Contribution of voltage-dependent K+ channels to metabolic control of coronary blood flow

The purpose of this investigation was to test the hypothesis that K-V channels contribute to metabolic control of coronary blood flow and that decreases in K-V channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of K-V channels with 4-aminopyridine (4-AP, 0.3 mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow similar to 15% at rest and similar to 20% during exercise. Inhibition of K-V channels also increased aortic pressure (P<0.01) while reducing coronary venous PO2 (P<0.01) at a given level of myocardial oxygen consumption (MVO2). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO2 in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a similar to 20% reduction in coronary K-V current (P<0.01) and decreased expression of K(V)1.5 channels in coronary arteries (P<0.01). Together, these data demonstrate that K-V channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVO2. Our findings also indicate that decreases in K-V channel current and expression contribute to impaired control of coronary blood flow in the MetS. This article is part of a Special Issue entitled "Coronary Blood Flow". (C) 2011 Elsevier Ltd. All rights reserved.