Secretin-induced gastric relaxation is mediated by vasoactive intestinal polypeptide and prostaglandin pathways

Secretin has been shown to delay gastric emptying and inhibit gastric motility. We have demonstrated that secretin acts on the afferent vagal pathway to induce gastric relaxation in the rat. However, the efferent pathway that mediates the action of secretin on gastric motility remains unknown. We recorded the response of intragastric pressure to graded doses of secretin administered intravenously to anaesthetized rats using a balloon attached to a catheter and placed in the body of the stomach. Secretin evoked a dose-dependent decrease in intragastric pressure. The threshold dose of secretin was 1.4 pmol kg(-1) h(-1) and the effective dose, 50% was 5.6 pmol kg(-1) h(-1). Pretreatment with hexamethonium markedly reduced gastric relaxation induced by secretin (5.6 pmol kg(-1) h(-1)). Bilateral vagotomy also significantly reduced gastric motor responses to secretin. Administration of N-G-nitro-L-arginine methyl ester (10 mg kg(-1)) did not affect gastric relaxation induced by secretin. In contrast, intravenous administration of a vasoactive intestinal polypeptide (VIP) antagonist (30 nmol kg(-1)) reduced the gastric relaxation response to secretin (5.6 pmol kg(-1) h(-1)) by 89 +/- 5%. Indomethacin (2 mg kg(-1)) reduced gastric relaxation induced by secretin (5.6 pmol kg(-1) h(-1)) by 87 +/- 5%. Administration of prostaglandin (48 mg kg(-1) h(-1)) prevented this inhibitory effect. Indomethacin also reduced gastric relaxation induced by VIP (300 pmol kg(-1)) by 90 +/- 7%. These observations indicate that secretin acts through stimulation of presynaptic cholinergic neurons in a vagally mediated pathway. Through nicotinic synapses, secretin stimulates VIP release from postganglionic neurons in the gastric myenteric plexus, which in turn induces gastric relaxation through a prostaglandin-dependent pathway.