Mechanisms of long-lasting effects of benidipine on Ca current in guinea-pig ventricular cells.

1. Benidipine (KW-3049), a new derivative of 1,4-dihydropyridine (DHP), showed dose-dependent inhibition of Ca current (ICa) which was elicited by depolarization from -40 mV to +10 mV at 0.2 Hz in single cardiac cells isolated from guinea-pig ventricle under whole cell voltage clamp. Half inhibition doses (IC50) of benidipine and nifedipine for the peak ICa at +10 mV were 2.7 nM and 63.1 nM, respectively. 2. A change in holding potential from -40 to -75 mV partially removed the block induced by both 10 nM benidipine and 100 nM nifedipine. The block of ICa by benidipine strongly depended upon holding potentials as did that induced by nifedipine. 3. The effect of 100 nM nifedipine was mostly removed when the cells were kept quiescent at holding potentials negative to -75 mV for 5 min after withdrawal of nifedipine. In contrast, hyperpolarization for several minutes did not significantly accelerate the removal of benidipine-induced block after withdrawal of the drug. Effects of 10 nM benidipine could not be washed out for up to 30 min regardless of the holding potentials. 4. It is suggested that the dissociation of benidipine from the DHP binding site, like that of nifedipine, is greatly accelerated by hyperpolarization. Benidipine but not nifedipine may have an additional interaction with the channel or lipid membrane and cannot be washed away even after the dissociation. Alternatively, the dissociation of benidipine from the DHP binding site may be too slow to occur substantially during the limited period of hyperpolarization in the present study (less than 30 min). In that case, however, the Ca channel bound by benidipine must become unblocked and available to be opened during the hyperpolarization.