Increasing doses of gastrin 1-17 (G1-17) were administered to totally isolated, vascularly perfused rat stomachs prestimulated with the phosphodiesterase inhibitor isobutyl methylxanthine (IMX). Vascular and luminal histamine outputs and luminal acid output were monitored at short intervals. G1-17 induced an immediate histamine release to the vascular perfusate, preceding the increase in acid secretion by approximately 10 min. Vascular histamine output increased from a base line (IMX only) of 4.0 +/- 0.4 to a maximum of 34.5 +/- 7.3 nmol/60 min (mean +/- SEM) after 1040 pM G1-17, and acid output from 8.0 +/- 2.8 to 61.5 +/- 7.0 mumol/60 min after 520 pM G1-17. Acid output was correlated to vascular histamine release (r = 0.64, p less than 0.001). Gastrin produced a histamine release giving gastric venous concentrations of the same magnitude as the concentration of histamine necessary to induce a comparable acid response. Histamine release to the lumen, on the other hand, paralleled the acid secretion in time, suggesting it to be a passive phenomenon secondary to acid secretion. Thus, the present study for the first time shows that gastrin induces vascular histamine release of such a magnitude that this substance could be the mediator of the gastrin effect on acid secretion.