To study the electrophysiologic effects of chronically administered amiodarone and its interaction with an I(Kr) blocker, amiodarone was injected i.p. daily for 7 days into male guinea pigs. Control animals received vehicle only. At 80 mg/kg, RR and rate corrected QT (QT(C)) intervals increased after 4 days from 209 +/- 5 ms and 162 +/- 3 respectively to 285 +/- 13 ms and 176 +/- 3 (P < .05, n = 10), respectively, and remained significantly high on the 8th day (256 +/- 14 ms and 173 +/- 4). Neither RR nor QT(C) intervals changed significantly in control animals. Twenty-four hours after the last injection, papillary muscles were isolated from both ventricles and superfused with Tyrode's solution not containing amiodarone. The preparations from amiodarone-treated animals manifested a statistically significant prolongation of action potential duration (APD) at all pacing cycle lengths (CL) (from 300 to 1500 ms). The amiodarone-induced increase of APD diminished with elevation of potassium concentration ([K+]O). Amiodarone did not modify the dependence of Vmax on membrane potential at different [K+]O. There was minimal to no summation of effects of chronic amiodarone and acute super-fusion of the I(Kr) blocker, E-4031 (3 x 10(-6) M) on APD at CL = 1500 ms. The data demonstrate that in chronically treated guinea pigs, amiodarone prolongs repolarization, manifests minimum reverse use-dependent in APD prolongation, and, at low pacing rate, shows no additive actions with an acutely superfused blocker of I(Kr).