Effects of class III antiarrhythmic agents in an in vitro rabbit model of spontaneous torsades de pointe.

Acquired long QT syndrome develops as a result of pharmacological interventions that prolong action potential duration. Excessive action potential prolongation may lead to torsade de pointes, a potentially fatal arrhythmia. To study this arrhythmia, in vivo models have been developed, but are difficult to interpret due to the complex nature of the intact metabolic, nervous and humoral systems. To more clearly examine the propensity of various Class III agents to elicit torsades de pointe, an in vitro model of spontaneous torsades de pointe was used in isolated perfused rabbit hearts. Male New Zealand white rabbits were anesthetized with sodium pentobarbital, and hearts isolated and perfused in a Langendorff apparatus. Electrocardiogram and epicardial monophasic action potentials were continuously recorded, and methoxamine (30 nM) and acetylcholine (0.3 microM) were given throughout the experiment. After 10 min of methoxamine and acetylcholine perfusion, Class III agents, dofetilide (0.1 to 0.7 microM), E-4031 (0.1 to 0.5 microM), D-sotalol (10 to 30 microM), or clofilium (0.1 to 0.3 microM), were given. All agents, except D-sotalol, induced torsades de pointe in 100% of hearts tested. D-Sotalol (30 microM) elicited a low incidence of torsades de pointe (25%). This could be explained by the limited prolongation of action potential duration with D-sotalol as compared to other Class III agents under these conditions. Dofetilide, a selective Class III agent, alone did not induce torsades de pointe. Nadolol (3 microM), a beta-adrenoceptor antagonist, increased the propensity of dofetilide to elicit torsades de pointe. In conclusion, increases in action potential duration (i.e., using Class III agents) in combination with a low heart rate (muscarinic receptor stimulation) and increases in intracellular Ca2+ (alpha-adrenoceptor stimulation) are needed to develop torsades de pointe in this model. Modulating these systems may provide us with new insights into preventing the initiation or maintenance of this arrhythmia.