Impaired function of coronary BKCachannels in metabolic syndrome

Abstract

The role of large-conductance Ca2+-activated K+(BKCa) 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 BKCaopener 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). BKCachannel α and β1protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BKCachannel function and is accompanied by significant increases in L-type Ca2+channel-mediated coronary vasoconstriction.