The non-dihydropyridine L-type voltage-sensitive calcium channel activator FPL 64176 enhances K(+)-evoked efflux of [3H]norepinephrine from rat neocortical slices.

The non-dihydropyridine FPL 64176 (methyl-2,5-dimethyl-4-(2-phenylmethyl)benzoyl-[1-H]pyrrole-3-carboxy la te) was tested for an interaction with neuronal L-type voltage-sensitive calcium channels (L-VSCCs) by using a [3H]isradipine ([3H]ISR) binding assay, and for its ability to enhance K(+)-evoked [3H]norepinephrine ([3H]NE) release from rat neocortical slices. The classical L-VSCC activator, the dihydropyridine (DHP) BAY K 8644, was also used for comparative purposes. FPL 64176 and BAY K 8644 both produced a similar concentration-dependent enhancement of 15 mM K(+)-evoked [3H]NE release which could be completely blocked by the L-VSCC blocker ISR (0.1 microM). FPL 64176, in contrast to BAY K 8644, was a very weak inhibitor of [3H]ISR binding to L-VSCCs. These findings indicate that FPL 64176 is a novel non-dihydropyridine L-VSCC activator, most probably by acting on a site different from the DHP binding site.