Role of VIP1/PACAP receptors in postoperative ileus in rats.

1. Vasoactive intestinal polypeptide (VIP) is an inhibitory neurotransmitter in the enteric nervous system. We investigated the role of VIP1/PACAP receptors in postoperative ileus in rats. 2. Different degrees of inhibition of the gastrointestinal transit, measured by the migration of Evans blue, were achieved by skin incision, laparotomy or laparotomy plus mechanical stimulation of the gut. 3. The transit after skin incision or laparotomy was not altered by the VIP1/PACAP receptor antagonist Ac-His1,D-Phe2, K15, R16, VIP(3-7), GRF(8-27)-NH2 nor by the VIP1/PACAP receptor agonist K15, R16, VIP(1-7), GRF(8-27)-NH2 and the VIP2/PACAP receptor agonist RO 25-1553 (5 microg kg(-1)). 4. However, the transit after laparotomy plus mechanical stimulation was significantly enhanced by the VIP1/PACAP receptor antagonist, whereas it was further inhibited by the VIP1/PACAP receptor agonist. The combination of the VIP1/PACAP receptor agonist and antagonist counteracted the effect of both drugs alone. The VIP2/PACAP receptor agonist did not alter the effect of the VIP1/PACAP receptor antagonist. 5. The combination of the VIP1/PACAP receptor antagonist plus the nitric oxide (NO) synthase inhibitor L-nitroarginine had no effect on the transit after laparotomy plus mechanical stimulation, while the transit after skin incision was significantly decreased. 6. These findings suggest the involvement of VIP1/PACAP receptors, next to NO, in the pathogenesis of postoperative ileus. However, the combination of the VIP1/PACAP antagonist and the NO synthase inhibitor abolished the beneficial effect of each drug alone, suggesting the need for one of the inhibitory neurotransmitters to enable normal gastrointestinal transit.