Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels

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 ₂S) 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 ₂S is a major physiological EDHF. Methods and Results: We now show that H ₂S is a major EDHF because in blood vessels of CSE-deleted mice, hyperpolarization is virtually abolished. H ₂S acts by covalently modifying (sulfhydrating) the ATP-sensitive potassium channel, as mutating the site of sulfhydration prevents H ₂S-elicited hyperpolarization. The endothelial intermediate conductance (IK _Ca) and small conductance (SK _Ca) potassium channels mediate in part the effects of H ₂S, as selective IK _Ca and SK _Ca channel inhibitors, charybdotoxin and apamin, inhibit glibenclamide-insensitive, H ₂S-induced vasorelaxation. Conclusions: H ₂S 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 ₂S biosynthesis offer therapeutic potential.