Inhibition of excitatory neurotransmitter-nitric oxide signaling pathway by inhalational anesthetics.
Primary cultures of cerebral neurons of Sprague-Dawley rats increased cyclic GMP production in response to the stimulation of excitatory amino acids, including N-methyl-D-aspartate, quisqualate, kainate and (+/-)-1-aminocylopentane-trans-1,3-dicarboxylic acid. This increased cyclic GMP production was significantly inhibited by halothane or isoflurane at clinically relevant concentrations (0.5-2%). This inhibition was reversible by treatment with L-arginine, the substrate of nitric oxide synthase. However, the increase of cyclic GMP production stimulated by sodium nitroprusside, an activator of soluble guanylate cyclase, was not inhibited by halothane or isoflurane. Neither halothane nor isoflurane affected the basal cyclic GMP production. Activation of the excitatory amino acid neurotransmitter-stimulated nitric oxide-guanylate cyclase signaling pathway increases intracellular cyclic GMP content in neurons. Our results suggest that halothane or isoflurane inhibited this signaling pathway stimulated by selective agonists of each subtype of receptors for excitatory amino acid neurotransmitters. This inhibition may be involved in mechanisms of anesthesia and analgesia. The site(s) of the inhibition is (are) proximal to the activation of neuronal nitric oxide synthase.
Zuo
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Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville 22906-0010, USA.
Tichotsky
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Johns
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D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D006221:Halothane / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D009599:Nitroprusside / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009599:Nitroprusside; D009569:Nitric Oxide; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; D001120:Arginine; D007530:Isoflurane; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D007608:Kainic Acid; D006221:Halothane