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.