title: KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart.
abstract: The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are favored by CaM kinase activation EADs were induced with clofilium in isolated rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92 (0.5 microM) for 10 min before clofilium exposure. EADs were significantly suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs present in 10/11 hearts) (P =.024). There were no significant differences in parameters favoring EADs such as monophasic action potential duration or heart rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased 37% in hearts with EADs compared to hearts without EADs (P =.015). This increase in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93 potently inhibited rabbit myocardial CaM kinase activity (calculated Ki </= 2.58 microM), but the inactive analog KN-92 did not (Ki > 100 microM). The actions of KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain preferential EAD suppression by KN-93. These data show a novel association between CaM kinase activation and EADs and are consistent with the hypothesis that the ICa and CaM kinase activation both contribute to EADs in this model.
authors.affiliation: The Cardiac Arrhythmia Section, Division of Cardiology, Departments of Internal Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Anderson
authors.forename: A P
authors.initials: AP
authors.lastname: Braun
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: H
authors.initials: H
authors.lastname: Schulman
authors.forename: R J
authors.initials: RJ
authors.lastname: Sung
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology; D011188:Potassium / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D011188:Potassium; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C022799:clofilium