Calmodulin Antagonist W‐7 Prevents Sparfloxacin‐Induced Early Afterdepolarizations (EADs) in Isolated Rabbit Purkinje Fibers: Importance of Beat‐to‐Beat Instability of the Repolarization

Abstract

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.

W-7 modulates Kv4.3: pore block and Ca2+-calmodulin inhibition

“…Attention has been drawn to the importance of increased Ca 2ϩ /CaMKII activity in the pathophysiology of different types of heart disease, including ventricular arrhythmias (2,4,23,36,45,46). W-7, a commonly used inhibitor of Ca 2ϩ -CaM, has been reported to suppress ventricular arrhythmias in animal models (4,26,36,45,46).…”

“…W-7, a commonly used inhibitor of Ca 2ϩ -CaM, has been reported to suppress ventricular arrhythmias in animal models (4,26,36,45,46). To gain an understanding of the mechanisms underlying the effects of W-7, we examined the effects of W-7 and KN-93 on the K v 4.3 voltage-gated K ϩ channel, which plays an important role in cardiac repolarization in atria and ventricles (13,16,53).…”

“…Since Ca 2ϩ overload leads to cardiac arrhythmias, KN-93 and W-7 have the potential to be better antiarrhythmic drugs than other class III antiarrhythmic drugs. In addition to the antiarrhythmic effects, alterations in I to resulting from a decrease in peak current and/or an acceleration of inactivation can lead to significant depolarizing shifts in notch potential and phase 2 of repolarization (45,62). The loss of the notch and depolarizing shift in the plateau has been shown to cause desynchronization of Ca 2ϩ sparks, prolongation and reduction in L-type Ca 2ϩ current, and intracellular Ca 2ϩ transients (62).…”

“…Ca 2ϩ /CaM-dependent protein kinase II (Ca 2ϩ /CaMKII) is among the many kinases and phosphatases responsive to the Ca 2ϩ -bound CaM (Ca 2ϩ -CaM) (31a, 34, 49, 56, 64, 71). Recent studies have implicated increased Ca 2ϩ /CaMKII activity in the pathophysiology of different types of heart disease, including ventricular arrhythmias (4,5,26,36,45,46). These data have shown that agents that lead to a decrease in Ca 2ϩ /CaMKII activity, such as W-7 and KN-93, are effective in different animal models of ventricular arrhythmias (4,26,36,45,46).…”

“…Recent studies have implicated increased Ca 2ϩ /CaMKII activity in the pathophysiology of different types of heart disease, including ventricular arrhythmias (4,5,26,36,45,46). These data have shown that agents that lead to a decrease in Ca 2ϩ /CaMKII activity, such as W-7 and KN-93, are effective in different animal models of ventricular arrhythmias (4,26,36,45,46). Despite their inhibition of a common final target, Ca 2ϩ /CaMKII, W-7, which inhibits Ca 2ϩ -CaM, could also modulate additional enzymes and/or ion channels (4,37,38,48,59,75).…”