Impaired hydrogen sulfide-mediated vasodilation contributes to microvascular endothelial dysfunction in hypertensive adults

摘要

Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (Na2S) would be attenuated in HTN compared to normotensive (NTN) adults. Fifteen NTN [51±2 yrs; blood pressure (BP) 116±3/76±3 mmHg] and 14 HTN adults (57±2 yrs; BP 140±3/89±2 mmHg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10⁻⁶ –10⁻¹ mol∙L⁻¹) and Na2S (10⁻⁵–10¹ mol∙L⁻¹) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (AOAA; 0.5 mmol∙L⁻¹). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all p<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN compared to NTN adults (p=0.012). AOAA attenuated ACh-induced vasodilation in NTN adults (ACh: 1.31±0.13 vs. ACh+AOAA: 1.07±0.09 flux∙mmHg⁻¹; P=0.025) but had no effect on vasodilation in HTN adults (ACh: 1.16±0.10 v. ACh+AOAA: 1.37±0.11 flux∙mmHg⁻¹; p=0.47). Na2S-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.