ELECTROPHYSIOLOGIC EFFECTS OF AMBASILIDE (LU-47110), A NOVEL CLASS-III ANTIARRHYTHMIC AGENT, ON THE PROPERTIES OF ISOLATED RABBIT AND CANINE CARDIAC-MUSCLE

Electrophysiologic effects of ambasilide in canine isolated cardiac muscle driven at 1 Hz and in rabbit sinoatrial (SA) node preparations were determined by standard microelectrode technique. Ambasilide (10(-7)-10(-5) M) produced concentration-dependent increases in action potential duration measured at -80 mV (APD-80) repolarization time in canine ventricular muscle and in Purkinje fibers. APD measured at -20 mV (APD-20) was also increased in ventricular muscle, but it shortened with 10(-5) M in Purkinje fibers; at this concentration, there was a negligible change in the amplitude and the maximum upstroke velocity (V(max)) of action potentials and in the resting membrane potential. With the stimulation frequency between 30/min and 120/min, ambasilide (10(-5) M) produced a parallel increase in APD-20 as well as in APD-20 of ventricular muscle. In Purkinje fibers, the prolonging effect of ambasilide on APD-20 was more pronounced at lower stimulation frequency, whereas APD-20 shortened at all stimulation frequencies. Ambasilide at 10(-5) M also produced a prolongation of the effective refractory period (ERP) in Purkinje fibers. The drug produced no significant change in the frequency-dependent relationship between ERP and APD-80. A small but significant frequency-dependent inhibition of V(max) was noted in both ventricular muscle and Purkinje fibers. When the stimulus cycle length was reduced from 1,000 to 300 mx, V(max) in ventricular muscle decreased by 8.4 +/- 3.4% in control solution but by 22.6 +/- 5.6% after 10(-5) M ambasilide (n = 8, p < 0.01). Ambasilide (10(-5) M) produced a marked increase in APD-20 measured at -20 and -40 mV in Purkinje fibers, with abnormal automaticity induced by 2 mM barium (n = 7). The spontaneous cycle length of these preparations increased from 931.1 +/- 205.3 to 1294.0 +/- 274.9 ms (p < 0.01). The drug had no significant effect on the amplitude and V(max) of such action potentials or on their maximum diastolic potentials. Ambasilide (10(-7)-10(-5) M) produced concentration-dependent increases in the cycle length in rabbit sinus node by increasing the APD measured at 80% repolarization time and by elevating the threshold of rapid depolarization but without a significant change in the amplitude, maximum diastolic potential, and the slope of phase 4 depolarization; however, all these parameters tended to decrease at 10(-5) M. The data indicate that ambasilide exerts a significant class III antiarrhythmic action with a minor class I effect in conjunction with an unusual aggregate of additional electrophysiologic effects that may lead to beneficial antifibrillatory actions with a reduced propensity for genesis of early afterdepolarizations.