Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes

Abstract

BackgroundStatins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown.MethodsPig 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.ResultsThe 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 KATP 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.ConclusionsSimvastatin 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 KATP channels, and phosphorylation of AMPKα-Thr172 and PP2A-Tyr307 resulted. Phosphorylation of PP2A-Tyr307 occurs at a site downstream of AMPKα-Thr172 phosphorylation.

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle

“…Thus, statin treatment is able to change pharmacological properties of BK channel, this result being consistent with previous reports. In particular, simvastatin was reported to markedly attenuated isopimaric acid-induced enhancement of the BK whole-cell current and cromakalim-induced K ATP current in porcine coronary artery smooth muscle [56,57]. However, the effect was observed upon acute simvastatin application, while our data mimic clinically relevant scenario when statins are administered persistently over an extended period of time.…”

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

“…Presynaptic changes at the transmitter release site affect mEPSC frequency, whereas changes at the postsynaptic membrane alter mEPSC amplitude (quantal size) (Toyoda et al, 2009;Han et al, 2010).We recorded mEPSCs in the CeLC in the presence of 1 mM tetrodotoxin. KN93 (10 mM) (Goforth et al, 2004;Shen et al, 2009;Seto et al, 2013) significantly decreased both the frequency (Fig. 5C) and amplitude (Fig.…”

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

“…After the contraction had reached a plateau, 10 μM simvastatin was added and changes in tone measured over 2 h. In some experiments, to evaluate the role of K + channels, the segments were incubated with the non-selective K + channel blocker tetraethylammonium (TEA; 10 mM), or the K ATP channel blocker glibenclamide (3 μM), or the mitochondrial K ATP channel inhibitor 5-hydroxydecanoate (1 mM; Jones et al, 2003) for 60 min prior to precontraction with U46619. The role of AMP kinase was determined by pre-incubation with the AMP kinase inhibitor dorsomorphin (10 μM; Seto et al, 2013).…”