The dihydropyridine nitrendipine reduces N-methyl-D-aspartate (NMDA)-evoked currents of rodent cortical neurons through a direct interaction with the NMDA receptor-associated ion channel.
The 1,4-dihydropyridine (DHP) nitrendipine was previously shown to concentration-dependently (0.1-1 microM) reduce N-methyl-D-aspartate (NMDA)-evoked calcium influx and single-channel activity of mouse cerebellar granule cells and to reduce [3H]dizocilpine (MK-801) binding to mouse cortical and hippocampal membranes. Using patch-clamp electrophysiology, the present study was designed to understand further the specific mechanism of interaction between nitrendipine and NMDA receptors. Experiments were conducted with primary cultures of rodent cortical neurons and utilized whole-cell and excised outside-out patch configurations. NMDA-evoked whole-cell currents were reduced by nitrendipine (1 microM) in a voltage- and an agonist-dependent manner suggesting that nitrendipine interacts with NMDA receptors by a mechanism similar to that described for open channel blockers, such as extracellular magnesium and the dissociative anesthetics (e.g., MK-801). To examine this further, the effects of nitrendipine on NMDA-evoked single-channel activity were quantitated from outside-out patch recordings. In these studies, nitrendipine reduced the frequency of openings and bursts, reduced the average duration of openings and bursts and reduced the single open time constant for the main conductance (48 pS) in a concentration (0.03-1 microM)- and voltage-dependent manner. Because these effects of nitrendipine on NMDA-evoked currents were not readily reversible, the rate of nitrendipine dissociation is probably slower than the rate of NMDA-activated channel closing. Nitrendipine did not alter the main channel conductance at any concentration tested. Based on these results, a kinetic model of interaction between nitrendipine and NMDA receptors is proposed that is most similar to that previously described for MK-801.
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
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Skeen
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White
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Twyman
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005260:Female; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D009568:Nitrendipine