The effect of secretin on pentagastrin- and gastrin-stimulated gastric histamine release and acid secretion was examined in the anesthetized dog model, where all compounds were infused directly into the artery supplying the gastric corpus. Secretin at an infusion rate of 10 ng/kg/min resulted in approximately 90% inhibition of gastric secretion in response to pentagastrin (20 ng/kg/min), whereas at the physiological postprandial concentration of 40 pg/ml it inhibited gastric secretion by approximately 55%. Gastric acid stimulated by gastrin I at the physiological post-prandial concentration of 150 pg/ml was inhibited by secretin at 40 pg/ml by approximately 80%. Pentagastrin stimulated histamine release to a peak of 168 +/- 34 ng/min, which was inhibited to 14 +/- 8 ng/min with the high concentration of secretin and to 85 +/- 21 ng/min at 40 pg/ml secretin. Gastrin I (150 pg/ml) stimulated histamine release to a peak of 10.6 +/- 4.6 ng/min, which was inhibited to 2.1 +/- 0.5 ng/min by secretin (40 pg/ml). Because secretin has been reported to stimulate gastric somatostatin release, we examined the somatostatin secretory rate concomitant with histamine release. Both doses of secretin stimulated gastric somatostatin release, compared with pentagastrin alone. The present data demonstrate that secretin, even at physiological concentrations, can inhibit gastric acid secretion in response to gastrin/pentagastrin, and one of the mechanisms of inhibition involves modulation of gastric histamine release. This effect of secretin on histamine release may be either direct, at the histamine-containing endocrine cells, or indirect, through somatostatin release.