CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N alpha-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 micromol/kg i.v.) or a 3-h infusion of A-70104 (3 micromol.kg(-1).h(-1) i.v.) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endogenous CCK appears to act both at CCK1 receptors beyond the blood-brain barrier and by a CCK1 receptor-mediated mechanism involving abdominal vagal nerves to inhibit food intake.

Background: Entry of nutrients into the small intestine activates neuro-hormonal signals that regulate food intake through induction of satiation. Objective: To evaluate whether caloric intake can be decreased by pharmacologically accelerating gastric emptying (GE) of nutrients into the small intestine. Methods: Subjects were tested in 2 days, at baseline (day1) and after randomly receiving, in a double-blind manner, a 1 h infusion of erythromycin (3 mg Kg À1 , to accelerate GE) or placebo (day 2). Ad libitum caloric intake and postprandial gastrointestinal symptoms were evaluated using a validated nutrient drink test, simultaneously measuring gastric by scintigraphy. Plasma levels of satiation factors were also measured to evaluate their role in the modification of caloric intake and postprandial symptoms. Acceleration of GE was assessed as the difference in percentage emptied between day 2 and day 1 (DGE). The effects of DGE on caloric intake and symptoms were evaluated using multiple (lineal) regression. Results: Among 30 overweight/obese subjects (24F and 6 M), 15 received erythromycin and 15 placebo. The overall median age was 36 years (IQR: 30-42) and body mass index was 30 Kg m À2 (IQR: 27-36). Subjects receiving erythromycin on day 2 presented accelerated GE as compared with placebo (P ¼ 0.0002). DGE at 15 min after initiating eating had a significant effect on prospective caloric intake (P ¼ 0.004). From the best-fitted regression model (R 2 ¼ 81%, Po0.0001), a 10% increase in GE at 15 min induced on an average a 135±43.5 Kcal decrease in caloric intake. Postprandial increase in cholecystokinin (CCK) (P ¼ 0.03) and insulin (P ¼ 0.02) was associated with decreased caloric intake. Acceleration of GE at 60 min after initiating eating increased postprandial symptom scores measured 30 min after the completion of food consumption (P ¼ 0.01). Postprandial increase in CCK (P ¼ 0.002) and PP (P ¼ 0.02) was associated with postprandial symptoms. Conclusion: Meal size can be reduced in overweight/obese subjects by pharmacologically accelerating GE. This may be a reasonable target in obesity management.