2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and phenyl-biguanide

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.

Topics: 2-Amino-5-phosphonovalerate; Animals; Biguanides; Blood Pressure; Cholecystokinin; GABA Agonists; Heart Rate; Kynurenic Acid; Male; Muscimol; Phenylephrine; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Reflex; Solitary Nucleus; Synaptic Transmission

1. We sought first to determine whether neurones in caudomedial aspects of commissural nucleus tractus solitarii (NTS) received input from cardiopulmonary C fibre endings supplied by the pulmonary versus systemic circulation. We then examined the role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in transmitting cardiopulmonary C fibre input to such NTS neurones. 2. Extracellular NTS unit activity, phrenic nerve activity and arterial blood pressure were recorded in urethane-anaesthetized rats. Unit responses to right atrial and left ventricular phenylbiguanide injections were compared in rats with arterial baroreceptors, carotid chemo-receptors and subdiaphragmatic vagal inputs eliminated. Right atrial phenylbiguanide injections produced greater peak responses (27 +/- 11 impulses s-1) than did left ventricular injections (11 +/- 3 impulses s-1) (n = 9). 3. The non-NMDA receptor agonist quisqualic acid (QUIS) and NMDA were ionophoresed onto NTS neurones that were synaptically activated by right atrial phenylbiguanide injection. Responses were compared before and during ionophoresis of the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(f)quinoxaline (NBQX), the NMDA receptor antagonist DL-2-amino-5-phosphovaleric acid (AP5), or the broad spectrum antagonist kynurenic acid (KYN). 4. NBQX, which blocked QUIS-but spared NMDA-evoked responses, significantly attenuated synaptic activation by 65% (n = 9). AP5, which blocked NMDA- but spared QUIS-evoked responses, did not significantly diminish synaptic activation (11%; n = 7). KYN, which blocked QUIS- and NMDA-evoked responses, decreased synaptic activation by 70% (n = 9). 5. The results suggest that input from cardiopulmonary C fibre endings, primarily supplied by the pulmonary circulation, is transmitted to this commissural NTS region largely via non-NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Afferent Pathways; Animals; Biguanides; Brain Mapping; Chemoreceptor Cells; Excitatory Amino Acid Antagonists; Heart; Heart Atria; Heart Conduction System; Heart Ventricles; Kynurenic Acid; Lung; Male; N-Methylaspartate; Nerve Fibers; Neurons; Pressoreceptors; Quinoxalines; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Solitary Nucleus; Vagus Nerve