title: Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation.
abstract: Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca(2+)-activated K(+) channels and inward rectifier K(+) channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.
authors.affiliation: Department of Physiology, Institute of Functional Genomics, Research Institute of Medical Science, School of Medicine, Konkuk University, Choongju, 380-701, Korea.
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Park
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Noh
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Sung
authors.forename: Jae Gon
authors.initials: JG
authors.lastname: Kim
authors.forename: Jeong Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Ryu
authors.forename: KyeongJin
authors.initials: K
authors.lastname: Kang
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D006861:Hydrogen Peroxide; D015761:4-Aminopyridine; D005980:Glutathione Reductase; D005978:Glutathione
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