TRANSMITTER MECHANISMS IN VAGAL AFFERENT-INDUCED REDUCTION OF LOWER ESOPHAGEAL SPHINCTER (LOS) PRESSURE IN THE RAT

The extrinsic neural pathways and transmitter mechanisms involved in n eural influences controlling lower oesophageal sphincter (LOS) pressur e have been evaluated in three groups of experiments in urethane anaes thetized rats. A miniature perfused sleeve/sidehole catheter measured gastric, LOS and oesophageal pressures. Group I: Vago-vagal and vago-s pinal reflex pathways were activated simultaneously via the central ne rvous system by stimulation of the central cut end of the left vagus. This caused a prolonged drop in LOS pressure with a rapid onset and a slow return to baseline. Subsequent right (bilateral) vagotomy in thes e animals increased basal LOSP (P < 0.001). Central vagal stimulation- induced reduction of LOSP was not significantly changed in amplitude b ut was shorter in duration (P < 0.01) than before bilateral vagotomy. IV administration of the 5-HT3 receptor antagonist granisetron (50 mu g/kg), after bilateral vagotomy had no effect on the response to centr al vagal stimulation. The nitric oxide (NO) synthase inhibitor L-nitro arginine methyl ester (L-NAME) (100 mg/kg) reduced the depth of relaxa tion (P < 0.01) and temporarily increased basal LOSP. Propranolol (1.5 mg/kg, i.v.) subsequently increased basal LOSP (P < 0.01), but had no further effect on the vagal stimulation-induced reduction in LOSP. Al pha adrenergic blockade with phentolamine (1 mg/kg, i.v.) decreased ba sal LOSP (P < 0.01), and nearly abolished the response to vagal stimul ation (P < 0.01). Group 2: Both alpha(1) and alpha(2)-adrenoceptors we re shown to be involved by the combined use of the more selective anta gonists yohimbine (1 mg/kg, i.v.) and prazosin (200 mu g/kg) in place of phentolamine. Group 3: To observe neurotransmitter mechanisms in th e vago-vagal pathway, central left vagal stimulation was performed aft er left vagotomy, and subsequently after blockade of sympathetic motor pathways with guanethidine (5 mg/kg), leaving intact efferent pathway s in the right vagus. Guanethidine increased basal LOSP (P < 0.01), an d reduced the duration of vagal-induced LOS relaxation (P < 0.05). Dep th of relaxation was unchanged. Subsequently, granisetron and L-NAME h ad no significant effects. Finally, additional right vagotomy abolishe d the remaining response. Our data indicate the existence of vago-spin al and vago-vagal inhibitory reflex pathways to the rat LOS. The inhib itory vago-spinal pathway is mainly cu-adrenergic, and has a minor NO- mediated component, but no 5-HT3 receptor-mediated mechanism. In the v ago-vagal pathway, no significant involvement of NO-mediated or 5-HT3 receptor-mediated effects was observed. Other non-adrenergic inhibitor y mechanisms were, however apparent. This study also shows the rat to be a useful new model for investigation of LOS physiology and pharmaco logy.