Paradoxical nifedipine facilitation of 45Ca uptake into rat hippocampal synaptosomes

Nifedipine has a high incidence of neurologic adverse reactions as compared with other dihydropyridine Cav1 (L-type) channel blockers used for treating cardiovascular diseases. The mechanism mediating neuronal excitation by nifedipine is still in debate. Nifedipine caused a dual role on veratridine-induced 45Ca uptake by rat hippocampal synaptosomes. In the nanomolar range (0.001-0.3 μM), nifedipine decreased 45Ca uptake in a cadmium-sensitive manner. In contrast with nitrendipine (0.001-10 μM), nifedipine consistently facilitated 45Ca accumulation when used in low micromolar concentrations (0.3-10 μM). The cadmium-insensitive nifedipine facilitation became less evident upon increasing veratridine concentration from 5 to 20 μM and was not detected when the synaptosomes where depolarised with 30 mM KCl. Na+ substitution by N-methyl-d-glucamine (132 mM) or blockade of Na+ currents with tetrodotoxin (1 μM) both prevented nifedipine excitation. The Na+/Ca2+-exchanger inhibitor, KB-R7943 (3-50 μM), did not reproduce nifedipine actions. Data suggest that tetrodotoxin-sensitive Na+ channels may operate paradoxical nifedipine facilitation of 45Ca uptake by rat hippocampal synaptosomes.