title: 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(+) (K(ir)) 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 Ba(2+), a K(ir) channel blocker, abolished the remaining dilation, whereas neither endothelial denudation nor Ba(2+) 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 α(1)-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 Ba(2+) in endothelium-intact vessels, whereas neither ouabain nor ouabain plus Ba(2+) 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 K(ir) 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.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. hmiura@medicine.nevada.edu
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Toyama
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Pratt
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001685:Biological Factors / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D015999:Multivariate Analysis; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase