BACKGROUND It is established that substance P (SP) is released by stimulation of nonadrenergic noncholinergic (NANC) excitatory nerves and vasoactive intestinal peptide (VIP) by stimulation of NANC inhibitory nerves. To evaluate the function of peptidergic nerves such as SP and VIP in small-bowel isografts, we examined the enteric nerve responses to SP and VIP in the isografted rat jejunum, using the normal rat jejunum as a control. METHODS Orthotopic entire small bowel transplantation (SBT) with portocaval drainage was performed from Lewis rats to Lewis rats. Grafted tissue specimens were obtained 130 days after SBT (n = 9). As controls, normal segments of the jejunum were obtained from untransplanted Lewis rats (n = 22). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the enteric nervous system before and after treatments with various autonomic nerve blockers and neuropeptides (SP and VIP). RESULTS SP concentration-dependently mediated the contraction reaction of NANC excitatory nerve in the isografted jejunum and to a lesser extent in the normal jejunum. In addition, there were significant diferences in the percentages showing contraction at 1 x 10(-8) and 1 x 10(-6)g/mL SP between the normal and isografted jejunal muscle strips (P < .05, respectively). VIP concentration dependently mediated the relaxation reaction of NANC inhibitory nerve in the normal jejunum and to a lesser extent in the isografted jejunum. In addition, there was a significant difference between the relaxation frequencies of the normal and those of isografted jejunal muscle strips at 1 x 10(-6) g/mL SP (P < .01). CONCLUSIONS Contraction reactions of SP were observed in both the normal and isografted jejunum but were increased in the isografted jejunum. Relaxation reactions of VIP were also observed in both the normal and isografted jejunum but were decreased in the isografted jejunum. The increase of the effects of SP via NANC excitatory nerves and the decrease of the effects of VIP in mediating NANC inhibitory nerves may be largely related to the peristaltic abnormalities seen in the isografted LEW rat jejunum.