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.

Cardiovascular consequences of metabolic syndrome

“…(84) Importantly, these changes occur prior to any evidence of overt atherosclerotic disease and have been associated with diminished diastolic and systolic contractile function in obese/MetS in humans(47, 86, 87) and in animal models. (20, 57, 88) These findings indicate that underlying coronary microvascular dysfunction likely contributes to reductions in cardiac contractile function,(45, 47, 48, 51) to concentric ventricular hypertrophy,(41, 44-48, 89) and to the significant increases in risk of myocardial infarction(17) and cardiovascular mortality(8, 90, 91) observed in obese individuals with the MetS.…”

“…(102) MetS is also associated with alterations in the functional expression of, and electromechanical coupling between, voltage-dependent K + and Ca 2+ channels. (7, 83, 84, 88, 103, 104) Continued research to elucidate the precise mechanisms responsible for the deleterious impact of the MetS on microvascular function is needed, and stands to provide novel targets for directed therapies needed to treat the pathologic consequences of this multifactorial syndrome.…”

Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation

“…The increase in baseline flow in this group of metabolic syndrome swine is puzzling but could be related to alterations in substrate utilization, internal work of the myocardium, and/or cardiac efficiency. Although these variables were not assessed in this group of animals, a recent study by our laboratory found that a trend for an increase in baseline flow in conscious, metabolic syndrome swine was associated with a reduction in average lactate uptake and cardiac index with no difference in myocardial oxygen consumption, i.e., altered substrate utilization and cardiac efficiency (5). It is important to recognize that the 21 Ϯ 1% stenosis in metabolic syndrome swine did not limit flow during hyperemia, since the peak hyperemic response (i.e., the minimum vascular resistance) and volume of repayment were not different between lean and metabolic syndrome swine (Table 2).…”

Mycotoxins, in a Prospection in the Causes and Treatment of Metabolic Syndrome

“…Coronary vascular dysfunction in MetS is related to impaired BK (Ca) channel function and is accompanied by significant increases in L-type Ca 2+ channel-mediated coronary vasoconstriction [5]. In another study of this research group, penitrem A (10µg/kg, i.v) revealed that the exercise-induced increases in blood pressure were significantly elevated in MetS swine [6]. and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers.…”