Prominent I(Ks) in epicardium and endocardium contributes to development of transmural dispersion of repolarization but protects against development of early afterdepolarizations.
BACKGROUND
Previous studies from our laboratory demonstrated (1) a much larger I(Ks) and (2) inability to induce early afterdepolarization (EAD) activity in epicardial and endocardial cells versus M cells. This study tests the hypothesis that these two characteristics are interrelated.


RESULTS
Standard and floating microelectrode techniques were used to record transmembrane activity from the canine left ventricular epicardial, M, and endocardial regions in isolated tissue slices and arterially perfused wedge preparations. The I(Kr) blocker E-4031 (1 to 10 microM) caused prominent prolongation of action potential duration (APD) and induced EADs in tissues isolated from the M region, but not those from epicardium or endocardium, causing a large transmural dispersion of APD. In contrast, the I(Ks) blocker chromanol 293B (10 to 30 microM) produced moderate prolongation of APD without EADs in all three tissue types. The combination of E-4031 (1 microM) and chromanol 293B (30 microM) resulted in profound prolongation of APD and the development of EADs in all three tissue types. In the perfused wedge, neither E-4031 nor chromanol 293B alone could induce EADs. In combination, the two drugs caused significant prolongation of APD and EADs in all three transmural regions.


CONCLUSIONS
Our results support the hypothesis that a prominent I(Ks) is responsible for the ability of epicardium and endocardium to resist some but not all of the arrhythmogenic effects of I(Kr) block. The data highlight the critical importance of I(Ks) in the canine heart and the significant role of electrotonic interactions in minimizing the development of an arrhythmogenic substrate when repolarization reserve is reduced.
Burashnikov
Alexander
A
Masonic Medical Research Laboratory, Utica, New York 13501, USA.
Antzelevitch
Charles
C
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D004285:Dogs; D004359:Drug Therapy, Combination; D004594:Electrophysiology / Q000379:methods; D004699:Endocardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008839:Microelectrodes; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane