The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (lca); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to lca. 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 fa-voring 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 ju,M). The actions of KN-93 and KN-92 on lca 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 lca and CaM kinase activation both contribute to EADs in this model.
|Original language||English (US)|
|Number of pages||11|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1998|
ASJC Scopus subject areas
- Molecular Medicine