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 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.
Original language | English (US) |
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Pages (from-to) | 1259-1268 |
Number of pages | 10 |
Journal | Circulation research |
Volume | 109 |
Issue number | 11 |
DOIs | |
State | Published - Nov 11 2011 |
Keywords
- EDHF
- hydrogen sulfide
- hyperpolarization
- potassium channel
- sulfhydration
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine