A new experimental model, the isolated perfused antrectomized pig stomach with intact vagal innervation, was shown to produce pepsinogen and gastric acid upon electrical stimulation of the vagus nerves and by intravascular administration of carbachol (from a basal value of 111 +/- 24 units of pepsin per minute and 0.044 +/- 0.012 mEq H+/min to 393 +/- 75 units of pepsin per minute and 0.102 +/- 0.022 mEq H+/min upon vagal stimulation). Vagal stimulation also increased the release of the neuropeptide gastrin-releasing peptide to the venous effluent from 0.42 +/- 0.12 to 3.1 +/- 0.95 pmol/min. Intravascular infusions of gastrin-releasing peptide at a concentration of 10(-8) mol/L resulted in a threefold increase in pepsinogen secretion and a small increase in acid output. Because gastrin-mediated effects of gastrin-releasing peptide are excluded with this preparation, our results show that gastrin-releasing peptide acts either directly or through another unknown local mediator on the pepsinogen-secreting cells. Gastrin-releasing peptide may thus participate in the vagal control of pepsinogen secretion.