ROLE OF L-TYPE CALCIUM-CHANNEL WINDOW CURRENT IN GENERATING CURRENT-INDUCED EARLY AFTERDEPOLARIZATIONS

Ionic Mechanism of EADs. Introduction: Early afterdepolarizations (EAD s) can give rise to triggered activity and thereby produce cardiac arr hythmias. We used the whole-cell patch clamp technique to examine the relationship between L-type Ca2+ channel window current and the genera tion of EADs in single ventricular myocytes isolated from guinea pig h earts. Methods and Results: With a high concentration of EGTA in the i nternal solution and Na+-containing physiologic external solution, EAD s were induced in unclamped cells by injecting intracellular depolariz ing current pulses. During voltage clamp protocols designed to simulat e action potentials interrupted by EADs, we recorded an inward shift i n total current up to 0.7 pA/pF over 400 msec at test steps in the ran ge of the take-off potential for EADs. Cd2+ (0.2 mM) blocked most of t he inward shift of current during the test steps and abolished EADs. W hen the same voltage clamp protocol was used following perfusion with an Na+-free, K+-free external solution, the Cd2+-sensitive inward curr ents recorded during the test steps were similar to those obtained in physiologic external solution. The overlapping range of potentials for partial activation of the d and f variables of L; type Ca2+ current ( ''window'' region) measured in Na+-free, K+-free external solution was virtually the same as the voltage range of the Cd2+-sensitive inward currents. Conclusion: Our experiments suggest that: (1) EADs can arise under conditions of high EGTA buffering of intracellular [Ca2+]; and (2) under these conditions, L-type Ca2+ channel window current plays a major role in the initiation of EADs.