Stimulant action of pituitary adenylate cyclase-activating peptide on normal and drug-compromised peristalsis in the guinea-pig intestine

1 Pituitary adenylate cyclase-activating peptide (PACAP) is known to influe nce the activity of intestinal smooth muscle. This study set out to examine the action of PACAP on normal and drug-inhibited peristalsis and to shed l ight on its site and mode of action. 2 Peristalsis in isolated segments of the guinea-pig small intestine was el icited by distension through a rise of the intraluminal pressure. Drug-indu ced motility changes were quantified by alterations of the peristaltic pres sure threshold at which aborally moving peristaltic contractions were trigg ered. 3 PACAP (1-30 nM) stimulated normal peristalsis as deduced from a concentra tion-related decrease in the peristaltic pressure threshold (maximum decrea se by 55%). The peptide's stimulant effect remained intact in segments pre- exposed to apamin (0.5 mu M), N-nitro-L-arginine methyl ester (300 mu M), n aloxone (0.5 mu M), atropine (1 mu M) plus naloxone (0.5 mu M) or hexametho nium (100 mu M) plus naloxone (0.5 mu M). 4 PACAP (10 nhl) restored peristalsis blocked by morphine (10 mu M), noradr enaline (1 mu M) or N-6-cyclopentyladenosine (0.3 mu M) and partially reins tated peristalsis blocked by Rp-adenosine-3',5'-cyclic monophosphothioate t riethylamine (100 mu M) but failed to revive peristalsis blocked by hexamet honium (100 mu M) or atropine (1 mu M). The peptide's spectrum of properist altic activity differed from that of naloxone (0.5 mu M) and forskolin (0.3 mu M). 5 The distension-induced ascending reflex contraction of the circular muscl e was facilitated by PACAP (1-30 nM) which itself evoked transient nerve-me diated contractions of intestinal segment preparations. 6 These data show that PACAP stimulates normal peristalsis and counteracts drug-induced peristaltic arrest by a stimulant action on excitatory enteric motor pathways, presumably at the intrinsic sensory neurone level. The act ion of PACAP seems to involve multiple signalling mechanisms including stim ulation of adenylate cyclase.