Contribution of K1.5 Channel to Hydrogen Peroxide-Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease.

RATIONALE

Hydrogen peroxide (HO) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca-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 HO-elicited dilation involves different K channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.

METHODS AND RESULTS

HO induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca-activated K channel blocker, and by 4-aminopyridine, a voltage-gated K (K) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that K1.5 is the major K1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective K1.5 blocker diphenylphosphine oxide-1 and the K1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced HO-elicited dilation to a similar extent as 4-aminopyridine, but the selective K1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, HO-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. K1.5 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, HO-induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca-activated K- and K (K1.5)-mediated vasodilation toward a large-conductance Ca-activated K-predominant mechanism of dilation. Loss of K1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.