Inhibitory effects of anesthetics on cyclic guanosine monophosphate (cGMP) accumulation in rat cerebellar slices.
General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
Terasako
K
K
Department of Anesthesia, Kyoto University Hospital, Japan.
Nakamura
K
K
Miyawaki
I
I
Toda
H
H
Kakuyama
M
M
Mori
K
K
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000096:biosynthesis*; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013874:Thiopental / Q000494:pharmacology
D000777:Anesthetics; D009599:Nitroprusside; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; D013874:Thiopental; D006221:Halothane