OP23 Role of hydrogen sulfide in leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats

Abstract

The adipose tissue hormone, leptin, is involved in the pathogenesis of cardiovascular complications of obesity/metabolic syndrome such as hypertension and atherosclerosis [1] . Previously, it has been demonstrated that leptin induces nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-dependent vasorelaxation and that in the short-lasting obesity its NO-mediated vasodilating effect is impaired and EDHF-mediated effect is enhanced [2] , [3] . Recently, H2S was identified as the EDHF in some blood vessels [4] . In the present study we examined if alterations of vascular effects of acutely administered leptin observed in obesity are accounted for by chronic hyperleptinemia and we aimed to elucidate the mechanism of leptin-induced EDHF in peripheral arteries. The study was performed in male Wistar rats divided into five groups: (1) control, (2) leptin-treated, in which hyperleptinemia was induced by administration of exogenous leptin (0.5 mg/kg/day for 7 days), (3) obese, fed highly palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin antagonist (PEG-SRLA, 7 mg/kg/day) for the last week, (5) lean rats treated with PEG-SRLA. Leptin-induced relaxation of phenylephrine-preconstricted mesenteric artery segments was examined in all groups by measuring isometric tension. Leptin induced endothelium-dependent vasorelaxation which was partially attenuated by NO synthase inhibitor, L-NAME, and partially by the mixture of apamin and TRAM-34 which are antagonists of SKCa and IKCa channels and block EDHF-mediated response. Total vasodilating effect of leptin was similar in all groups. However, in leptin-treated and obese groups NO-dependent component was impaired and EDHF-dependent component was augmented. PEG-SRLA reversed these changes in obese rats but had no effect in lean animals. EDHF-mediated component of leptin-induced vasorelaxation was abolished by propargylglycine – the inhibitor of H2S-generating enzyme cystathionine γ-lyase as well as by H2S scavenger, bismuth (III) subsalicylate. Synthetic H2S donor, GYY4137, induced concentration-dependent vasorelaxation which was partially endothelium-dependent, and this endothelium-dependent component was abolished by apamin and TRAM-34. The sensitivy to GYY4137-induced vasorelaxation was enhanced in leptin-treated and obese rats which, in the latter group, was prevented by PEG-SRLA. In conclusion, NO-dependent component of leptin-induced vasorelaxation is impaired in short-lasting obesity but this is compensated by up-regulation of EDHF. Both effects are accounted for by chronic hyperleptinemia. EDHF-dependent component of leptin-induced vasorelaxation is mediated by H2S which activates endothelial SKCa and IKCa channels. Increase in EDHF in hyperleptinemic and obese rats is accounted for, at least in part, by greater sensitivity of endothelium to H2S.