Ketamine inhibits glutamate-, N-methyl-D-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons

• Published in: Anesthesiology (Philadelphia) 1995, Vol.82 (1), p.205-213
• Main Authors: GONZALES, J. M, LOEB, A. L, REICHARD, P. S, IRVINE, S
• Format: Article
• Language: English
• Subjects: Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Brain - cytology; Brain - drug effects; Cells, Cultured; Cyclic GMP - biosynthesis; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - pharmacology; Ketamine - pharmacology; Medical sciences; N-Methylaspartate - antagonists & inhibitors; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Nitric Oxide - biosynthesis; Nitroprusside - pharmacology; Pharmacology. Drug treatments; Quisqualic Acid - antagonists & inhibitors; Rats; Rats, Sprague-Dawley
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-199501000-00025

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). 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. 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. 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.