title: Attenuation of acetylcholine activated potassium current (I KACh) by simvastatin, not pravastatin in mouse atrial cardiomyocyte: possible atrial fibrillation preventing effects of statin.
abstract: Statins, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are associated with the prevention of atrial fibrillation (AF) by pleiotropic effects. Recent clinical trial studies have demonstrated conflicting results on anti-arrhythmia between lipophilic and hydrophilic statins. However, the underlying mechanisms responsible for anti-arrhythmogenic effects of statins are largely unexplored. In this study, we evaluated the different roles of lipophilic and hydrophilic statins (simvastatin and pravastatin, respectively) in acetylcholine (100 µM)-activated K+ current (IKACh, recorded by nystatin-perforated whole cell patch clamp technique) which are important for AF initiation and maintenance in mouse atrial cardiomyocytes. Our results showed that simvastatin (1-10 µM) inhibited both peak and quasi-steady-state IKACh in a dose-dependent manner. In contrast, pravastatin (10 µM) had no effect on IKACh. Supplementation of substrates for the synthesis of cholesterol (mevalonate, geranylgeranyl pyrophosphate or farnesyl pyrophosphate) did not reverse the effect of simvastatin on IKACh, suggesting a cholesterol-independent effect on IKACh. Furthermore, supplementation of phosphatidylinositol 4,5-bisphosphate, extracellular perfusion of phospholipase C inhibitor or a protein kinase C (PKC) inhibitor had no effect on the inhibitory activity of simvastatin on IKACh. Simvastatin also inhibits adenosine activated IKACh, however, simvastatin does not inhibit IKACh after activated by intracellular loading of GTP gamma S. Importantly, shortening of the action potential duration by acetylcholine was restored by simvastatin but not by pravastatin. Together, these findings demonstrate that lipophilic statins but not hydrophilic statins attenuate IKACh in atrial cardiomyocytes via a mechanism that is independent of cholesterol synthesis or PKC pathway, but may be via the blockade of acetylcholine binding site. Our results may provide important background information for the use of statins in patients with AF.
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Kyoung-Im
authors.initials: KI
authors.lastname: Cho
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cha
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: In-Kyeung
authors.initials: IK
authors.lastname: Shim
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Heo
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Hyun-Su
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Kyoung-Lyoung
authors.initials: KL
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Institute, Department of Internal Medicine, Kosin University College of Medicine, Busan, South Korea.
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000517:prevention & control*; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006325:Heart Atria / Q000166:cytology* / Q000503:physiopathology; D057927:Hydrophobic and Hydrophilic Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism*; D017035:Pravastatin / Q000737:chemistry / Q000494:pharmacology; D019821:Simvastatin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D017035:Pravastatin; D000109:Acetylcholine; D011188:Potassium