Analysis of the electrophysiological effects of ambasilide, a new antiarrhythmic agent, in canine isolated ventricular muscle and Purkinje fibers

The aim of the study was to determine the in vitro rate-dependent cellular electrophysiological effects of ambasilide (10 and 20 mu M/l), a new invest igational antiarrhythmic agent, in canine isolated ventricular muscle and P urkinje fibers by applying the standard microelectrode technique. At the cy cle length (CL) of 1000 ms, ambasilide significantly prolonged the action p otential duration measured at 90% repolarization (APD(90)) in both ventricu lar muscle and Purkinje fibers. Ambasilide (10 mu M/l) produced a more mark ed prolongation of APD(90) at lower stimulation frequencies in Purkinje fib ers (at CL of 2000 ms = 56.0 +/- 16.1%, n = 6, versus CL of 400 ms = 15.1 /- 3.7%, n = 6; p < 0.05), but, in 20 mu M/l, this effect was considerably diminished (15.2 +/- 3.6%, n = 6, versus 7.3 +/- 5.1%, n = 6, p < 0.05). In ventricular muscle, however, both concentrations of the drug induced an al most frequency-independent lengthening of APD(90) in response to a slowing of the stimulation rate (in 20 mu M/l at CL of 5000 ms = 19.0 +/- 1.5%, n = 91 versus CL of 400 ms = 16.9 +/- 1.4%, n = 9). Ambasilide induced a marke d rate-dependent depression of the maximal rate of rise of the action poten tial upstroke (V-max) (in 20 mu M/l at CL of 300 ms = -45.1 +/- 3.9%, n = 6 , versus CL of 5000 ms = -8.5 +/- 3.9%, n = 6, p < 0.05, in ventricular mus cle) and the corresponding recovery of V-max time constant was tau = 1082.5 +/- 205.1 ms (n = 6). These data suggest that ambasilide, in addition to i ts Class III antiarrhythmic action, which is presumably due to its inhibito ry effect on the delayed rectifier potassium current, possesses I/B type an tiarrhythmic properties as a result of the inhibition of the fast sodium ch annels at high frequency rate with relatively fast kinetics. This latter ef fect may play an important role in its known less-pronounced proarrhythmic ("torsadogenic") potential. (C) 2000 Elsevier Science Inc. All rights reser ved.