title: H₂S is an endothelium-derived hyperpolarizing factor.
abstract: OBJECTIVE
  Endothelium-dependent vasorelaxation is mediated by endothelium-derived relaxing factor and endothelium-derived hyperpolarizing factor (EDHF). However, the molecular entity of EDHF remains unclear. The present study examined whether hydrogen sulfide (H₂S) acts as EDHF and how H₂S mediates EDHF pathways from endothelial origination to downstream target of smooth muscle cells (SMCs).
  
  
  RESULTS
  We found that knocking-out the expression of cystathionine γ-lyase (CSE) in mice (CSE-knockout [KO]) elevated resting-membrane-potential of SMCs and eliminated methacholine-induced endothelium-dependent relaxation of mesenteric arteries, but not that of aorta. Methacholine, a cholinergic-muscarinic agonist, hyperpolarized SMC in endothelium-intact mesenteric arteries from wide-type mice. This effect was inhibited by muscarinic antagonist (atropine) or the co-application of charybdotoxin and apamin, which blocked intermediate- and small-conductance KCa (IKCa and SKCa) channels, or abolished in CSE-KO mice. Supplementation of exogenous H₂S hyperpolarized vascular SMCs and endothelial cells from wide-type and CSE-KO mice. Both methacholine and H₂S induced greater SMC hyperpolarization of female wide-type mesenteric arteries than that of male ones. H2S-induced hyperpolarization is blocked by -SH oxidants and -SSH inhibitor. The expression of SK2.3 but not IK3.1 channel in vascular tissues was increased by H₂S and decreased by CSE inhibitor or CSE gene KO.
  
  
  CONCLUSIONS
  Taken together, H₂S is an EDHF. The identification of H2S as an EDHF will not only solve one of the long-lasting perplexing puzzles for the mechanisms underlying endothelium-dependent vasorelaxation, but also shed light on potential therapeutic effects of H₂S on pathological abnormalities in peripheral resistance arteries.
authors: 1 Department of Biology, Lakehead University , Thunder Bay, Ontario, Canada .
authors: Guanghua
authors: G
authors: Tang
authors: Guangdong
authors: G
authors: Yang
authors: Bo
authors: B
authors: Jiang
authors: Youngjun
authors: Y
authors: Ju
authors: Lingyun
authors: L
authors: Wu
authors: Rui
authors: R
authors: Wang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001685:Biological Factors / Q000378:metabolism* / Q000494:pharmacology*; D015153:Blotting, Western; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003542:Cystathionine gamma-Lyase / Q000172:deficiency / Q000378:metabolism; D005260:Female; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects
chemical_list: D001685:Biological Factors; D016085:Bronchoconstrictor Agents; C067410:endothelium-dependent hyperpolarization factor; D016210:Methacholine Chloride; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide