Rate-Dependent Effects of Dofetilide on Epicardial Monophasic Action Potentials in Isolated Rabbit Heart with Atrial Pacing


Abstract: Dofetilide (UK 68,798), a new antiarrhythmic agent, blocks potassium channels selectively and acts primarily by prolonging repolarization duration. The aim of this study was to investigate rate-dependent repolarization changes due to dofetilide in a fast beating in-vitro heart model. The study was designed using Langendorff perfusion of rabbit hearts at the drug concentrations of 1 nM, 3 nM and 10 nM. The electrophysiological evaluations were performed using the recording of epicardial monophasic action potentials. Atrial pacing was set at the cycle length (ms) of 300, 325, 350, 375 and 400 so that repolarization duration could be measured in different heart rates. The study also focused on the interventricular repolarization heterogeneity between the right and left epicardial regions. Dofetilide prolonged monophasic action potential duration at 90 % of repolarization on both sides of the epicardium in a concentration- and reverse-rate-dependent manner. However, the rate-dependent prolongation of action potential duration due to dofetilide was not accompanied by increased interventricular dispersion of repolarization. No proarrhythmia due to dofetilide was seen in our model. This may be explained by the rate-dependent stability in repolarization dispersion. Thus, the presented model indicated that dofetilide-induced prolongation of repolarization is not proarrhythmic in isolated fast beating hearts.

Keywords: Dofetilide, Rate dependency, Monophasic action potential duration, Interventricular dispersion, Langendorff perfusion

Full Text: PDF