Respiratory effects produced by microinjection of L-glutamate and an uptake inhibitor of L-glutamate into the caudal subretrofacial area of the medulla.
The purposes of our study were to determine the type of respiratory changes that would occur when either an excitatory amino acid receptor agonist or an uptake inhibitor was administered into the caudal subretrofacial area. This was done by microinjecting either L-glutamate or L-pyrrolidine-2,4-dicarboxylate (L-trans-2,4-PDC) into the caudal subretrofacial area while monitoring tidal volume, respiratory rate, mean arterial blood pressure and heart rate. Bilateral microinjection of 2.5 nmol of L-glutamate into the caudal subretrofacial area produced apnea in eight of eight animals tested, and the duration of apnea was 27 +/- 2 s. To determine the type of L-glutamate receptor responsible for mediating the apneic response, antagonists of the N-methyl-D-aspartate (NMDA) and non-NMDA receptor, namely, 3-[(RS)-carboxypiperazin-4-yl]-propyl-phosphonic acid (CPP), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively, were tested. Neither antagonist in doses that blocked NMDA (in the case of CPP) and amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) (in the case of CNQX) blocked apnea elicited by L-glutamate. In addition, kynurenic acid, an antagonist of NMDA and non-NMDA ionotropic receptors, failed to block the effect of L-glutamate. Microinjection of the metabotropic receptor agonist drug, trans-L-1-amino-1,3-cyclopentone-dicarboxylic acid (L-trans-ACPD), into the caudal subretrofacial area failed to have any effect on respiratory activity. Because of the inability to block the effect of L-glutamate in the caudal subretrofacial area, and the lack of effect of L-trans-ACPD, the data suggest that the apneic response produced by L-glutamate is mediated by an as yet undefined receptor. Microinjection of the L-glutamate uptake inhibitor, L-trans-2,4-PDC, was found to produce apnea. Using the dose of 0.5 nmol of L-trans-2,4-PDC, we examined the type of excitatory amino acid receptor that mediated the response. Neither pretreatment with the NMDA receptor antagonist, CPP, nor the non-NMDA receptor antagonist, CNQX, affected L-trans-2,4-PDC-induced apnea. However, combined use of these two antagonists prevented L-trans-2,4-PDC-induced apnea. These data suggest that the effect of synaptically released exitatory amino acid at the caudal subretrofacial area on breathing is apnea, and that this effect is mediated by simultaneous activation of both NMDA and non-NMDA ionotropic receptors.
McManigle
J E
JE
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Panico
W H
WH
DaSilva
A M
AM
Gillis
R A
RA
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001049:Apnea / Q000139:chemically induced; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests; D013990:Tidal Volume / Q000187:drug effects; D014275:Trigeminal Caudal Nucleus / Q000187:drug effects* / Q000378:metabolism
D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D011759:Pyrrolidines; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D007736:Kynurenic Acid