Abstract

Rationale: Nitric oxide, the classic endothelium-derived relaxing factor (EDRF), acts through cyclic GMP and calcium without notably affecting membrane potential. A major component of EDRF activity derives from hyperpolarization and is termed endothelium-derived hyperpolarizing factor (EDHF). Hydrogen sulfide (H 2 S) is a prominent EDRF, since mice lacking its biosynthetic enzyme, cystathionine γ-lyase (CSE), display pronounced hypertension with deficient vasorelaxant responses to acetylcholine. Objective: The purpose of this study was to determine if H 2 S is a major physiological EDHF. Methods and Results: We now show that H 2 S is a major EDHF because in blood vessels of CSE-deleted mice, hyperpolarization is virtually abolished. H 2 S acts by covalently modifying (sulfhydrating) the ATP-sensitive potassium channel, as mutating the site of sulfhydration prevents H 2 S-elicited hyperpolarization. The endothelial intermediate conductance (IK Ca ) and small conductance (SK Ca ) potassium channels mediate in part the effects of H 2 S, as selective IK Ca and SK Ca channel inhibitors, charybdotoxin and apamin, inhibit glibenclamide-insensitive, H 2 S-induced vasorelaxation. Conclusions: H 2 S is a major EDHF that causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating the ATP-sensitive, intermediate conductance and small conductance potassium channels through cysteine S -sulfhydration. Because EDHF activity is a principal determinant of vasorelaxation in numerous vascular beds, drugs influencing H 2 S biosynthesis offer therapeutic potential.