GABA(B) receptor-mediated effects on vagal pathways to the lower oesophageal sphincter and heart

1. GABA(B) receptors influencing vagal pathways to the lower oesophageal sphincter and heart were investigated. 2. In urethane-anaesthetized ferrets, the GABA(B) agonist baclofen (7 μmol kg^-1 i.v.) increased basal lower oesophageal sphincter (LOS) pressure. This was reversed by antagonism with CGP35348 (100 μmol kg^-1 i.v.). Baclofen's effect was abolished by vagotomy, suggesting a central action, yet it was ineffective when given centrally (3-6 nmol i.c.v.). 3. Peripheral vagal stimulation (10 Hz, 5 s duration) caused LOS inhibition, followed by excitation, then prolonged inhibition. Bradycardia was also evoked during stimulation. Bradycardia and LOS responses were abolished after chronic supranodose vagotomy, indicating that they were due to stimulation of vagal pre-ganglionic neurones, not antidromic stimulation of afferents. 4. Baclofen (1-10 μmol kg^-1) reduced bradycardia and enhanced LOS excitation, which was also seen in animals pretreated with atropine (400 μg kg^-1 i.v.) and guanethidine (5 mg kg^-1 i.v.), but not in those pretreated with L-NAME (100 mg kg^-1 i.v.). 5. Effects of baclofen (7 μmol kg^-1 i.v.) on vagal stimulation-induced LOS and cardiac responses were unchanged by the GABA(B) antagonists CGP35348 or CGP36742 (up to 112 μmol kg^-1 i.v.), but were reversed by CGP62349 (ED₅₀ 37 nmol kg^-1 i.v.) or CGP54626 (ED₅₀ 100 nmol kg^-1 i.v.). 6. Responses of isolated LOS strips to electrical stimulation, capsaicin, NK-1, NK-2 and nicotinic receptor agonists were all unaffected by baclofen (≤ 200 μM). 7. We conclude that baclofen reduces vagal output at two peripheral sites: one presynaptically on pre-ganglionic neurones (CGP35348-insensitive), and another (CGP35348-sensitive) that could not be identified. This demonstrates heterogeneity of GABA(B) receptors through differential sensitivity to antagonists.