Frequency-dependent depression of Vmax of slow response action potentials by a high concentration of papaverine

The maximum upstroke velocity (Vmax) of Ca2+-dependent action potentials was used to measure relative changes in the slow inward current (Isi) caused by 10(-4) M papaverine as a function of pacing frequency in K-depolarized guinea pig ventricular strips. Papaverine caused a pronounced frequency-dependent depression of Vmax presumed to be correlated with a decrease in the rate of recovery from inactivation of Isi. Papaverine (10(-4) M) tripled the time constants for the biexponential recovery from depression of Vmax (determined by a paired pulse protocol) relative to the control. Depression of Vmax by papaverine during a 1 Hz stimulus train preceded by a long rest period reached a new steady state within three depolarizations. Complete poststimulation recovery from the depression of Vmax was also relatively rapid, unlike that described for verapamil. Preparations exposed to Mn2+ (after pretreatment with Ba2+ to restore excitability) showed a depressed steady-state Vmax independent of frequency. It is concluded that the frequency-dependent blockers of Vmax (papaverine and verapamil) differ in their rates of association and dissociation with the slow inward channel.