Role of L‐Type Calcium Channel Window Current in Generating Current‐Induced Early Afterdepolarizations

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Abstract
Ionic Mechanism of EADs. Introduction: Early afterdepolarizations (EADs) can give rise to triggered activity and thereby produce cardiac arrhythmias. We used the whole‐cell patch clamp technique to examine the relationship between L‐type Ca2+ channel window current and the generation of EADs in single ventricular myocytes isolated from guinea pig hearts. Methods and Results: With a high concentration of EGTA in the internal solution and Na+‐containing physiologic external solution, EADs were induced in unclamped cells by injecting intracellular depolarizing current pulses. During voltage clamp protocols designed to simulate action potentials interrupted by EADs, we recorded an inward shift in total current up to 0.7 pA/pF over 400 msec at test steps in the range of the take‐off potential for EADs. Cd2t (0.2 mM) blocked most of the inward shift of current during the test steps and abolished EADs. When the same voltage clamp protocol was used following perfusion with an Na+‐free, K+‐free external solution, the Cd2+‐sensitive inward currents 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 intraccllular [Ca2+]; and (2) under these conditions, L‐type Ca2+ channel window current plays a major role in the initiation of EADs.