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.
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).


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 micromol/L) was used to block I(Ks) (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in beta-adrenergic tone, d-sotalol (100 micromol/L) to block I(Kr) (LQT2 model), and ATX-II (20 nmol/L) to augment late I(Na) (LQT3 model). Isoproterenol+chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD(90)) 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 micromol/L) abbreviated the QT interval and APD(90) of the 3 cell types in the 3 models. High concentrations (10 to 20 micromol/L) completely reversed the effects of 293B+/-isoproterenol and those of d-sotalol to increase APD(90) and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 micromol/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 I(Kr) or I(Ks) but less so when it is due to augmented late I(Na).
Shimizu
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W
Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA.
Antzelevitch
C
C
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000378:metabolism / Q000503:physiopathology*; D020108:Nicorandil / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D011930:Reaction Time / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000188:drug therapy / Q000517:prevention & control*
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D002839:Chromans; D003064:Cnidarian Venoms; D015221:Potassium Channels; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D020108:Nicorandil; C028800:toxin II (Anemonia sulcata); D013015:Sotalol; D007545:Isoproterenol