Functional interaction between benzothiazepine- and dihydropyridine binding sites of cardiac L-type Ca2+ channels

We have previously shown, in a radioligand binding study with single ventricular myocytes, that benzothiazepine and dihydropyridine binding sites interact with each other. To further examine whether this interaction between the two binding sites is reflected in the function of L-type Ca2+ channels, the blocking action of diltiazem, nitrendipine, and the combination of these two drugs on L-type Ca2+ channel currents was investigated using baby hamster kidney cells expressing the alpha 1C, alpha 2/delta, beta and gamma subunits of the Ca2+ channel. The effects of diltiazem and nitrendipine were additive at room temperature but synergistic at 33 degrees C. The use-dependent block by 3 microM of diltiazem was significantly enhanced from 28% to 68% by addition of 30 nM of nitrendipine, which by itself did not have a blocking effect. Thus, we conclude that benzothiazepine- and dihydropyridine binding sites interact and potentiate their blocking action on L-type Ca2+ channels in a temperature-dependent manner.