EFFECTS OF LONG-TERM ORAL-ADMINISTRATION OF AMIODARONE ON THE ELECTROMECHANICAL PERFORMANCE OF RABBIT VENTRICULAR MUSCLE

1 The effects of long-term administration of oral amiodarone on transmembrane action potential and contraction of ventricular muscle were investigated in rabbits. 2 ECGs of rabbits that received oral amiodarone 50 mg or 100 mg kg-1 daily for 4 weeks, showed a significant prolongation of RR, QT and corrected QT (QTc) intervals, whereas PQ and QRS were unaffected. Serum and myocardial tissue amiodarone concentrations were 0.14-0.18 mug ml-1 and 1.47-3.63 mug g-1 wet wt. respectively. 3 Right ventricular papillary muscles isolated from treated rabbits were characterized by a moderate prolongation of action potential duration (APD) compared with controls. A slight decrease of the maximum upstroke velocity (V(max)) was also observed at the higher dose. The APD prolongation by chronic amiodarone, unlike acute effects of sotalol, E-4031, Cs+ and 4-aminopyridine, did not show marked reverse use-dependence. 4 APD and V(max) restitution following slow basic stimuli (0.03 Hz) were unaffected by chronic treatment with amiodarone. 5 Acute application of amiodarone (10 muM) caused a significant decrease in APD and developed tension, as well as a marked use-dependent V(max) inhibition with fast recovery kinetics. 6 These findings suggest that a major and consistent electro-physiological effect of chronic amiodarone is repolarization delay (Class-III action) showing minimal frequency-dependence. However, when amiodarone above a certain concentration is present in the extracellular space, a fast kinetic Class-I action would be added as an acute effect.