title: Contribution of KV1.5 Channel to Hydrogen Peroxide-Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease.
abstract: BACKGROUND
  Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca2+-activated K+channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) when compared with those with CAD remain unknown.
  
  
  OBJECTIVE
  We hypothesize that H2O2-elicited dilation involves different K+channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.
  
  
  RESULTS
  H2O2induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca2+-activated K+channel blocker, and by 4-aminopyridine, a voltage-gated K+(KV) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective KV1.5 blocker diphenylphosphine oxide-1 and the KV1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H2O2-elicited dilation to a similar extent as 4-aminopyridine, but the selective KV1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced, and this dilation was inhibited by paxilline but not by 4-aminopyridine, diphenylphosphine oxide-1, or 5-(4-phenylbutoxy)psoralen. KV1.5 cell membrane localization and diphenylphosphine oxide-1-sensitive K+currents were markedly reduced in isolated vascular smooth muscle cells from CAD arterioles, although mRNA or total cellular protein expression was largely unchanged.
  
  
  CONCLUSIONS
  In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca2+-activated K+- and KV(KV1.5)-mediated vasodilation toward a large-conductance Ca2+-activated K+-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Dawid S
authors.initials: DS
authors.lastname: Chabowski
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Ankush
authors.initials: A
authors.lastname: Korishettar
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Alyce
authors.initials: A
authors.lastname: Ge
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: Rodney
authors.initials: R
authors.lastname: Sparapani
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI.
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.affiliation: From the Department of Medicine (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Cardiovascular Center (Y.N., S.C., D.S.C., A.K., A.G., X.Z., D.D.G., D.X.Z.), Department of Pharmacology and Toxicology (D.S.C., A.K.), Division of Biostatistics (R.S.), Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center (D.D.G.), Milwaukee, WI. xfzhang@mcw.edu.
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D001160:Arterioles / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000473:pathology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D006861:Hydrogen Peroxide
keywords: arterioles; endothelium; hydrogen peroxide; potassium channels; vasodilation