Calmodulin antagonist W-7 prevents sparfloxacin-induced early afterdepolarizations (EADs) in isolated rabbit purkinje fibers: importance of beat-to-beat instability of the repolarization.
BACKGROUND
The occurrence of early afterdepolarizations (EADs) has been related to the incidence of torsades de pointes in drug-induced long QT (LQT). The generation of EADs may be facilitated by Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase).


RESULTS
In the present study, we investigated a possible involvement of Ca(2+)/Calmodulin dependent protein kinase in the generation of sparfloxacin-induced EADs in isolated rabbit Purkinje fibers by means of a calmodulin antagonist W-7. EADs were evident in 8 of the 10 preparations perfused with sparfloxacin at 1 x 10(-4) M and stimulated at 0.2 Hz. The induction of EADs by sparfloxacin was associated with a large prolongation of the duration of the action potential (APD), an increase in the triangulation, and the short-term instability of the repolarization. CaM kinase blockade with the calmodulin antagonist W-7 inhibited sparfloxacin-induced EADs in a concentration-dependent manner (EADs were induced in 3 of 10, 1 of 10, and 0 of 8 preparations in the presence of W-7 at 5 x 10(-7) M, 5 x 10(-6) M, and 5 x 10(-5) M, respectively; P < 0.01 at 5 x 10(-6) M and 5 x 10(-5) M). The inhibition of sparfloxacin-induced EADs by W-7 at 5 x 10(-7) M and 5 x 10(-6) M was associated with a significant decrease in the beat-to-beat instability but not associated with a significant shortening of the APD and reduction of V(max).


CONCLUSIONS
The present findings support the hypothesis that CaM kinase may be a proarrhythmic signaling molecule and demonstrate that CaM kinase may be involved in the generation of EADs in drug-induced LQT and enhanced beat-to-beat instability of repolarization is essential for the genesis of EADs in rabbit in vitro.
Lu
Hua Rong
HR
Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V. B-2340, Beerse, Belgium. hlu@prdbe.jnj.com
Vlaminckx
Eddy
E
Van de Water
Andre
A
Gallacher
David J
DJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D022062:Electrophysiologic Techniques, Cardiac; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D024841:Fluoroquinolones / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D011690:Purkinje Fibers / Q000187:drug effects / Q000503:physiopathology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D013449:Sulfonamides; C017967:W 7; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C061363:sparfloxacin