ALLOSTERIC INTERACTIONS AT L-TYPE CALCIUM CHANNELS BETWEEN FPL-64176 AND THE ENANTIOMERS OF THE DIHYDROPYRIDINE BAY-K-8644

Functional interactions between the enantiomers of the dihydropyridine -5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid me thyl ester (Bay K 8644) and the benzoylpyrrole methyl 4-[2(phenylmethy l)benzoyl]-H-pyrrole-3-carboxylate (FPL 64176) were investigated on L- type Ca++ channels in guinea pig ileal longitudinal smooth muscle. The effects of these drugs, when applied individually, were as described in earlier studies. For instance, both (-)-(S)-Bay K 8644 and FPL 6417 6 caused concentration-dependent contraction, which is consistent with Ca++ channel activation, whereas (+)-(R)-Bay K 8644 gave concentratio n-dependent relaxation, which is consistent with Ca++ channel inhibiti on. The activities of the different drugs were dependent on the extrac ellular levels of KCI. When applied in combination, however, the respo nses evoked were not those predicted from the effects of the drugs app lied individually. Contractions produced by FPL 64176 (25 nM to 1 mu M ) were abolished in the presence of 100 nM (-)-(S)-Bay K 8644 but were potentiated by 10 to 150 nM (+)-(R)-Bay K 8644 and inhibited by 1 mu M (+)-(R)-Bay K 8644. Conversely, contractile responses to (-)-(S)-Bay K 8644 were abolished by 100 nM FPL 64176. In the presence of 1 mu M FPL 64176, however, (-)-(S)-Bay K 8644 gave concentration-dependent re laxation of the muscle, which is consistent with Ca++ channel inhibiti on. The relaxant effects of (+)-(R)-Bay K 8644 at concentrations up to 100 nM were opposed by FPL 64176, but the response to 1 mu M (+)-(R)- Bay K 8644 was unaffected by FPL 64176. These results demonstrate func tional interactions between FPL 64176 and the enantiomers of Bay K 864 4. They are consistent with allosteric coupling between a receptor for FPL 64176 and two dihydropyridine receptors on the L-type Ca++ channe l.