Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome.
OBJECTIVE
Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to Torsades de Pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS.


RESULTS
We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased I(Kr) in cardiomyocytes isolated from normal and bradycardia-remodelled rabbits by approximately 75% and 50%, respectively (P < 0.001 for each). Similarly, NS1643 restored I(Kr) suppressed by 5 nmol/L dofetilide (tail current 0.28 +/- 0.03 pA/pF pre-dofetilide, 0.20 +/- 0.01 pA/pF in the presence of dofetilide, 0.27 +/- 0.02 pA/pF after adding NS1643 to dofetilide-containing solution, P < 0.01).


CONCLUSIONS
Pharmacological activation of I(Kr) reverses acquired LQTS and TdP caused by bradycardic remodelling and I(Kr)-blocking drugs. I(Kr)-activating drug therapy could be a potentially interesting treatment approach for LQTS.
Diness
Thomas G
TG
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8.
Yeh
Yung-Hsin
YH
Qi
Xiao Yan
XY
Chartier
Denis
D
Tsuji
Yukiomi
Y
Hansen
Rie S
RS
Olesen
Soren-Peter
SP
Grunnet
Morten
M
Nattel
Stanley
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D054537:Atrioventricular Block / Q000150:complications; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D003408:Cresols / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000819:agonists*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D003408:Cresols; D051668:Delayed Rectifier Potassium Channels; D010627:Phenethylamines; D010671:Phenylurea Compounds; D013449:Sulfonamides; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; C063533:dofetilide