BACKGROUND The present study was designed to identify the mechanism by which distention regulates gastrin secretion. METHODS The distal stomach of the isolated vascularly perfused rat was distended to varying degrees for 10-minute periods with an air-filled balloon. RESULTS Low distention caused a decrease in gastrin (39% +/- 5%; P < 0.001) and an increase in somatostatin (58% +/- 4%; P < 0.001) secretion. High distention caused an opposite effect, i.e., an increase in gastrin (49% +/- 11%; P < 0.01) and a decrease in somatostatin (44% +/- 11%; P < 0.01) secretion. All responses were abolished by the axonal blocker, tetrodotoxin. Atropine had no effect on the responses to low distention, but converted the pattern of response with high distention to that observed with low distention. Both high and low distention were accompanied by a sustained increase in vasoactive intestinal peptide (VIP) secretion. The selective VIP antagonist, VIP[10-28], abolished both the gastrin and somatostatin responses to low distention. CONCLUSIONS Low gastric distention activates preferentially VIP neurons that stimulate somatostatin and thus inhibit gastrin secretion. Increasing distention leads to progressive recruitment of cholinergic neurons that cause a reversal in the pattern to one of increase in gastrin and decrease in somatostatin secretion.