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 intervent ions that prolong action potential duration. Excessive action potential pro longation may lead to torsade de pointes, a potentially fatal arrhythmia. T o study this arrhythmia, in vivo models have been developed, but are diffic ult to interpret due to the complex nature of the intact metabolic, nervous and humoral systems. To more clearly examine the propensity of various Cla ss III agents to elicit torsades de pointe, an in vitro model of spontaneou s torsades de pointe was used in isolated perfused rabbit hearts. Male New Zealand white rabbits were anesthetized with sodium pentobarbital, and hear ts isolated and perfused in a Langendorff apparatus. Electrocardiogram and epicardial monophasic action potentials were continuously recorded, and met hoxamine (30 nM) and acetylcholine (0.3 mu M) were given throughout the exp eriment. After 10 min of methoxamine and acetylcholine perfusion, Class In agents, dofetilide (0.1 to 0.7 mu M), E-4031 (0.1 to 0.5 mu M), D-sotalol ( 10 to 30 mu M), or clofilium (0.1 to 0.3 mu M), were given. All agents, exc ept D-sotalol, induced torsades de pointe in 100% of hearts tested. D-Sotal ol (30 mu M) elicited a low incidence of torsades de pointe (25%). This cou ld be explained by the limited prolongation of action potential duration wi th D-sotalol as compared to other Class III agents under these conditions. Dofetilide, a selective Class III agent, alone did not induce torsades de p ointe. Nadolol (3 mu M), a beta-adrenoceptor antagonist, increased the prop ensity 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 i ntracellular Ca2+ (alpha-adrenoceptor stimulation) are needed to develop to rsades de pointe in this model. Modulating these systems may provide us wit h new insights into preventing the initiation or maintenance of this arrhyt hmia. (C) 1999 Elsevier Science B.V. All rights reserved.