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The effects of nifedipine and nicardipine, 2 dihydropyridines (DHP) used in the treatment of cardiovascular disorders, were compared in frog atrial fibers. Rapid photolysis of nifedipine with a single UV flash (1-ms duration) reversed the block, allowing comparison of effects of both drugs on the same preparation, and manipulation of the calcium channel on a millisecond timescale. The results show that inhibition of the action potential (AP) and slow inward current (Isi) is more pronounced with nifedipine than with nicardipine. Concentration-effect relationships confirm that nicardipine (IC50 = 1 microM) is less potent than nifedipine (IC50 = 0.2 microM) in blocking cardiac calcium channels. Both DHP block calcium channels in the closed state at the resting potential, inducing a large tonic block (in the absence of stimulation). An additional phasic block can be observed with nifedipine and nicardipine. A slight voltage dependence to the block is observed for both DHP, their effects being enhanced depolarization holding potentials. Rapid unblocking of calcium channels by a single light flash, presented during the decay phase of Isi, reveals a higher affinity of DHP for inactivated channels. This effect is most pronounced when inactivation is slowed by using Ba++, Sr++, or Na+ ions as the current carriers. Open channel block is also suggested. The mechanism of DHP action on calcium channels can be described according to the "modulated receptor hypothesis". These DHP exhibit an additional nonspecific effect on potassium channels. It is concluded that nicardipine is a less potent Ca++ antagonist than nifedipine in atrial fibers and that the reduction of delayed potassium current, which occurs in a similar range of concentrations to the blockade of Isi, could also be involved in its therapeutic effects.

The double electrode voltage-clamp technique was used to study voltage-dependent Ca*' channels in Pleurodeles oocytes. From a holding potential of -80 mV, Ba-current (ZBa) (recorded in Cl-free solution, Ba 2+ = 40 mM) activated at -36.7 + 4 mV, peaked at -11.6 f 4 mV and reversed at 55 + 7 mV (n = 24). This current activated slowly (rise time was 0.98 f 0.2 s; n = 14 at -10 mV) and was not inactivated. Cadmium (Cd", 5OOpM) completely inhibited I,,. The effect of Cd2+ was dose-dependent (ECSo = 37 + 5pM; n = 5). Moreover, ZBa was insensitive to w-conotoxin (10pM) but interestingly this ZBa displayed dihydropyridine (DHP) sensitivity. Bay K 8644 (SpM), a DHP activator, increased the peak current amplitude in a dose-dependent manner (EC,,, = 5.9 f 0.6 PM; n = 10) and shifted the threshold and the maximum of current/voltage relationship towards negative potentials by -10 mV. Nifedipine (5 PM), a DHP antagonist, decreased Z,, by 80% at HP of -80 mV (EC,, = 1.2 + 0.2 PM; n = 6). We concluded that Pleurodeles oocytes possess High-Voltage Activated Ca" channels with properties similar to L-type Ca" channels.