THE DIHYDROPYRIDINE NITRENDIPINE MODULATES N-METHYL-D-ASPARTATE RECEPTOR-CHANNEL FUNCTION IN MAMMALIAN NEURONS

Nitrendipine and other dihydropyridine voltage-sensitive calcium chann el (VSCC) antagonists have been demonstrated to possess anticonvulsant and neuroprotectant activity in a variety of model systems. Likewise, antagonists of the NS-methyl-D-aspartate (NMDA) glutamate receptor su btype act as potent anticonvulsant and neuroprotective agents. Both VS CC and NMDA antagonists exert their effects by inhibiting the neuronal influx of calcium associated with activation of VSCCs or the NMDA rec eptor, respectively. Although results that provide evidence for cross- reactivity between compounds acting at dihydropyridine-sensitive VSCCs and the NMDA receptor-channel complex have been reported, direct modu lation of NMDA receptor function by dihydropyridines has not been demo nstrated. In the present investigation, we report that nanomolar conce ntrations of nitrendipine reduced NMDA/glycine-evoked calcium flux and single-channel current in mouse cerebellar granule cell cultures. As measured with the calcium-specific probe indo-1, nitrendipine (0.1-10 mum) attenuated inward calcium flux evoked by bath application of NMDA (100 mum) and glycine (100 mum), in a concentration-dependent (IC50, 0.56 +/- 0.21 muM; 95% confidence interval, 0.191. 3 mum) and reversib le manner. Over a similar concentration range (0.01-100 mum), nitrendi pine also inhibited the binding of [H-3]MK-801 to mouse cortical and h ippocampal membranes (IC50, 0.56 +/- 0.12 mum; 95% confidence interval , 0.37-0.84 mum). Finally, nitrendipine concentration- and voltage-dep endently reduced the frequency of NMDA (10 mum)- and glycine (1 muM)ev oked single-channel openings and bursts recorded from excised outside- out patches of mouse cerebellar granule cells. These results indicate that nitrendipine suppresses NMDA/glycine-mediated calcium influx by a rapid and direct interaction with the NMDA receptor-channel complex. Furthermore, these results suggest that the interaction of nitrendipin e with the NMDA receptor-channel complex is not tissue specific and pr obably does not require participation of calcium-dependent second mess enger systems. Together, the data presented here support the novel hyp othesis that nitrendipine may exhibit anticonvulsant and neuroprotecta nt activity via the combined ability to modulate both NMDA-associated ion channels and L-type VSCCs.