Block of I(Ks) does not induce early afterdepolarization activity but promotes beta-adrenergic agonist-induced delayed afterdepolarization activity.
BACKGROUND
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(Kr)) and LQT3 (augmented late I(Na)), but not LQT1 (reduced I(Ks)), conditions. The present study examines these electrophysiologic characteristics during I(Ks) block.


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(Ks) blocker chromanol 293B (293B, 30 microM), 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 microM failed to induce EADs or delayed afterdepolarizations (DADs) in any of the four tissue types. Isoproterenol (ISO, 0.1 to 1.0 microM) in the presence of 293B 30 microM significantly prolonged the APD of the M cell (basic cycle length > or = 1 sec), abbreviated that of Purkinje, and caused little change in that of Epi and Endo. The combination of 293B 30 microM and ISO 0.2 microM 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.


CONCLUSIONS
Our results indicate that I(Ks) 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.
Burashnikov
A
A
Masonic Medical Research Laboratory, Utica, New York 13501, USA.
Antzelevitch
C
C
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D004285:Dogs; D004359:Drug Therapy, Combination; D004594:Electrophysiology / Q000379:methods; D004699:Endocardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D008839:Microelectrodes; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D016276:Ventricular Function
D000319:Adrenergic beta-Antagonists; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D007545:Isoproterenol