Contribution of K V 1.5 Channel to Hydrogen Peroxide-Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease.

RATIONALE: Hydrogen peroxide (H2 O2 ) 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 H2 O2 -elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.

METHODS AND RESULTS: H2 O2 induced 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 KV 1.5 is the major KV 1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective KV 1.5 blocker diphenylphosphine oxide-1 and the KV 1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H2 O2 -elicited dilation to a similar extent as 4-aminopyridine, but the selective KV 1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H2 O2 -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. KV 1.5 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, H2 O2 -induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca2+ -activated K+ - and KV (KV 1.5)-mediated vasodilation toward a large-conductance Ca2+ -activated K+ -predominant mechanism of dilation. Loss of KV 1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.