Abnormal regulation of vascular tone plays an important role in the pathogenesis of obesity-associated hypertension. We examined the effect of leptin on vascular tone in lean and obese rats. Male Wister rats were fed either standard diet (control group) or highly-palatable diet to induce obesity for either 1 or 3 months (obese O1 and O3 groups). Effect of leptin on vascular tone of phenylephrine-reconstructed mesenteric artery rings was examined. In addition, membrane potential of cultured endothelial cells isolated from these three groups of animals was measured by potential sensitive euros cent probe. The effect of leptin on hydrogen sul.de (H2S) production by endothelial cells was measured by sul.de-sensitive microelectrode. Leptin induced con- centration-dependent relaxation of mesenteric artery rings and its effect was blocked by NO synthase inhibitor, L-NAME, as well as by small- and intermediate-conductance Ca2+-activated K+ channels inhibitors, apamin and TRAM-34, indicating that vascular effect of leptin is mediated by both NO and endothelium-dependent hyperpolarization. The latter component was inhibited by H2S-synthesizing enzyme, cystathionine ƒ-lyase, inhibitor, propargylglycine, as well as by H2S scavenger, bismuth subsalicylate. The NO-dependent component of vascular effect of leptin was impaired in both obese groups whereas the EDH/H2S-dependent component was up-regulated in the O1 and impaired in the O3 group. Leptin increased H2S production by endothelial cells and induced cell hyperpolarization; these effects were impaired in the 3-month obesity. The results indicate that leptin induces NO- and H2S-dependent vasorelaxation and dietary- induced obesity has a time-dependent influence on vascular effect of leptin.
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