PACAP is a stimulator of neurogenic contraction in guinea pig ileum

The myotropic effect of pituitary adenylate cyclase-activating polypeptide (PACAP), a novel brain-gut peptide with high sequence homology to vasoactive intestinal polypeptide (VIP), was studied in the isolated guinea pig ileum in vitro. PACAP contracts the guinea pig ileum significantly more potently and efficiently compared with VIP. PACAP-induced contraction was abolished by tetrodotoxin, dynorphin, and somatostatin, partially reduced by atropine, and not affected by ganglionic and adrenergic blockade. The atropine-resistant component was sensitive to spantide, to the induction of tachyphylaxis with substance P, and to omega-conotoxin. Ileal strips desensitized to PACAP did not respond to VIP, although they maintained their sensitivity to PACAP after desensitization to VIP. COOH-terminal-truncated derivatives of PACAP exhibited full biological activity, although some of them showed substantially reduced potency. Deletion of NH2-terminal amino acids abolished biological activity. PACAP produced a concentration-dependent increase in the release of [3H]acetylcholine from longitudinal muscle-myenteric plexus preparations preloaded with [3H]choline. This effect was Ca2+ dependent, tetrodotoxin sensitive, and resistant to hexamethonium and scopolamine. In contrast, PACAP inhibited release of acetylcholine evoked by field stimulation. In summary, PACAP-induced contraction of the guinea pig ileum is mediated via release of acetylcholine and substance P through interaction with PACAP-1 and VIP/PACAP-2 receptors. PACAP has to be added to the list of myotropic neuropeptides of the gastrointestinal tract.