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

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Abstract
The frequency-dependency and voltage-dependency of the suppressing effect of pirmenol, a novel antiarrhythmic agent, on the maximum upstroke velocity (.ovrhdot.Vmax) of action potentials were examined and compared with those of disopyramide in guinea pig papillary muscles. Pirmenol in concentrations higher than 3 .mu.M decreased .ovrhdot.Vmax with a slight increase in action potential duration. The reduction of .ovrhdot.Vmax by pirmenol was enhanced in a frequency-dependent manner over the range of 0.1-2.0 Hz. Pirmenol (30 .mu.M) produced a small resting block (5.5%), whereas disopyramide (100 .mu.M) produced a greater one (25.8%). The onset of frequency-dependent .ovrhdot.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 .ovrhdot.Vmax along the voltage axis in the hyperpolarizing direction. Thus, pirmenol is a Class Ia drug that has frequency- and voltage-dependent inhibitory actions on .ovrhdot.Vmax, and its onset and offset kinetics are relatively slow.