The role of dihydropyridine voltage-sensitive calcium channel antagonists as N-methyl-D-aspartate antagonists

Nitrendipine and other 1,4-dihydropyridine (DHP) voltage-sensitive calcium channel (VSCC) antagonists have been shown to possess anticonvulsant and neuroprotectant activity in a variety of model systems. Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype are also anticonvulsant and neuroprotectant. Both VSCC and NMDA antagonists exert their effects by inhibiting the neuronal influx of calcium associated with activation of VSCCs or NMDA receptors, respectively. Although results which provide evidence for cross-reactivity between compounds acting at DHP-sensitive VSCCs and NMDA receptors have been reported, direct modulation of NMDA receptor function by DHPs has not been demonstrated. The objectives of this investigation were to determine (1) if the DHP nitrendipine modulates NMDA receptor function, (2) if this effect of nitrendipine can be observed within various brain structures, (3) the specific mechanism of nitrendipine's interaction with NMDA receptors, and (4) if the effects of nitrendipine are universal for all, or for only specific DHP compounds. Nitrendipine reduced NMDA-evoked calcium flux (measured via the calcium-specific fluorescent probe indo-1) into mouse cerebellar granule cells in a concentration-dependent manner. Over a similar concentration range, nitrendipine reduced the binding of the NMDA antagonist [3H] dizocilpine (MK-801) to mouse brain sections and cortical and hippocampal membranes. Therefore, nitrendipine reduced the function of NMDA receptors throughout mouse brain. A mechanism which could account for nitrendipine's effects on NMDA receptor function was identified via patch clamp electrophysiology with primary cultures of rodent cortical neurons. In these studies, nitrendipine voltage- and use-dependently reduced NMDA-evoked whole-cell current in a manner which was accounted for by reductions in single-channel kinetics (open and burst frequencies and average durations, and the open time constant). Collectively, these results suggest that nitrendipine interacts with NMDA receptors by a mechanism most similar to the open channel trap block model described for the interaction of MK-801 with NMDA receptors. This interaction of nitrendipine with NMDA receptors may be unique amongst the DHPs since similar concentrations of the DHPs nimodipine and nifedipine did not greatly affect NMDA-evoked calcium influx, [3H] MK-801 binding or NMDA-evoked currents.