Pituitary adenylate cyclase activating polypeptides, PACAP-27 and PACAP-38: stimulators of electrogenic ion secretion in the rat small intestine.

1. The effects of pituitary adenylate cyclase activating polypeptide (PACAP)-27 and PACAP-38 were investigated and compared with vasoactive intestinal polypeptide (VIP) responses in voltage clamped preparations of rat jejunum. Under these conditions electrogenic ion secretion was continuously recorded. 2. PACAP-27 is the most potent secretagogue described thus far, exhibiting a concentration-dependent dual secretory action. At low concentrations it stimulated rapid, transient secretory responses (not seen with either PACAP-38 or VIP) and these were inhibited by tetrodotoxin (TTX). At higher nM concentrations of PACAP-27 more prolonged secretory responses predominated which were insensitive to TTX. 3. In the presence of TTX, the concentration-response curve to PACAP-27 gave an EC50 value of 29.4 +/- 5.4 nM (n = 4) compared with 0.8 +/- 0.1 nM (n = 9) for PACAP-27 alone and 30.6 +/- 5.6 nM (n = 5) for PACAP-38. C-terminal fragments of PACAP-38 were not significantly effective. 4. Blockade of muscarinic and nicotinic receptors partially inhibited the low concentration effects of PACAP-27. Substance P desensitization and capsaicin pretreatment were effective at inhibiting the transient secretory PACAP-27 responses. Evidence is presented for selective, high affinity PACAP-27 receptors on submucous neurones innervating the mucosal region of the rat jejunum.