Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

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 in 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 (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) 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) and sodium sulfide (10^-5-10¹ mol/L) using intradermal microdialysis; the functional role of H₂S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). 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 adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-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.