The role of NMDA and non-NMDA receptors in the NTS in mediating three distinct sympathoinhibitory reflexes.
Cholecystokinin (CCK) elicits a sympathetic vasomotor reflex that is implicated in gastrointestinal circulatory control. We sought to determine (1) the site in the solitary tract nucleus (NTS) responsible for mediating this reflex and (2) the possible involvement of excitatory amino acid (EAA) receptors. In addition, we sought to determine whether the NTS site responsible for mediating the baroreflex (phenylephrine, PE, 10 microg/kg i.v.) and the von Bezold-Jarisch reflex (phenylbiguanide, PBG, 10 microg/kg i.v) overlap with that involved in the CCK-induced reflex (CCK, 4 microg/kg, i.v.), and to compare the relative importance of NMDA and non-NDMA receptors in these reflexes. In separate experiments, the effects of PE, PBG, and CCK on mean arterial blood pressure, heart rate, and splanchnic sympathetic nerve discharge were tested before and after bilateral microinjection into the NTS of the gamma-aminobutyric acid(A) (GABA(A)) agonist muscimol, the EAA antagonist kynurenate, the NMDA receptor antagonist D: (-)-2-amino-5-phosphopentanoic acid (AP-5), the non-NMDA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), AP-5 + NBQX, or vehicle. While all treatments (except vehicle) significantly attenuated/abolished/reversed the splanchnic sympathoinhibitory responses to PE, PBG, and CCK, the extent of blockade varied between the different treatment groups. Both NMDA and non-NMDA receptors were essential to the baroreflex and the von Bezold-Jarisch reflex, whereas the CCK reflex was more dependent on non-NMDA receptors. Muscimol, kynurenate, and AP-5 + NBQX significantly attenuated the bradycardic responses to PE and PBG (P < 0.05), whereas AP-5, NBQX, or vehicle did not. The bradycardic responses to CCK remained intact after all treatments. These results suggest that while there is overlap in the area of the NTS responsible for eliciting all three reflexes, NMDA and non-NMDA receptors are recruited differentially for the full expression of these reflexes. The CCK-induced sympathoinhibitory reflex is unique in that it relies predominantly on non-NMDA receptors in the NTS and elicits bradycardic effects that are independent of the NTS.
Sartor
Daniela M
DM
Department of Medicine, Clinical Pharmacology and Therapeutics Unit, Austin Health, University of Melbourne, Heidelberg, Victoria, 3084, Australia. dsartor@unimelb.edu.au
Verberne
Anthony J M
AJ
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002766:Cholecystokinin / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012018:Reflex / Q000502:physiology*; D017552:Solitary Nucleus / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
D015763:2-Amino-5-phosphonovalerate; D001645:Biguanides; D002766:Cholecystokinin; D018755:GABA Agonists; D007736:Kynurenic Acid; D009118:Muscimol; D010656:Phenylephrine; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C008846:phenyl biguanide