Chronic versus acute effects of amiodarone on the Vmax-conduction velocity relationship and on the space constant in canine myocardium

Isolated tissue experiments (canine ventricular epicardium) and computer simulations were used to characterize the relationship between changes in maximum rate of depolarization during upstroke (Vmax) and the conduction velocity (theta) induced after long-term therapy with amiodarone and to compare these data with those obtained after acute superfusion with either desethylamiodarone or the parent compound. After chronic amiodarone, the changes in Vmax were linearly related to the square of the changes in theta during longitudinal propagation (LP) (slope = 0.93, r = 0.93, p = NS with respect to slope = 1), whereas during transverse propagation (TP), the slope of the relationship between both variables was slightly decreased (slope = 0.88, r = 0.96, p < 0.05 with respect to slope = 1). Similar results were observed after acute superfusion with desethylamiodarone (LP), (slope = 1, r = 0.05, p = NS with respect to slope = 1). In contrast, a significant increase in slope (p < 0.05 with respect to slope = 1) was observed after acute superfusion (slope = 1.45, r = 0.85 and slope = 1.48, r = 0.75 during LP and TP, respectively). In addition, the space constant (lambda) after chronic amiodarone (1.05 +/- 0.06 mm) was not significantly different from control (0.98 +/- 0.04 mm), but was slightly though significantly increased after acute amiodarone administration (1.07 +/- 0.03 mm, p < 0.03). Data are mean +/- SEM. Experimental data from chronic amiodarone were well fitted in a one-dimensional Beeler-Reuter-based discrete cable by reducing sodium conductance (GNa) exclusively. In contrast, data from acute superfusion were fitted only when junctional resistance (rj) and GNa were simultaneously reduced. These data suggest that acute amiodarone may modify both active and passive membrane properties whereas chronic amiodarone appears to alter only the active properties; the data further indicate that desethylamiodarone may play an important role in the mechanism of action of chronic amiodarone treatment.