The effect of electrical stimulation of splanchnic and vagal nerve supply to the in vivo isolated porcine LES on the lower esophageal sphincter pressure (LESP) and the secretion of VIP and SP into the venous effluent into the venous effluent of the LES was investigated. Functional integrity of the autonomic nerve supply was assessed by the effect of nerve stimulation on heart rate. Vagal nerve stimulation increased LESP (8-Fold) as well as VIP output (3 Fold) significantly (p less than 0.01) whereas the secretion of SP was unaffected of vagal nerve stimulation. Splanchnic nerve stimulation increased heart rate significantly but was without effect on LESP, VIP, and SP outputs. Atropine partially abolished the effect of vagal nerve stimulation on LESP but the VIP secretion was completely resistant to atropine blockade. Administration of guanethidine was without effect on LESP, VIP, and SP outputs during vagal as well as splanchnic nerve stimulation. It is concluded that VIP acts as a neuro-transmitter since vagal stimulation increase the release of VIP from LESP. However, the finding of a partial atropine resistance of the LESP despite an unchanged release of VIP and SP, suggests that other transmitters participate in vagal activation of LESP.