Semenykhina O. Role of hydrogen sulfide in the regulation of vascular smooth muscle tone and cardioprotective mechanisms of its action

The study is aimed at estimating the contribution of hydrogen sulfide to the regulation of vascular smooth muscle tone by the example of the aorta and the portal vein, elucidating its involvement in the heart responses to ischemia – reperfusion, as well as the mechanisms related to the change in the heart functional state in these pathological conditions, including mitochondrial membrane permeability due to formation of Ca2+-induced cyclosporin A-sensitive (CsA) mitochondrial permeability transition pore (MPTP) and a change in the level of cardiomyocyte energy metabolism. We have obtained evidence that NaHS, a hydrogen sulfide donor, changes the smooth muscle (SM) tone of isolated aortic and portal vein preparations in a concentration- dependent manner. It has been shown that NaHS-induced SM relaxation is only partially mediated through endothelium-dependent mechanisms. The priority data have been obtained that the adventitia is involved in responses to hydrogen sulfide. Important cellular mechanisms of hydrogen sulfide operation include stimulation of KATP channels. Moreover, we have found that SM contractile activity of the aorta and the portal vein changes in response to L- cysteine, a precursor of hydrogen sulfide synthesis, indicating endogenous hydrogen sulfide involvement in the vascular tone control. However, we can not exclude a direct effect of L- cysteine on the vascular SM tone without its conversion to hydrogen sulfide. The introduction of NaHS was accompanied by an increase in the heart functional reserves in response to volume loading, indicating a decrease in diastolic myocardial stiffness and an increase in elastic properties of the myocardium. We have investigated the protective effect of hydrogen sulfide donor on reperfusion-induced disorders of the heart. In the experiments, introduction of NaHS was followed by a strong tendency to increase coronary flow, indicating that hydrogen sulfide regulates the coronary vascular tone. A significant reduction of reperfusion-induced dysfunction of the heart has been shown, which indicates the triggering of powerful protective mechanisms that counteract oxidative stress during reperfusion. The studies of a degree of reperfusion-induced injuries, manifested as a change in the mitochondrial membrane permeability, showed that hydrogen sulfide donor helped to preserve the integrity of the organelle membranes. A decrease in the MPTP sensitivity to Ca2+, an inducer of its opening, under a single intraperitoneal administration of NaHS and L- cysteine to rats has been observed for the first time. NaHS at concentrations of 10-9, 10-8, mol / l evokes a decrease in the rate of oxygen uptake by the heart mitochondria of adult animals at states 3 and 4 (by Chance). This is accompanied by an increase in oxidation/phosphorylation coupling, as evidenced by an increase in respiratory control and ADP/O ratio, which indicates t the cardioprotective effect of NaHS on the functional state of the respiratory chain. Thus, H2S is an important regulatory molecule in the cardiovascular system both in physiological and pathological states.