Comparison of the Proarrhythmic Effect of GLG‐V‐13, a Novel Class III Antiarrhythmic Compound, in Two Rabbit Models of Torsades de Pointes Ventricular Tachycardia

Objective: The proarrhythmic potential of a new I Kr ‐blocking Class III antiarrhythmic agent, GLG‐V‐13 was studied and compared in two rabbit models of torsades de pointes (TdP) ventricular tachycardia (TdP). Methods: Chloralose‐anesthetized rabbits (n = 8) were given a concomitant infusion of GLG‐V13 (84 nmol/kg per min) and the α 1 ‐agonist methoxamine (70 nmol/kg per min); in another set of experiments, GLG‐V‐13 was administered solely into the ear vein of electrode catheter instrumented conscious rabbits (n = 6). The doses of GLG‐V‐13, to produce maximum prolongation of the QTU c interval or the right ventricular effective refractory period (VERP), and that inducing ventricular ectopic beats (EBs) and TdP, respectively, were determined. Results: In anesthetized rabbits, GLG‐V‐13 increased QTU c from 125 ± 3 to 161 ± 6 ms after a cumulative dose of 0.84 μmol/kg (P < 0.001) and caused EBs at a mean cumulative dose of 3.9 ± 1.1 μmol/kg. In five of the rabbits, the EBs turned into TdP at a dose of 5.2 ± 3.2 μmol/kg. In conscious rabbits, maximum prolongation of the VERP (27%± 4.3%; P < 0.01) by GLG‐V‐13 was seen at a dose of 1.2 ± 0.54 μmol/kg, whereas EBs and TdP were induced after 6.3 ± 1.4 (6/6) and 8.1 ± 1.4 μmol/kg (6/6), respectively. Conclusion: (1) The dose‐dependent “torsadogenic” potential of I Kr ‐blockers can be evaluated in conscious rabbits without concomitant methoxamine administration; (2) in the conscious state, the EB‐ and TdP‐inducing dose of GLG‐V‐13 is about 50% higher than in the chloralose‐anesthetized animal; and (3) irrespective of the chemical nature of the compound applied, blockade of the cardiac I Kr potassium channel is associated with proarrhythmic effect.