PACAP IS A STIMULATOR OF NEUROGENIC CONTRACTION IN GUINEA-PIG ILEUM

The myotropic effect of pituitary adenylate cyclase-activating polypep tide (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 signif icantly more potently and efficiently compared with VIP. PACAP-induced contraction was abolished by tetrodotoxin, dynorphin, and somatostati n, partially reduced by atropine, and not affected by ganglionic and a drenergic blockade. The atropine-resistant component was sensitive to spantide, to the induction of tachyphylaxis with substance P, and to o mega-conotoxin. Ileal strips desensitized to PACAP did not respond to VIP, although they maintained their sensitivity to PACAP after desensi tization to VIP. COOH-terminal-truncated derivatives of PACAP exhibite d full biological activity, although some of them showed substantially reduced potency. Deletion of NH2-terminal amino acids abolished biolo gical activity. PACAP produced a concentration-dependent increase in t he release of [H-3]acetylcholine from longitudinal muscle-myenteric pl exus preparations preloaded with [3H]choline. This effect was Ca2+ dep endent, tetrodotoxin sensitive, and resistant to hexamethonium and sco polamine. In contrast, PACAP inhibited release of acetylcholine evoked by field stimulation. In summary, PACAP-induced contraction of the gu inea pig ileum is mediated via release of acetylcholine and substance P through interaction with PACAP-1 and VIP/PACAP-2 receptors. PACAP ha s to be added to the list of myotropic neuropeptides of the gastrointe stinal tract.