Contribution of K_V1.5 Channel to Hydrogen Peroxide-Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease.

Abstract

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. We hypothesize that H₂O₂-elicited dilation involves different K⁺ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. H₂O₂ 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⁺ (K_V) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that K_V1.5 is the major K_V1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective K_V1.5 blocker diphenylphosphine oxide-1 and the K_V1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H₂O₂-elicited dilation to a similar extent as 4-aminopyridine, but the selective K_V1.3 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. K_V1.5 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. 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 K_V (K_V1.5)-mediated vasodilation toward a large-conductance Ca²⁺-activated K⁺-predominant mechanism of dilation. Loss of K_V1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.