Drug-induced ventricular tachyarrhythmia in isolated rabbit hearts with atrioventricular block.
The aims of this study were to develop a suitable model to study proarrhythmic potential using isolated rabbit hearts with atrioventricular block and to examine the proarrhythmic potential of several drugs using this model. With a normal K/Mg solution (K+=5.7 mM and Mg2+=1 mM), d,l-sotalol (10 and 30 microM), a class III antiarrhythmic drug, prolonged ventricular repolarization, such as QT intervals and monophasic action potential duration, and induced early after-depolarization and polymorphic ventricular tachyarrhythmia. Cisapride (0.1 and 0.3 microM), a 5-HT4 receptor agonist, also prolonged the ventricular repolarization, and induced early after-depolarization. With a low K/Mg solution (K+=1.5 mM and Mg2+=0.35 mM), d,l-sotalol at 30 microM and cisapride at 0.3 microM more potently prolonged the ventricular repolarization than with a normal K/Mg solution. Furthermore, the incidence of polymorphic ventricular tachyarrhythmia caused by cisapride at 0.3 microM with a low K/Mg solution was higher than that with a normal K/Mg solution. Mosapride citrate, another 5-HT4 receptor agonist, at 10 microM prolonged the ventricular repolarization and induced early after-depolarization with a low K/Mg solution, whereas the drug at 1 and 3 microM did not affect any of the parameters examined. Des-4-fluorobenzyl-mosapride, a metabolite of mosapride citrate, at 10 microM slightly prolonged the ventricular repolarization without inducing early after-depolarization or ventricular tachyarrhythmia. These results suggest that mosapride citrate and des-4-fluorobenzyl-mosapride have much less proarrhythmic potential than cisapride and that isolated rabbit heart with atrioventricular block, perfused with a low K/Mg solution, is a suitable model for predicting the proarrhythmic potential of drugs.
Kii
Yoshihide
Y
Department of Safety Pharmacology, Developmental Research Laboratories, Dainippon Pharmaceutical Co. Ltd., Osaka, Japan. yoshihide-kii@dainippon-pharm.co.jp
Ito
Tsugutaka
T
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001549:Benzamides / Q000009:adverse effects; D020117:Cisapride / Q000009:adverse effects; D004121:Dimethyl Sulfoxide / Q000009:adverse effects; D004195:Disease Models, Animal; D004562:Electrocardiography; D006327:Heart Block / Q000150:complications*; D066298:In Vitro Techniques; D008278:Magnesium Sulfate / Q000009:adverse effects; D008297:Male; D009025:Morpholines / Q000009:adverse effects; D011188:Potassium / Q000009:adverse effects; D011817:Rabbits; D012997:Solvents; D013015:Sotalol / Q000009:adverse effects; D013610:Tachycardia / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D009025:Morpholines; D012997:Solvents; C467826:des-4-fluorobenzyl-mosapride; D008278:Magnesium Sulfate; D013015:Sotalol; C062720:mosapride; D011188:Potassium; D020117:Cisapride; D004121:Dimethyl Sulfoxide