title: KN-93, A CaMKII inhibitor, suppresses ventricular arrhythmia induced by LQT2 without decreasing TDR.
abstract: Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Chong-Qiang
authors.initials: CQ
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Cun-Tai
authors.initials: CT
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Huazhong University of Science and Technology, Wuhan, 430030, China. lujiagao@tjh.tjmu.edu.cn.
authors.forename: Jia-Gao
authors.initials: JG
authors.lastname: Lv
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001596:Benzylamines / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000150:complications*; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D000096926:Benzenesulfonamides
chemical_list: D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C072105:KN 93; D000096926:Benzenesulfonamides