A canine model of torsades de pointes.
Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.
Leichter
D
D
Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York 10032.
Danilo
P
P
Boyden
P
P
Rosen
T S
TS
Rosen
M R
MR
D000157:Aconitine; D031841:Aconitum / Q000031:analogs & derivatives; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D004567:Electrodes, Implanted; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D011802:Quinidine; D013610:Tachycardia / Q000139:chemically induced* / Q000503:physiopathology
D011802:Quinidine; D000157:Aconitine