Acute Simvastatin Inhibits K_ATP Channels of Porcine Coronary Artery Myocytes

Background:Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular K_ATP channel gatings are unknown.Methods:Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca²⁺]_i, [ATP]_i and [glucose]_o uptake measurements.Results:The cromakalim (10 nM to 10 μM)- and pinacidil (10 nM to 10 μM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 μM). Simvastatin (1, 3 and 10 μM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 μM)- and pinacidil (10 μM)-mediated opening of whole-cell K_ATP channels of arterial myocytes. Simvastatin (10 μM) and AICAR (1 mM) elicited a time-dependent, compound C (1 μM)-sensitive [³H]-2-deoxy-glucose uptake and an increase in [ATP]_i levels. A time (2-30 min)- and concentration (0.1-10 μM)-dependent increase by simvastatin of p-AMPKα-Thr¹⁷² and p-PP2A-Tyr³⁰⁷ expression was observed. The enhanced p-AMPKα-Thr¹⁷² expression was inhibited by compound C, ryanodine (100 μM) and KN93 (10 μM). Simvastatin-induced p-PP2A-Tyr³⁰⁷ expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 μM), and in [glucose]_o-free or [Na⁺]_o-free conditions.Conclusions:Simvastatin causes ryanodine-sensitive Ca²⁺ release which is important for AMPKα-Thr¹⁷² phosphorylation via Ca²⁺/CaMK II. AMPKα-Thr¹⁷² phosphorylation causes [glucose]_o uptake (and an [ATP]_i increase), closure of K_ATP channels, and phosphorylation of AMPKα-Thr¹⁷² and PP2A-Tyr³⁰⁷ resulted. Phosphorylation of PP2A-Tyr³⁰⁷ occurs at a site downstream of AMPKα-Thr¹⁷² phosphorylation.