Ketamine inhibits glutamate-, N-methyl-D-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons.
BACKGROUND
Glutamatergic signaling has been linked to the recently discovered neurotransmitter/neuromodulator nitric oxide (NO), and several classes of anesthetics block some step in glutamatergic signaling. This study was designed to determine whether or not ketamine would prevent NO-dependent cGMP production stimulated by glutamate (GLU) and the GLU analogs NMDA, quisqualate (QUIS), and kainate (KAIN).


METHODS
Primary cultures of cortical neurons and glia (prepared from 16-day gestational rat fetuses) were used after 12-16 days in culture. Reactions were carried out in magnesium-free buffer containing 100 microM 3-isobutyl-1-methylxanthine, and cGMP content of cultures was used as a bioassay of NO production.


RESULTS
Cyclic GMP production stimulated by sodium nitroprusside (100 microM) occurred predominately in neurons and not in glia. Neurons were spontaneously active in these cultures; basal cGMP production was decreased by 50% in the presence of 1 microM tetrodotoxin (TTX). Glutamate (100 microM), NMDA (100 microM), QUIS (300 microM), and KAIN (100 microM) each increased cGMP content of neuronal cultures. L-NMMA (100 microM), a NO synthase inhibitor, prevented the stimulation of cGMP production by GLU or its analogs. Pretreatment with MK-801 (1 microM) or ketamine (10-100 microM) inhibited GLU-, NMDA-, and QUIS-stimulated cGMP production. Quisqualate-stimulated responses were the most sensitive to inhibition by ketamine and NMDA-stimulated responses were the least sensitive to inhibition. MK-801 and ketamine did not significantly inhibit KAIN-stimulated cGMP production. CNQX (10 microns) blocked KAIN-stimulated cGMP production only.


CONCLUSIONS
The authors' data demonstrate that ketamine inhibited NO synthesis stimulated by NMDA- and non-NMDA-receptor specific analogs. Our findings indicate that blockade of QUIS- as well as NMDA-subtypes of GLU- receptor may be important in the development of ketamine-induced anesthesia.
Department of Anesthesia, University of Pennsylvania, Philadelphia.
J M
JM
Gonzales
A L
AL
Loeb
P S
PS
Reichard
S
S
Irvine
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D016318:Quisqualic Acid / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D009599:Nitroprusside; D009569:Nitric Oxide; D018698:Glutamic Acid; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D016318:Quisqualic Acid; D006152:Cyclic GMP