The effect of rapid wash-out of the duodenum with phosphate buffered saline on exocrine pancreatic secretion and plasma levels of secretin, VIP, gastrin and CCK was studied. Furthermore, the possible nervous role in this effect was checked after atropine and hexamethonium treatment. Rapid wash-out significantly increased protein output (35.0 micrograms/min, in the control group without duodenal perfusion and 72.15 micrograms/min, in the perfused group) and the plasma levels of CCK (from 5.2 to 13.17 fmol/ml). Intravenous infusion of atropine significantly reduced the protein output (from 78.19 to 32.45 micrograms/min) and the plasma levels of CCK (from 10.1 to 5.55 fmol/ml), with no change in the remaining parameters in the intraduodenally perfused group. Intravenous administration of hexamethonium significantly stimulated hydroelectrolyte secretion (from 6.99 to 15.15 microliters/min) and the plasma levels of VIP (from 4.8 to 7.3 fmol/ml) and reduced the protein output (from 61.47 to 30.75 micrograms/min) and the plasma levels of CCK (from 14.56 to 6.25 fmol/ml) in the intraduodenally perfused group. Our results suggest that, in the interdigestive state, the exocrine pancreatic secretion of the rabbit is tonically inhibited. This inhibition can be divided into two different mechanisms: on the one hand there is a decrease in enzyme secretion produced by a duodenal factor and mediated by CCK and muscarinic mechanisms and on the other, there is an inhibition of hydroelectrolyte secretion with no duodenal participation which is probably controlled by nervous non-muscarinic mechanisms and VIP involvement.