Comparison of papaverine and verapamil on frequency-dependent changes in Vmax of K-depolarized ventricular tissue

The maximum upstroke velocity (Vmax) of K-depolarized guinea pig ventricular strips was used to indirectly measure frequency-dependent changes in slow inward current (Isi) caused by papaverine, verapamil, Ba2+, and isoproterenol. The effects of verapamil were studied after pretreatment with 0.8 mM Ba2+ to restore excitability of the K-depolarized tissue. Similar steady-state, frequency-dependent (0.1--4.0 Hz) changes in Vmax were observed in tissues exposed to papaverine (10(-5), Ba2+ (0.2 mM, 0.8 mM), or isoproterenol (5 x 10(-7) M). Verapamil (10(-7) M) caused a marked frequency-dependent inhibition of Vmax relative to the Ba2+-treated condition. Step increases in stimulation frequency resulted in a new steady state after only one to three depolarizations under all conditions except during exposure to verapamil. Vmax decreased exponentially after an increase in stimulation frequency during verapamil exposure, and therefore required many stimuli before a new quasi-steady-state was attained. The time constant for the recovery from inactivation of Isi determined by a paired pulse protocol was 169 +/- 16 ms for 10(-5) M papaverine, 185 +/- 14 ms for 0.8 mM Ba2+, and about 390 ms for 10(-7) M verapamil. The time required for half-recovery of Vmax after a train of 1-Hz stimuli (preceded by a rest period) was 2.5--3 s for papaverine or Ba2+ but 30--38 s for verapamil-treated preparations. The results show that papaverine is not a Ca antagonist like verapamil. The results also suggest that Ba2+ may be useful for restoring excitability in K-depolarized tissues to study the frequency-dependent changes in Vmax caused by drugs that alter Isi.