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 Barodka, Farah K. Gazi, Roxanne K Barrow, Rui Wang, Mario L Amzel, Dan E Berkowitz, Solomon H Snyder

Research output: Contribution to journalArticle

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

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Hydrogen Sulfide
Potassium Channels
Endothelium
Endothelium-Dependent Relaxing Factors
Cystathionine
Vasodilation
Lyases
Blood Vessels
Small-Conductance Calcium-Activated Potassium Channels
Charybdotoxin
Apamin
KATP Channels
Glyburide
Cyclic GMP
Vasodilator Agents
Vascular Smooth Muscle
Membrane Potentials
Acetylcholine
Smooth Muscle Myocytes
Cysteine

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. / Mustafa, Asif K.; Sikka, Gautam; Gazi, Sadia K.; Steppan, Jochen; Jung, Sung M.; Bhunia, Anil K.; Barodka, Viachaslau; Gazi, Farah K.; Barrow, Roxanne K; Wang, Rui; Amzel, Mario L; Berkowitz, Dan E; Snyder, Solomon H.

In: Circulation Research, Vol. 109, No. 11, 11.11.2011, p. 1259-1268.

Research output: Contribution to journalArticle

Mustafa, Asif K. ; Sikka, Gautam ; Gazi, Sadia K. ; Steppan, Jochen ; Jung, Sung M. ; Bhunia, Anil K. ; Barodka, Viachaslau ; Gazi, Farah K. ; Barrow, Roxanne K ; Wang, Rui ; Amzel, Mario L ; Berkowitz, Dan E ; Snyder, Solomon H. / Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. In: Circulation Research. 2011 ; Vol. 109, No. 11. pp. 1259-1268.
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AU - Gazi, Sadia K.

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AU - Jung, Sung M.

AU - Bhunia, Anil K.

AU - Barodka, Viachaslau

AU - Gazi, Farah K.

AU - Barrow, Roxanne K

AU - Wang, Rui

AU - Amzel, Mario L

AU - Berkowitz, Dan E

AU - Snyder, Solomon H

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