Octreotide, a somatostatin analogue that inhibits the release of most gut peptides, hastens the resolution of experimental postoperative ileus, suggesting that gut peptides mediate this process. We studied the role of two gut peptides involved in the control of normal gut motility, vasoactive intestinal peptide (VIP), and substance P (SP), in the initiation and maintenance of postoperative small bowel ileus in rats by preoperative administration of VIP and SP receptor antagonists, (VIP-ra and SP-ra). Thirty male Sprague-Dawley rats (300-350 g) underwent laparotomy. One half underwent placement of a duodenal catheter for transit studies while the other half had serosal electrodes placed on the proximal jejunum for myoelectric recordings. Six days later, animals were separated into three treatment groups of five each. Control animals were pretreated with ip saline, while the others received either VIP-ra or SP-ra prior to standardized laparotomy. Following abdominal closure, [Na51]CrO4 was injected into the duodenum and the animals were sacrificed 25 min later. The small bowel was then excised and divided into 10 equal segments. Small bowel transit was calculated as the geometric center of [Na51]CrO4 distribution. The interval until the return of migrating myoelectric complexes (MMCs) was determined in animals with intestinal electrodes. VIP-ra-treated rats demonstrated a 67% improvement in the geometric center of radiolabel relative to controls and SP-ra-treated rats had a 23% improvement (3.67 +/- 0.06 VIP-ra vs 2.69 +/- 0.09 SP-ra vs 2.20 +/- 0.09 control, P < 0.01). MMCs returned 180 +/- 17 min in controls vs 99 +/- 14 min in VIP-ra-treated rats (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)