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

Abstract

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, 0.3mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of K(V) channels also increased aortic pressure (P<0.01) while reducing coronary venous PO(2) (P<0.01) at a given level of myocardial oxygen consumption (MVO(2)). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO(2) in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~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 MVO(2). 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".

Figure 1

Effect of K_V channel inhibition on the relationship between coronary venous Po₂ and myocardial oxygen consumption in lean (A) and MetS (B) swine. Inhibition of K_V channels with 4-aminopyridine (4-AP) significantly reduced coronary venous Po₂ at a given level of metabolism in lean (P < 0.01) but not MetS swine (P = 0.84). The slope of this relationship was also significantly decreased in untreated lean vs. MetS swine (P < 0.02).

Figure 2

Whole-cell voltage-dependent K⁺ current in coronary smooth muscle of lean and MetS swine. (A) Families of current traces from representative cells of lean and MetS pigs. Voltage template is 400 ms long. K_V channels produce characteristic tail currents upon repolarization of the membrane (inset), the magnitude of which was reduced in cells from MetS pigs. (B) Group I-V data demonstrate a significant reduction in outward K⁺ current at potentials greater than 0 mV, i.e. currents biophysically consistent with K_V channels. (C) Group G-V curves derived from tail currents at −40 mV. The voltage-sensitivity of the currents were not different (voltage of half activation and slope factor of −6 ± 1 mV and 8 ± 1 vs. −8 ± mV and 8 ± 1 in control and MetS pigs, respectively. * P < 0.01 vs. lean, same voltage.

Figure 3

Expression of K_V1.5 and K_V3.1 channels in coronary arteries of lean and MetS swine. (A) Western blot analysis demonstrated a significant reduction in K_V1.5 channel protein expression in coronary arteries from MetS swine. (B) Expression of coronary K_V3.1 channel protein was not significantly affected by induction of MetS (P = 0.36). * P < 0.05 vs. lean.