Impaired function of coronary BK_Ca channels in metabolic syndrome

The role of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels in regulation of coronary microvascular function is widely appreciated, but molecular and functional changes underlying the deleterious influence of metabolic syndrome (MetS) have not been determined. Male Ossabaw miniature swine consumed for 3-6 mo a normal diet (11% kcal from fat) or an excess-calorie atherogenic diet that induces MetS (45% kcal from fat, 2% cholesterol, 20% kcal from fructose). MetS significantly impaired coronary vasodilation to the BKCa opener NS-1619 in vivo (30-100 μg) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 μM). MetS reduced whole cell penitrem A (1 μM)-sensitive K⁺ current and NS-1619-activated (10 μM) current in isolated coronary vascular smooth muscle cells. MetS increased the concentration of free intracellular Ca²⁺ and augmented coronary vasoconstriction to the L-type Ca²⁺ channel agonist BAY K 8644 (10 pM-10 nM). BK_Ca channel α and β1 protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BK_Ca channel function and is accompanied by significant increases in L-type Ca²⁺ channel-mediated coronary vasoconstriction.