Dual action of FRC8653, a novel dihydropyridine derivative, on the Ba²⁺ current recorded from the rabbit basilar artery

Actions of FRC8653 on the macroscopic and unitary Ba²⁺ currents were studied using the rabbit basilar artery. Application of (±)-FRC8653 (<1 μM) increased the amplitude of the inward current when depolarization pulses more negative than -10 mV were applied but inhibited it when depolarization was more positive than 0 mV (in each case from a holding potential of -80 mV). At a holding potential of -40 mV, (±)-FRC8653 (>0.1 nM) consistently inhibited the inward current. (-)-FRC8653 (>1 nM) inhibited the amplitude of the inward current evoked by a depolarizing pulse more positive than -10 mV (the holding potential being -80 mV). At the holding potential of -80 mV, but not at -40 mV, (+)-FRC8653 (1 μM) enhanced the current amplitude evoked by a depolarizing pulse more negative than -10 mV but inhibited the current evoked by a pulse more positive than 0 mV. (±)-FRC8653 shifted the voltage-dependent inhibition curves to the left, and the slope of the curve became steeper (test pulse of +10 mV). Two types of single Ca²⁺ channel currents (12 and 23 pS) were recorded from the basilar artery by the cell-attached patch-clamp method. Opening of the 12-pS channel occurred with a depolarizing pulse (-20 mV) from a holding potential of -80 mV, but not from one of -60 mV. (+)-FRC8653 activated, and (-)-FRC8653 inhibited, the 23-pS channel. These results indicate that (+)-FRC8653 had dual actions (excitatory and inhibitory) on the Ca²⁺ channels in the rabbit basilar artery. Excitatory actions of (±)-FRC8653 result mainly from the actions of (+)-FRC8653 on the 23-pS channel, but this was reversed to an inhibitory action at a holding potential of -40 mV. Therefore, FRC8653 dominantly acts as a Ca²⁺ channel blocker in the rabbit basilar artery, since this tissue has a resting membrane potential of -50 to -60 mV.