Frequency-Dependence of Vmax in K-Depolarized Guinea Pig Ventricle

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Abstract
Right ventricular strips from guinea pig hearts were used to compare the effects of nifedipine and verapamil on the maximal upstroke velocity (Vmax) of rapid depolarization in potassium-depolarized preparations. The Vmax was used as an indirect measure of the slow inward current (1). Barium (0.8 m M) was added to the Tyrode solution to restore excitability of the K-depolarized tissue. The effects of nifedipine and verapamil on rested state Vmax(VmaxRS). frequency-dependent changes in Vmax and recovery of Vmax as a function of diastolic interval were studied. The depression of Vmax at rested state (RS). following 3–5-min rest, was concentration-dependent for both drugs, although the effect of nifedipine was greater. The percentage depression of VmaxRSby nifedipine was 24.3 + 6.4 at 10 8M, 51.3 + 2.6 at 5 x 10 8M, and 74.0 + 1.0 at 10 M. For verapamil the values were 6.2 + 3.8 at 10 M. 13.1 + 0.9 at 5 x 10 7M, and 42.0 + 0.5 at 10 M. The depression of Vmax by each drug was frequency-dependent over a range from 0.05 to 2.0 Hz. Frequency-dependence was quantitatively greater with verapamil. The kinetics of recovery of Vmax were assessed by means of paired stimuli given at varying diastolic intervals during recovery from a RS depolarization. The recovery curve was biexponential. In the drug-free condition, the time constant for the first phase of recovery (T) was 140 + 12 ms and the time constant for the second phase (T) was 2689 + 146 ms. Alteration of T by either nifedipine or verapamil was not statistically significant, although the trend was a concentration-dependent increase. Both drugs produced a significant concentration-dependent increase in T. The values for nifedipine were 3.418 + 53 ms at 10 8M. and 5.125 × 211 ms at 5 x 10 8M. For verapamil the values were 3.449 × 123 ms at 10 8M. 5.409 × 206 ms at 5 a 10M, and 7.846 + 258 ms at 10 M. Based upon the changes in Vmax it is concluded that nifedipine is five to seven times more depressant to I in guinea pig ventricular tissue than is verapamil. The action of nifedipine on the Ca2 channel is frequency-dependent and is associated with a drug-induced delay in the recovery of Vmax following prior depolarization. However, frequency-dependence is less prominent with nifedipine than with verapamil. On the other hand, frequency-independent depression is much greater with nifedipine.