Contribution of BK(Ca) channels to local metabolic coronary vasodilation: Effects of metabolic syndrome

Abstract

This investigation was designed to examine the hypothesis that impaired function of coronary microvascular large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in metabolic syndrome (MetS) significantly attenuates the balance between myocardial oxygen delivery and metabolism at rest and during exercise-induced increases in myocardial oxygen consumption (MVo(2)). Studies were conducted in conscious, chronically instrumented Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) that induces many common features of MetS. Data were collected under baseline/resting conditions and during graded treadmill exercise before and after selective blockade of BK(Ca) channels with penitrem A (10 microg/kg iv). We found that the exercise-induced increases in blood pressure were significantly elevated in MetS swine. No differences in baseline cardiac function or heart rate were noted. Induction of MetS produced a parallel downward shift in the relationship between coronary venous Po(2) and MVo(2) (P < 0.001) that was accompanied by a marked release of lactate (negative lactate uptake) as MVo(2) was increased with exercise (P < 0.005). Inhibition of BK(Ca) channels with penitrem A did not significantly affect blood pressure, heart rate, or the relationship between coronary venous Po(2) and MVo(2) in lean or MetS swine. These data indicate that BK(Ca) channels are not required for local metabolic control of coronary blood flow under physiological (lean) or pathophysiological (MetS) conditions. Therefore, diminished function of BK(Ca) channels does not contribute to the impairment of myocardial oxygen-supply demand balance in MetS.

Fig. 1.

Metabolic syndrome (MetS) atherosclerosis is not occlusive. A: representative intravascular ultrasound (IVUS) image of lean left anterior descending (LAD) artery demonstrating method of determining percent wall coverage. B: representative IVUS image of MetS LAD demonstrating method of determining percent stenosis. The 13% stenosis corresponds to 56% wall coverage in this example. C: atherosclerosis is increased in MetS LAD compared with lean. D: %stenosis at the site of maximum atherosclerosis in the LAD demonstrates atherosclerosis in MetS is not flow-limiting. *P < 0.05, Lean vs. MetS.

Fig. 2.

Effect of MetS on mean aortic pressure (A) and heart rate (B) at rest and during graded treadmill exercise. Mean aortic pressure was not different at rest but was elevated with exercise intensity in MetS relative to lean swine. No differences in heart rate were noted between lean and MetS swine at rest or during exercise.

Fig. 3.

Effect of MetS on the relationship between myocardial oxygen consumption and coronary venous Po₂ (A) and myocardial lactate uptake (B). The relationship between coronary venous Po₂ and myocardial oxygen consumption revealed a parallel downward shift in coronary venous Po₂ at a given level of myocardial oxygen consumption in MetS swine. This impairment of myocardial oxygen supply-demand balance was accompanied by a marked release of lactate (negative lactate uptake) in MetS swine as myocardial oxygen consumption was elevated.

Fig. 4.

Representative 2-dimensional (2-D) guided M-mode echocardiograms through the midleft ventricular level in lean and MetS swine. M-mode echocardiograms showed no significant difference in cardiac fractional shortening, end-diastolic dimension (EDD), or end-systolic dimension (ESD) between lean and MetS swine at rest. AW, anterior wall; PW, posterior wall.

Fig. 5.

Effect of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel inhibition on the relationship between coronary venous Po₂ and myocardial oxygen consumption in lean (A) and MetS (B) swine. Inhibition of BK_Ca channels with penitrem A did not significantly affect the relationship between coronary venous Po₂ and myocardial oxygen consumption in either lean or MetS swine.