Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Abstract

Rationale: Hydrogen peroxide (H 2 O 2 ) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca 2+ -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 H 2 O 2 -elicited dilation involves different K + channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. Methods and Results: H 2 O 2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca 2+ -activated K + channel blocker, and by 4-aminopyridine, a voltage-gated K + (K V ) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that K V 1.5 is the major K V 1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective K V 1.5 blocker diphenylphosphine oxide-1 and the K V 1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H 2 O 2 -elicited dilation to a similar extent as 4-aminopyridine, but the selective K V 1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H 2 O 2 -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. K V 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, H 2 O 2 -induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca 2+ -activated K + - and K V (K V 1.5)-mediated vasodilation toward a large-conductance Ca 2+ –activated K + –predominant mechanism of dilation. Loss of K V 1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.