Influence of coordinating compounds of copper, derivatives of thiosemicarbazide, on nitric oxide homeostasis in hepatic tissue

Abstract

Introduction. The researches carried out in the last decades have brought more and more evidence that nitric oxide (NO) and its derivatives play an important role in various physiological and pathological processes, including liver diseases. The therapeutic efficacy of the thiosemicarbazide derivatives is known, but the data regarding their influence on the main nitric oxide metabolites – nitrite (NO2) and nitrate (NO3) in the liver tissue are missing. Aim of the study. Based on the above, the purpose of the study is to investigate the influence of new copper coordinating compounds (CCCs), thiosemicarbazide derivatives on the level of nitric oxide metabolites in vivo in laboratory animal studies. Materials and methods. The Research Ethics Committee of the Nicolae Testemitanu SUMP (favourable opinion no. 73 of 26.04.2017) approved the research. The action of the thiosemicarbazide derivatives – CMJ-33 and CMT-67 was evaluated in experiments on 40 male white Wistar rats randomly divided into the following groups: I control – intact animals; II and III – animals, which were administered CMJ-33 and CMT-67, respectively, at a dose of 1.0 mg/kg body weight for 30 days. The determination of NO metabolites was performed according to the methods described previously. Results. The study shows that the tested CCCs induced statistical changes in the content of NO metabolites in the liver tissue. Thus, CMJ-33 and CMT-67 statistically significantly increase the summary content of NO2 + NO3 by 32% and 20% compared to the values attested in the control group. The concentration of NO2 after administration of CMJ-33 and CMT-67 increases by 43% and, respectively, by 23% compared to the control values. The NO2/NO3 ratio relevantly increases after CMJ-33 administration by 47%, while CMT-67 causes a discrete increase of this ratio by 12% in the liver. Conclusions. The obtained results demonstrate the ability of the CMJ-33 and CMT-67 to induce the formation of NO derivatives, in particular, NO2 in liver tissue. This can be certified as a positive moment because nitrite acts by a mechanism distinct from that of nitric oxide, and it is capable of modulating multiple intracellular/extracellular signaling pathways, at lower concentrations than those required for induction of methemoglobinemia and vasodilation. Evaluation of the NO homeostasis is important for the research of new bioactive compounds for a better understanding of their mechanisms of action, which will facilitate not only the discovery of new targets for their action, but also the development of new therapeutic agents.