The purpose of this study was to assess the role of endogenous cholecystokinin (CCK) in regulating fat-induced changes in human gastric relaxation. Proximal gastric pressure-volume relationships were determined in 12 healthy volunteers during a series of gastric distensions, both fasting and after intragastric instillation of 250 ml of 10% Intralipid. All subjects were studied twice, in a randomized, double-blind study, during intravenous infusion of either loxiglumide (CCK-A antagonist) or saline. For each distension, intragastric pressure and compliance were determined together with perception intensity. During saline infusion, Intralipid reduced intragastric pressure (prelipid, 11.7 +/- 0.8; postlipid, 9.7 +/- 0.6 mmHg; P = 0.002) and increased compliance (pressure-volume slope values: prelipid, 87.6 +/- 9.7; postlipid, 47.2 +/- 7; P < 0.01). Loxiglumide infusion during fasting exerted no effect on either intragastric pressure or compliance. After lipid, however, loxiglumide abolished the expected postlipid reduction in intragastric pressure (prelipid, 12.1 +/- 0.7; postlipid, 11.5 +/- 0.8 mmHg; P = 0.4) but did not consistently abolish the postlipid increase in compliance. Loxiglumide exerted no effect on the cumulative perception score or on the volume at perception threshold, although it prevented the fat-induced reduction in pressure at perception threshold [control: prelipid, 15.4 +/- 1.1; postlipid, 10.7 +/- 0.5 (P < 0.05); loxiglumide: prelipid, 13.8 +/- 1.5; postlipid, 12.2 +/- 0.9 (P > 0.05)]. Endogenous CCK or CCK-A receptors therefore play a role in the fat-induced reduction of intragastric pressure and might also modulate gastric perception after lipid.