Nifedipine inhibits movement of cardiac calcium channels through late, but not early, gating transitions

L-type Ca²⁺ channels were studied in guinea pig ventricular myocytes by examining how photoinactivation of nifedipine affected the Ca²⁺ current (I(Ca)) and the Ca²⁺ channel gating current (Ig). 1(Ca), blocked by nifedipine, reappeared in qualitatively different phases (immediate and delayed) following photoinactivation of nifedipine. Immediate recovery was attributed to unblock of closed Ca²⁺ channels, while delayed recovery was attributed to unblock of inactivated channels. In contrast to the I(Ca) results, photoinactivation of nifedipine produced only delayed recovery of I(g). Analysis of these results suggests the following conclusions. First, the actions of inhibitory dihydropyridines can be attributed to binding to either the inactivated or the closed conformation, but only binding to the inactivated state is associated with reduction of I(g). Second, the action of inhibitory dihydropyridines on closed channels is to retard their movement through a final, voltage-independent transition to the open state. This effect seems to be the converse of a major action of stimulatory dihydropyridines and thus is the principal mechanistic difference between stimulatory and inhibitory dihydropyridines.