PACAP-(6–38) inhibits the effects of vasoactive intestinal polypeptide, but not PACAP, on the small intestinal circular muscle

Abstract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide-(1–38) (PACAP) have been found to stimulate distension-induced peristaltic motility in the guinea-pig isolated small intestine. In this study, we tested whether the putative VIP/PACAP receptor antagonist PACAP-(6–38) counteracts the properistaltic effect of VIP and PACAP in isolated segments of the guinea-pig small intestine. VIP (100 nM) and PACAP (30 nM) had a stimulatory effect, i.e., lowered the peristaltic pressure threshold at which peristaltic waves were triggered and enhanced the frequency of peristaltic waves. PACAP-(6–38) (3 μM) was per se without effect on peristalsis but prevented or reversed the peristaltic motor stimulation caused by VIP, when it was given before or after the agonist, respectively. PACAP-(6–38), however, failed to antagonize the properistaltic effect of PACAP. In ileal circular strips treated with tetrodotoxin (1 μM) and indomethacin (3 μM), spontaneous myogenic activity was inhibited by VIP (5–30 nM). This effect was significantly reduced by a pretreatment with PACAP-(6–38) (3 μM). A similar inhibition by PACAP-(1–38) (10–500 nM) was not influenced by the antagonist. It is concluded that PACAP-(6–38) is a VIP receptor antagonist, both in the peristaltic motor pathways and at the level of the circular muscle of the guinea-pig small intestine. The lack of a motor effect of PACAP-(6–38) on its own indicates that VIP acting on PACAP-(6–38)-sensitive receptors (located on neurons and/or the smooth muscle) is unlikely to participate in peristaltic motor regulation.