Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels

Asif K. Mustafa, Gautam Sikka, Sadia K. Gazi, Jochen Steppan, Sung M. Jung, Anil K. Bhunia, Viachaslau M. Barodka, Farah K. Gazi, Roxanne K. Barrow, Rui Wang, L. Mario Amzel, Dan E. Berkowitz, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)1259-1268
Number of pages10
JournalCirculation research
Volume109
Issue number11
DOIs
StatePublished - Nov 11 2011

Keywords

  • EDHF
  • hydrogen sulfide
  • hyperpolarization
  • potassium channel
  • sulfhydration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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