ASSESSMENT OF TRIMETHAZIDINE AND THIOTRIAZOLINE INFLUENCE ON THE STATE OF THE CYSTATIONINEγ-LYASE / H2S SYSTEM IN THE LIVER AND SKELETAL MUSCLES OF RATS WITH HYPERCHOLESTEROLEMIA UNDER SIMVASTATIN USING

Voloshchuk N. I., Melnik A. V., Danchenko О. P.

CLINICAL AND EXPERIMENTAL MEDICINE

Scentific article

Currently cardiovascular diseases remain the major cause of mortality and disability in the world. Among the drugs for treatment, primary and secondary prevention of cardiovascular events inhibitors of 3-hydroxy3-methylglutaryl-coenzyme A reductase (statins) represent one of the most powerful agents because in addition to beneficial lipid-lowering action, statins seem to have wide spectrum of non-lipid-mediated pleiotropic effects. Myotoxicity and hepatotoxicity are the most common side effects associated with the use of statins. Consequently, it remains relevant to conduct significant studies to determine statin toxicity mechanisms for searching ways to reduce the adverse reactions of their using. The aim of our studies was to evaluate the effect of thiotriazoline or trimetazidine on simvastatin-induced changes in the state of the cystathionine-γ-lyase (CSE) / hydrogen sulfide (H2S) system in the liver and skeletal muscles hypercholesterolemic rats. Object and methods. 121 Wistar male rats were fed with control (normal) or a high cholesterol diet (rat chow supplemented with 3% cholesterol) for 4 weeks). Hypercholesterolemic rats were divided into groups and were treated with either simvastatin (60 mg/kg body weight/day), simvastatin plus thiotriazoline (50 mg/kg body weight/ day) or simvastatin plus trimetazidine (10 mg/kg body weight/day). Two series of studies were carried out. The activity of cytolytic markers enzymes in the serum, the content of H2S and CSE in the homogenates and post-nuclear supernatants of the liver and skeletal muscles as well as the effect of propargylglycine (PAG) which is an inhibitor of CSE on hepato- and myotoxicity of simvastatin were determined. Results. It has been found that hypercholesterolemic diet is accompanied by a decreasing in H2S production in the liver and skeletal muscles, which is associated with hepatocytes and skeletal muscle damage. Simvastatin using to intensifies the inhibitory effect of hypercholesterolemia on the H2S production via CSE-mediated synthesis and exacerbate the scale of abnormalities accompanied by hepatocytes and skeletal muscles damages. The use of PAG significantly inhibits the H2S deficiency induced by simvastatin, and also is accompanied by increasing in the activity of cytolytic markers in the serum, which significantly and inversely correlated with the activity of CSE and H2S in the organs. Trimetazidine using has had no affect on neither production nor content of H2S in the liver and skeletal muscles. While thiotriazoline using prevents the inhibition of H2S synthesis induced by simvastatin and hypercholesterolemia. Conclusion. Thus, it has been shown thiotriazoline using prevents simvastatin-induced changes in the state of the CSE / H2S system in the liver and skeletal muscles of hypercholesterolemic rats, this effect is associated with its hepatoprotective and myotropic action. Probably, thiotriazoline action is connected with its distinct antioxidant activity.

hypercholesterolemia, simvastatin, trimetazidine, tiotriazoline, hydrogen sulpfide, hepatotoxicity, myotoxicity.

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«Bulletin of problems biology and medicine» Issue 4 part 1 (146), 2018 year, 60-65 pages, index UDK 615.015:616.9:616.633.972:599.823.4

10.29254/2077-4214-2018-4-1-146-60-65