The effect of intraduodenal infusion of amino acids, glucose, fat, HCl, ethanol, or saline on plasma VIP concentration was investigated in 7 normal subjects, 5 post-vagotomy patients, and 12 anaesthetized pigs. Furthermore, the concentrations of VIP in plasma after ingestion of a mixed meal were measured in 6 normal subjects. In normal subjects the median peripheral concentration of VIP in the basal state was 4.3 pmol X I-1 (range 0--12.0). No significant changes occurred after amino acids, glucose, saline, or ingestion of a meal. In contrast infusion of HCl, fat, or ethanol resulted in a rise in plasma VIP concentration in all the subjects studied. The peak values (medians and ranges) after HCl, fat, or ethanol were 9.8 (5.9--12.6), 7.5 (2.4--10.2), and 12.6 (7.8--16.8)pmol X I-1, respectively. Truncal vagotomy did not change the response of HCl. The results from measurements in portal plasma of pigs confirmed the findings in peripheral plasma of normal subjects and showed that the levels of VIP in portal plasma are 1.6--2.9 times higher than the levels of VIP in arterial plasma. The pH threshold to release of VIP was pH 1.1--2.1, and the effect of HCl was not abolished by ganglionic blockade.