Frequency- and Voltage-Dependent Depression of Maximum Upstroke Velocity of Action Potentials by Pirmenol in Guinea Pig Ventricular Muscles

Abstract

The frequency-dependency and voltage-dependency of the suppressing effect of pirmenol, a novel antiarrhythmic agent, on the maximum upstroke velocity (Vmax) of action potentials were examined and compared with those of disopyramide in guinea pig papillary muscles. Pirmenol in concentrations higher than 3 μM decreased Vmax with a slight increase in action potential duration. The reduction of Vmax by pirmenol was enhanced in a frequency-dependent manner over the range of 0.1-2.0 Hz. Pirmenol (30 μM) produced a small resting block (5.5%), whereas disopyramide (100 μM) produced a greater one (25.8%). The onset of frequency-dependent Vmax reduction at 2.0 Hz followed a monoexponential function with a slow rate constant (0.308±0.055 AP-1). The time constant for the recovery from the frequency-dependent block by pirmenol was also slow (33.5±5.4 sec), but faster than that of disopyramide (82.5±12.3 sec). At 1.0 Hz, pirmenol caused a shift (9.5 mV) of the curve relating the resting membrane potential and Vmax along the voltage axis in the hyperpolarizing direction. Thus, pirmenol is a Class la drug that has frequency- and voltage-dependent inhibitory actions on Vmax, and its onset and offset kinetics are relatively slow.