Cigarette smoking impairs Na+-K+-ATPase activity in the human coronary microcirculation

Abstract

The extracellular K+ concentration ([K+]o) has been proposed to link cardiac metabolism with coronary perfusion and arrhythmogenesis, particularly during ischemia. Several animal studies have also supported K+ as an EDHF that activates Na+-K+-ATPase and/or inwardly rectifying K+ (Kir) channels. Therefore, we examined the vascular reactivity of human coronary arterioles (HCAs) to small elevations in [K+]o, the influence of risk factors for coronary disease, and the role of K+ as an EDHF. Changes in the internal diameter of HCAs were recorded with videomicroscopy. Most vessels dilated to increases in [K+]o with a maximal dilation of 55 ± 6% primarily at 12.5–20.0 mM KCl ( n = 38, average: 16 ± 1 mM). Ouabain, a Na+-K+-ATPase inhibitor, alone reduced the dilation, and the addition of Ba2+, a Kir channel blocker, abolished the remaining dilation, whereas neither endothelial denudation nor Ba2+ alone reduced the dilation. Multivariate analysis revealed that cigarette smoking was the only risk factor associated with impaired dilation to K+. Ouabain significantly reduced the vasodilation in HCAs from subjects without cigarette smoking but not in those with smoking. Cigarette smoking downregulated the expression of the Na+-K+-ATPase catalytic α1-subunit but not Kir2.1 in the vessels. Ouabain abolished the dilation in endothelium-denuded vessels to a same extent to that with the combination of ouabain and Ba2+ in endothelium-intact vessels, whereas neither ouabain nor ouabain plus Ba2+ reduced EDHF-mediated dilations to bradykinin and ADP. A rise in [K+]o dilates HCAs primarily via the activation of Na+-K+-ATPase in vascular smooth muscle cells with a considerable contribution of Kir channels in the endothelium, indicating that [K+]o may modify coronary microvascular resistance in humans. Na+-K+-ATPase activity is impaired in subjects who smoke, possibly contributing to dysregulation of the coronary microcirculation, excess ischemia, and arrhythmogenesis in those subjects. K+ does not likely serve as an EDHF in the human coronary arteriolar dilation to bradykinin and ADP.