The effect of short-term intragastric arterial infusion of pentagastrin and methacholine on histamine and N tau-methyl histamine secretory rates was evaluated in mongrel dogs in vivo. Doses of pentagastrin and methacholine were chosen that stimulate gastric acid secretion equivalently. Histamine and N tau-methyl histamine secretory rates were evaluated by measuring the arterial and gastric venous plasma histamine and N tau-methyl histamine concentrations at several time points during the secretagogue infusion, and gastric blood flow was continuously monitored. Histamine and N tau-methyl histamine plasma concentrations were analyzed by stable isotope dilution technique using gas chromatography/negative ion-chemical ionization mass spectrometry. Histamine and N tau-methyl histamine secretory rates were calculated by subtracting the arterial from the venous plasma concentrations and multiplying the difference by gastric plasma flow. Infusion of pentagastrin resulted in large pulsed increase of histamine release from 1.5 +/- 0.7 ng/min at time 0 to 72 +/- 20 ng/min at 5 minutes, which decreased to a plateau of 20 +/- 8 ng/min at 20 minutes. N tau-Methyl histamine secretory rate increased from 6.7 +/- 1.9 ng/min at baseline to a maximum of 42.5 +/- 13.1 ng/min at 10 minutes, and the increase was maintained for the duration of the pentagastrin infusion. Methacholine infusion was associated with a small but sustained increase in histamine release, from a baseline of 1.6 +/- 0.6 ng/min to 5.9 +/- 1.7 ng/min at 5 minutes. N tau-Methyl histamine secretory rate was unchanged by methacholine. Gastric blood flow changes to pentagastrin roughly paralleled the extent of histamine release, but methacholine is a gastric vasodilator in its own right. Our data indicate that pentagastrin is a much more effective stimulator of gastric histamine release than methacholine and that the overall role of histamine in gastrin-stimulated acid output is likely to be different from the role of histamine in cholinergic-mediated gastric acid output.