Block of IKs does not induce early afterdepolarization activity but promotes β-adrenergic agonist-induced delayed afterdepolarization activity

Block of I-kappa s Does Not Induce EADs. Introduction: An early afterdepolarization (EAD) induced triggered beat is thought to precipitate torsade de pointes (TdP) in the long QT syndrome (LQTS). Previous studies demonstrated the development of EAD activity and dispersion of repolarization under LQT2 (reduced I-kappa r) and LQT3 (augmented late I-Na), but not LQT1 (reduced I-kappa s), conditions. The present study examines these electrophysiologic characteristics during I-kappa s block. Methods and Results: Canine epicardial (Epi), M, and endocardial (Endo) tissues and Purkinje fibers isolated from the canine left ventricle were studied using standard microelectrode recording techniques. The I-kappa s blocker chromanol 293B (293B, 30 mu M), produced a homogeneous rate-independent prolongation of action potential duration (APD) in Epi, M, and Endo, but little to no APD prolongation in Purkinje, Chromanol 293B 1 to 30 mu M failed to induce EADs or delayed afterdepolarizations (DADs) in any of the four tissue types, Isoproterenol (ISO, 0.1 to 1.0 mu M) in the presence of 293B 30 mu M significantly prolonged the BPD of the hf cell (basic cycle length greater than or equal to 1 sec), abbreviated that of Purkinje, and caused little change in that of Epi and Endo, The combination of 293B 30 mu M and ISO 0.2 mu M did not induce EADs in any of the four tissue types, but produced DAD activity in 4 of 8 Epi, 7 of 10 M cells, and 3 of 8 Endo. Conclusion: Our results indicate that I-kappa s block alone or in combination with beta-adrenergic stimulation does not induce EADs in any of the four canine ventricular tissue types, but that the combination of the two induces DADs as well as accentuated dispersion of repolarization.