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
Ga. Skeen et al., 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 Journal of pharmacology and experimental therapeutics, 271(1), 1994, pp. 30-38
The 1,4-dihydropyridine (DHP) nitrendipine was previously shown to con
centration-dependently (0.1-1 mu M) reduce N-methyl-D-aspartate (NMDA)
-evoked calcium influx and single-channel activity of mouse cerebellar
granule cells and to reduce [H-3]dizocilpine (MK-801) binding to mous
e cortical and hippocampal membranes. Using patch-clamp electrophysiol
ogy, the present study was designed to understand further the specific
mechanism of interaction between nitrendipine and NMDA receptors. Exp
eriments were conducted with primary cultures of rodent cortical neuro
ns and utilized whole-cell and excised outside-out patch configuration
s. NMDA-evoked whole-cell currents were reduced by nitrendipine (1 mu
M) in a voltage- and an agonist-dependent manner suggesting that nitre
ndipine interacts with NMDA receptors by a mechanism similar to that d
escribed for open channel blockers, such as extracellular magnesium an
d the dissociative anesthetics (e.g., MK-801). To examine this further
, the effects of nitrendipine on NMDA-evoked single-channel activity w
ere quantitated from outside-out patch recordings. In these studies, n
itrendipine reduced the frequency of openings and bursts, reduced the
average duration of openings and bursts and reduced the single open ti
me constant for the main conductance (48 pS) in a concentration (0.03-
1 mu M)- and voltage-dependent manner. Because these effects of nitren
dipine on NMDA-evoked currents were not readily reversible, the rate o
f nitrendipine dissociation is probably slower than the rate of NMDA-a
ctivated channel closing. Nitrendipine did not alter the main channel
conductance at any concentration tested. Based on these results, a kin
etic model of interaction between nitrendipine and NMDA receptors is p
roposed that is most similar to that previously described for MK-801.