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Vol. 287, Issue 3, 996-1006, December 1998
The Cardiac Arrhythmia Section, Division of Cardiology, Departments
of Internal Medicine and Pharmacology, Vanderbilt University Medical
Center (M.E.A., Y.W.1), Nashville, Tennessee and the
Cardiac Electrophysiology and Arrhythmia Service, 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 µM) 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 µM), but the inactive analog KN-92
did not (Ki > 100 µM). 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.
0022-3565/98/2873-0996$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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