contractile tension and the rate of tension development (dT/dt), transiently increased coronary flow rate but prolonged conductance through the AV node. No arrhythmias were seen. At 30 microM, ventricular premature contractions and irregular rhythms occurred, progressing to asystole. Thioridazine 5-sulfoxide was arrhythmogenic at 15 and 30 microM. Atrial premature contractions and paroxysmal atrial tachycardia progressed to second degree AV block. Contractile tension and dT/dt declined although not as quickly when compared to thioridazine. Each isomeric form of thioridazine 5-sulfoxide was also cardiotoxic at 15 and 30 microM. There were minor differences in the onset and degree of toxicity but the overall results did not suggest a stereoselective effect. Lactic dehydrogenase and aspartate aminotransferase concentrations were unchanged after thioridazine 5-sulfoxide perfusion indicating no direct tissue damage. Thioridazine 5-sulfoxide induced arrhythmias could not be prevented or reversed by treatment with adrenergic agonists. They were reversible upon washout, however. The other metabolites were not arrhythmogenic at 15 microM. Racemic thioridazine 5-sulfoxide appears to be qualitatively and quantitatively more arrhythmogenic than thioridazine, an action that does not appear to be stereoselective.
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PMID:Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine 5-sulfoxide in the isolated perfused rat heart. 376 35

The present study was attempted to assess the prophylactic and the therapeutic effect of human recombinant activated protein C (APC; drotrecogin-alpha, activated) in experimental heat stroke. Anesthetized rats were divided into two groups and given vehicle solution 1 h before the start or immediately after the termination of heat stress (isotonic sodium chloride solution, 2 mL kg(-1) of body weight, i.v.) or APC (1-10 mg in 2 mL of isotonic sodium chloride solution per kilogram of body weight, i.v.). They were exposed to ambient temperature of 40 degrees C for 100 min to induce heat stroke. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 57 to 71 min. Pretreatment or treatment with APC significantly increased survival time (122-221 min). All vehicle-pretreated heat stroke animals displayed systemic inflammation (evidenced by increased TNF-alpha, IL-1alpha, and IL-6) and activated coagulation (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer and decreased levels of both platelet count and protein C). Biochemical assay also revealed that both renal and hepatic dysfunction (e.g., increased plasma levels of blood urea nitrogen, creatinine, adenine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) were noted during heat stroke. A significant decrease in both cerebral blood flow and partial pressure of oxygen in hypothalamus were also observed in vehicle-pretreated heat stroke animals. These heat stroke reactions were all significantly reduced by pretreatment or treatment with human recombinant APC. The results indicate that human recombinant APC can be used as a prophylactic and a therapeutic agent for experimental heat stroke by ameliorating systemic inflammation, hypercoagulable state, and multiple organ dysfunction.
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PMID:Activated protein C can be used as a prophylactic as well as a therapeutic agent for heat stroke in rodents. 1929 93