Sodium nitroprusside inhibits N-methyl-D-aspartate-evoked calcium influx via a nitric oxide- and cGMP-independent mechanism.
In primary cultures of rat cerebellar granule cells, sodium nitroprusside (SNP), a vasodilator that generates nitric oxide (NO), potently inhibited N-methyl-D-aspartate (NMDA)-evoked 45Ca2+ influx (IC50 = 6.6 microM). This inhibition was time dependent and was complete when SNP was applied 10 min before NMDA stimulation. The effect of SNP was transient and the ability of NMDA to stimulate 45Ca2+ influx was restored after SNP withdrawal. The effect of SNP was selective for the NMDA-sensitive glutamate receptor, because SNP failed to antagonize kainate-stimulated 45Ca2+ influx. The action of SNP was independent of the ability of this agent to generate NO; S-nitroso-N-acetylpenicillamine, an NO-containing compound that was 100 times more potent than SNP in stimulating cGMP accumulation, failed to inhibit NMDA-evoked 45Ca2+ influx. In contrast, K4Fe(CN)6, a compound structurally similar to SNP but devoid of NO, inhibited both 45Ca2+ influx (IC50 = 27 microM) and cGMP accumulation evoked by NMDA; K3Fe(CN)6 was inactive. Thus, in cerebellar granule cells, SNP and K4Fe(CN)6 interfere with the function of NMDA receptors, possibly at the level of the receptor recognition site. The resulting blockade of Ca2+ influx through NMDA receptor channels accounts for the reported ability of these compounds to protect granule cells from NMDA-induced neurotoxicity. This protection is not mediated by an NO-dependent mechanism but depends on the action of the ferrocyanide portion of the SNP molecule.
Kiedrowski
L
L
Fidia-Georgetown Institute for the Neurosciences, Georgetown University School of Medicine, Washington, DC 20007.
Costa
E
E
Wroblewski
J T
JT
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D009599:Nitroprusside; D009569:Nitric Oxide; D016202:N-Methylaspartate; D006152:Cyclic GMP; D002118:Calcium