Rate-related electrophysiologic effects of long-term administration of amiodarone on canine ventricular myocardium in vivo.

Abstract

The electrophysiologic efects of amiodarone were examined in 13 dogs that received 30 g amiodarone orally during 3 weeks and compared with 13 control dogs that did not receive amiodarone. Longitudinal and transverse epicardial conduction velocities were estimated with a square array of 64 closely spaced electrodes and a computer-assisted acquisition and analysis system. Amiodarone caused a rate-dependent decrease in conduction velocity with a slightly greater effect in the longitudinal direction of propagation. Rate-related depression of conduction velocity developed rapidly after abrupt shortening of the pacing cycle length; 67% of the change occurred between the first two beats of the rapid train, and little change occurred after the 10th beat. Recovery from use-dependent depression of conduction velocity was exponential with a mean time constant of 447±+172 msec in the longitudinal direction and 452±265 msec in the transverse direction. Repolarization intervals, defined as the interval between the activation time and the repolarization time in the unipolar electrograms, correlated highly with refractory period determinations in the absence and presence of amiodarone at each cycle length tested. The increase in repolarization intervals and refractory periods resulting from amiodarone treatment did not vary with cycle length. Amiodarone treatment also resulted in a significant rate-related reduction in systolic blood pressure. The systolic blood pressure in the group that received amiodarone decreased by a mean of 50±23% between steady-state pacing cycle lengths of 1,000 and 200 msec, whereas the corresponding decrease in the control group was 21±32% (p < 0.05). Plasma and myocardial amiodarone and desethylamiodarone levels were comparable to those observed clinically. We conclude that long-term amiodarone administration causes rate-dependent reductions in conduction velocity and blood pressure and causes rateindependent increases in repolarization intervals. (Circulation 1989;79:948-958) Amiodarone is an effective, widely used antiarrhythmic drug.1 Reduction of conduction velocity may be an important antiarrhythmic effect of amiodarone. Previous investigations showed that amiodarone decreases sodium current,2 reduces the maximum upstroke velocity of the action potential (VmX)3-6 and prolongs QRS duration,7-9 but its effects on myocardial conduction velocity have not been reported.

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle

“…However, the reverse use-dependence has not been completely confirmed to be a general characteristic of agents with the property of I K block. For instance, another class III antiarrhythmic agent, amiodarone, lengthens APD at normal and slow heart rates to a similar extent [12], and the potassium channel block by other agents with both class I and III antiarrhythmic effects (flecainide and encainide) is identical to the type of use-dependence described previously for sodium channel block [13].…”

Effects of class III antiarrhythmic drugs on the Na+‐activated K+ channels in guinea‐pig ventricular cells

“…However, most new class III compounds show a more prominent APD-prolonging effect at slow heart rate (so-called reverse use-dependence) (Tande et al, 1990;Nakaya et al, 1993;Hiraoka et al, 1994). In contrast, it has been found that amiodarone shows little reverse use-dependence during chronic administration (Anderson et al, 1989). The inhibitory action of amiodarone on the KNa channels that were activated during repetitive stimulation might be partly involved in the more favourable APD prolongation.…”

Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

“…Whether such an additional property might contribute to the overall antiarrhythmic actions of these drugs remains uncertain. In AM, the associated class I antiarrhythmic effect is of moderate potency, 21,23,24 but its ratedependency has not been as compellingly uniform. 21 Our data indicating that SR, a noniodinated benzofuran derivative, might have a similar potency for blocking the fast channel in ventricular myocardium are of particular interest relative to its similarity to the overall properties of AM.…”