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).
Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA.
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Shimizu
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Antzelevitch
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