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

Abstract

This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Studies were conducted in anesthetized miniature 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) for 20 wk. The latter diet induces metabolic syndrome, increasing body weight, fasting glucose, total cholesterol, and triglyceride levels. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Coronary reactive hyperemia was diminished by metabolic syndrome as the repayment of flow debt was reduced approximately 30% compared with lean swine. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. Subsequent inhibition of K(V) channels significantly reduced the repayment of flow debt ( approximately 25%) in both lean and metabolic syndrome swine. Additional blockade of K(ATP) channels further diminished ( approximately 45%) the repayment of flow debt in lean but not metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia.

Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes

“…Coronary vascular alterations have been studied extensively in high-fat-fed prediabetic large animal models, including both dogs (33,36,58) and pigs (9,10,44), the results of which could be of value for patients with the metabolic syndrome (32). Also, atherosclerotic DM porcine models have been developed and successfully employed (16,17,23,37,41,63).…”

Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+Channels in Vascular Function

“…An alternative explanation is that BK channels may play a minimal role in regulating total peripheral resistance. Thus, the power of traditional pharmacological approaches to inhibit BK channels to elucidate a mechanism of action should not be underestimated, because we (Borbouse et al, 2009(Borbouse et al, , 2010a and others (Node et al, 1997) have demonstrated previously little, if any role, for BK channels in regulating coronary vascular tone by using penitrem A, charybdotoxin, or iberiotoxin. No comparable studies of organ blood flow are available for BK channel subunit knockout mice, probably because of the difficulty of instrumenting small animals.…”

“…1). In addition, the use of penitrem A to study BK channels has been, until recently (Borbouse et al, 2009(Borbouse et al, , 2010a, limited to in vitro studies, particularly patch-clamp experiments. Thus, we further investigated penitrem A as a BK channel inhibitor to assess vascular function in vitro and in vivo.…”

BKCa channels as physiological regulators: a focused review

“…80 Inhibition of BK Ca channels by these G-protein-coupled receptors may alter several of the downstream signaling cascade, mainly protein kinase C 44 , c-Src kinase, 42 and so on. However, studies designed to explore the role of BK Ca channels in ischemic 81 and metabolic vasodilation 82 showed no or little effect. Nevertheless, alterations in the activity of BK Ca channels were demonstrated in several vascular pathologies, including diabetes, 20,83,84 atherosclerosis and ischemia, 85 hypertension, 25,51,76 cardiac hypertrophy, 15 and cardiomyopathy.…”