Mys L. Th.e role of activation of endogenous hydrogen sulfide synthesis in the restoration of the functional state of the cardiovascular system in old rats

The dissertation is devoted to the study of stimulation of endogenous hydrogen sulfide (H2S) synthesis and its influence on the functional state of the cardiovascular system of old rats. It has been shown that the content of this endogenous transmitter is significantly reduced and oxidative-nitrosative stress also develops in the tissues of the heart and blood vessels of old rats. To stimulate the synthesis of endogenous hydrogen sulfide, we used the coenzyme of H2S-synthesizing enzymes – pyridoxal-5-phosphate (PLP). For the first time, we have shown that the course administration of PLP restored the content of endogenous H2S in the tissues of the cardiovascular system of old animals, that occurred due to increased expression of CSE and 3-MST genes. Such activation of endogenous H2S synthesis was accompanied by a significant inhibition of oxidative stress, a decrease in the rate of generation of superoxide, hydroxyl anion radicals and the content of lipid peroxidation products compared with old animals kept on standard diet. Due to the stimulation of endogenous H2S synthesis in old rats, there was also a decrease in nitrosative stress, namely the activity of inducible NO synthase was decreased and activity of constitutive NO synthase was increased that led to increased constitutive NO synthesis, which plays a significant role in reactions of cardiovascular systems. The protective mechanisms of action of H2S can be associated with the restoration of constitutive Ca2+-dependent synthesis of NO (cNOS), inhibition of oxidative stress and the impact on intracellular structures, namely nonspecific megachannel – mitochondrial permeability transition pore (MPTP). We showed for the first time that consumption of PLP inhibited Ca2+-induced opening of the MPTP due to a decrease in its sensitivity to the inducer which is significantly increased in old rats. Inhibition of the mitochondrial H2S-synthesizing enzyme 3-MST by O-CMH reduced the protective effects of PLP on the MPTP opening in the heart of old rats which indicates the H2S-dependent mechanism of PLP. We have found that consumption of PLP prevented the development of ischemic-reperfusion disturbances of the heart function. This was evidenced by the prevention of a drastic drop in pressure in the left ventricle and the rate of contraction and relaxation of the myocardium. PLP significantly improved endothelium-dependent aortic smooth muscle relaxation in old rats. Thus, the amplitude of acetylcholine-induced relaxation which was significantly reduced in old rats was increased more than 2.5-fold. This effect was reversed by inhibitors of NO-synthase and 3-mercaptopyruvate sulfurtransferase indicating the involvement of NO and H2S in the improved endothelium-dependent vascular relaxation. Thus, PLP restored of the endogenous H2S synthesis, constitutive NO and inhibited oxidative-nitrosative stress in the tissues of the cardiovascular system of old rats which helped to improve the endothelium-dependent relaxation of aortic smooth muscle and heart function in old rats.