(Circulation. 2000;102:706.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Effects of a K+ Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome
Presented in part at the 19th Scientific Sessions of the North American Society of Pacing and Electrophysiology, San Diego, Calif, May 9, 1998, and published in abstract form (Pacing Clin Electrophysiol. 1998;21:846).
From the Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501-1787. E-mail ca{at}mmrl.edu
Background—This study examines the effects of nicorandil, a K+ channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS).
Methods and Results—Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 µmol/L) was used to block IKs (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in ß-adrenergic tone, d-sotalol (100 µmol/L) to block IKr (LQT2 model), and ATX-II (20 nmol/L) to augment late INa (LQT3 model). Isoproterenol+chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD90) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 µmol/L) abbreviated the QT interval and APD90 of the 3 cell types in the 3 models. High concentrations (10 to 20 µmol/L) completely reversed the effects of 293B±isoproterenol and those of d-sotalol to increase APD90 and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 µmol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6).
Conclusions—Our data suggest that K+ channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced IKr or IKs but less so when it is due to augmented late INa.
Key Words: long-QT syndrome • arrhythmia • genes • nicorandil • cells
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