Статеві відмінності H2S-ініційованої вазодилятації аорти за умов гіпергомоцистеїнемії

Abstract

Досліджено вплив гіпергомоцистеїнемії (ГГЦ) на ініційовану гідроген сульфідом (H2S) вазодилятацію аорти у самців та самок щурів. Встановлено, що у самців чутливість аорти до H2S-індукованої вазодилятації вірогідно менша, ніж у самок. Введення тіолактону гомоцистеїну (100 мг/кг 28 діб інтрагастрально) викликає достовірне зменшення H2S-індукованої вазодилятації аорти у щурів обох статей, причому у самців вказані зміни були більш виразними. На тлі ГГЦ відмічається поглиблення статевих відмінностей чутливості аорти до вазодилятуючої дії H2S; Исследовано влияние гипергомоцистеинемии (ГГЦ) на инициированную гидроген сульфидом (H2S) вазодилятацию аорты у самцов и самок крыс. Установлено, что у самцов чувствительность аорты к H2S-индуцированной вазодилятации достоверно меньше, чем у самок. Введение тиолактона гомоцистеина (100 мг/кг 28 суток интрагастрально) вызывает достоверное уменьшение H2S-индуцированной вазодилятации аорты у крыс обоего пола, причем у самцов указанные изменения были более выраженными. На фоне ГГЦ отмечается усиление половых различий чувствительности аорты к вазодилятирующему действию H2S; Hyperhomocysteinemia is a recognized independent risk factor for vascular diseases and is implicated in pathological vascular remodeling, activation of systemic inflammation, thrombogenesis, and so on. Among the pathophysiological mechanisms of endotheliotoxic action of high concentrations of homocysteine there are hypomethylation, oxidative stress, homocysteinylation of proteins, endoplasmatic-reticular stress etc. It is known, that the regulation of vascular tone is significantly different in individuals of different sex, for the most part it is determined by the different biological effects of testosterone and estrogen. However, the sexual features of hyperhomocysteinemia influence on vascular tone remain unexplored. The aim of the study is to evaluate the influence of hyperhomocysteinemia on H2S-initiated vasodilation of aorta in male and female rats. The experiments were performed on 40 white laboratory rats of both sexes weighing 220-280 g. The model of hyperhomocysteinemia was created by introducing of thiolactone D, L-homocysteine (Sigma, USA) intraperitoneally at a dose of 100 mg/kg on 1% starch solution, 1 time a day during 28 days. Registration of contractility of thoracic aorta circular fragments was performed in a model system in vitro. First, we evaluated H2S-stimulated relaxation of aortic rings in male and female rats. It turned out that in the males H2S concentrations of 1 μМ, 10 μМ, 100 μМ and 1000 μМ caused a dose-dependent relaxation of circular fragments of aorta, respectively by 5,93±0,58%; 10,9±0,69%; 29,6±1,23% and 57.0±1,10%. At the same time, females have a relaxation of the aortic rings in these concentrations of H2S was greater and was accordingly 6,39±0,24%; 12,7±0,65%; 34,7±1,49% (р<0,05) and 61.5±0,54% (р<0,05). Under these conditions ЕС50 H2S in aorta in males was 94,1±4,28 μМ and in females was by 21,5% (р<0,05) less and was 73,9±4,35 μМ. Hyperhomocysteinemia is accompanied by a reliable decrease in H2S-induced relaxation of aorta in male and female rats. In males relaxation of aortic rings under the indicated concentration of H2S was less by 24,5; 35,2; 63,2 and 29,3% (р<0,05), and of ЕС50 H2S in aorta – more by 32,8% (р<0,05) than in the control group. At the same time, in females hyperhomocysteinemia caused less pronounced changes of H2S-induced relaxation: reduction of relaxation of circumferential aortic fragments in these concentrations of H2S was 12,8; 16,5; 14,7 and 9,4% (р<0,05), and increase of ЕС50 H2S in aorta – 21,1% (р<0,05) compared to the control group. Clarification of molecular mechanisms of sex differences in the regulation of vascular tone under conditions of hyperhomocysteinemia will allow to develop approaches for effective correction of the vascular pathology associated with impaired metabolism of sulfur-containing amino acids in individuals of different sexes. It is established that in males the sensitivity of aorta to H2S-induced vasodilatation is significantly lower than in females. Introduction to thiolactone homocysteine (100 mg/kg during 28 days, intragastrically) causes significant decrease in H2S-induced vasodilatation of aorta in rats of both sexes, and in males these changes were more expressive. On the background of hyperhomocysteinemia there are sex differences in sensitivity of aorta to vasodilatory action of H2S.