Vagal neurotransmission to the ferret lower oesophageal sphincter: inhibition via GABAB receptors

Abstract

GABA(B) receptors modulate the function of the lower oesophageal sphincter (LOS) in vivo by inhibiting neurotransmitter release in the vagal pathway controlling LOS relaxation. We aimed to determine whether this effect was mediated peripherally on vagal motor outflow to the ferret LOS in vitro. The LOS, with intact vagal innervation, was prepared from adult ferrets and LOS tension measured. Vagal stimulation (0.5 - 10 Hz, 30 V) evoked a tetrodotoxin-sensitive, frequency-dependent relaxation. Both GABA (3x10(-4) M) and (+/-)baclofen (2x10(-4) M) inhibited vagally-stimulated LOS relaxation. The potent GABA(B) receptor-selective agonist 3-APPA dose-dependently inhibited vagally-stimulated LOS relaxation, with an EC(50) value of 0.7 microM Decreased responses following vagal stimulation in the presence of (+/-)baclofen or 3-APPA were reversed with the potent GABA(B) receptor antagonist CGP 62349. Neither CGP 62349 nor muscimol (GABA(A) receptor agonist) alone affected LOS responses following vagal stimulation. Agonists of other G protein-coupled receptors (clonidine (alpha(2)-adrenoceptor) (5x10(-6) M), U50488 (kappa opioid) (10(-5) M), neuropeptide Y (10(-6) M)) did not affect vagally-mediated LOS relaxation. The present study supports a discrete presynaptic inhibitory role for GABA(B) receptors on vagal preganglionic fibres serving inhibitory motorneurones in the ferret LOS.