The mechanism by which lipid in the duodenum inhibits gastric emptying was investigated in awake rats fitted with chronic gastric and duodenal cannulas. Perfusion of the duodenum with lipid (Intralipid, 5 and 10%; total amount 50 and 100 mg) caused a significant inhibition (26 and 78%, respectively) of gastric emptying of a nonnutrient liquid (0.9% saline). Functional ablation of the capsaicin-sensitive vagal, but not the spinal, sensory innervation to the upper gastrointestinal tract significantly attenuated by 57% lipid-induced inhibition of gastric emptying. In intact rats, administration of a specific cholecystokinin (CCK)-A receptor antagonist, devazepide, significantly attenuated by 66% the response to lipid. Administration of devazepide in perivagal capsaicin-treated rats did not further reduce the response to lipid. These results suggest that lipid in the duodenum inhibits gastric emptying via a mechanism involving an action of CCK at type A receptors and capsaicin-sensitive vagal afferents.
We synthesized PYY-(1-36) (nonselective between Y(1) and Y(2) receptor subtype agonists), [Pro(34)]PYY (selective for Y(1)), and PYY-(3-36) (selective for Y(2)) to determine whether solution conformation plays a role in receptor subtype selectivity. The three peptides exhibited the expected specificities in displacing labeled PYY-(1-36) from cells transfected with Y(1) receptors (dissociation constants = 0.42, 0.21, and 1,050 nM, respectively) and from cells transfected with Y(2) receptors (dissociation constants = 0.03, 710, and 0.11 nM, respectively) for PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36). Sedimentation equilibrium analyses revealed that the three PYY analogs were 80-90% monomer at the concentrations used for the subsequent circular dichroism (CD) and (1)H-nuclear magnetic resonance (NMR) studies. CD analysis measured helicities for PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36) of 42%, 31%, and 24%, suggesting distinct differences in secondary structure. The backbone (1)H-NMR resonances of the three peptides further substantiated marked conformational differences. These patterns support the hypothesis that Y(1) and Y(2) receptor subtype binding affinities depend on the secondary and tertiary solution state structures of PYY and its analogs.
Gastrin has been shown to stimulate the growth of carcinogenic-induced colon cancer in animals, and some human colon cancers grown in vitro or as xenografts in nude mice. We determined fasting plasma gastrin levels in control subjects and patients with adenomatous polyps or adenocarcinoma of the colon to determine whether abnormal levels occurred in either patient group. Blood samples were obtained from 73 patients undergoing colonoscopy, primarily for evaluation of Hemoccult-positive stools. Fasting plasma gastrin was significantly greater in patients with adenomatous polyps (24.2 +/- 5.7 pM, N = 25) or colon cancer (84.5 +/- 28.5 pM, N = 20) than in controls (9.9 +/- 0.9 pM, N = 28). Elevations were due to gastrin values greater than control mean + 2 SD in nine patients with polyps (19.5-150.2 pM) and eight with cancer (20.7-403.2 pM). None of the patients had identifiable causes (drugs, prior surgery) for elevated gastrin levels. Our results indicate that elevated plasma gastrin occurs in subgroups of patients with adenomatous polyps or adenocarcinoma of the colon. The cause and potential role of elevated gastrin for polyp and tumor growth in these patients is not known.
Rats were given injections of caerulein, secretin, or a combination of these two peptides subcutaneously 3 times daily for 5, 10, or 15 days. Caerulein produced significant dose- and time-dependent increases in pancreatic weight and content of DNA, RNA, protein, amylase, and trypsinogen. Secretin produced significant increases in pancreatic weight and content of RNA and lipase after 15 days of treatment. After only 5 days of treatment with a combination of secretin plus caerulein, pancreatic weight and content of RNA and protein more than doubled, and trypsinogen content increased more than fivefold. Comparing the averages across the 5-, 10-, and 15-day values, increases in weight, protein, and trypsinogen with the combination of secretin plus caerulein were significantly greater than the sum of the effects of the peptides given singly. Using increase in DNA content as an index of hyperplasia and increases in the ratios of pancreatic weight, RNA content, and protein content to DNA content as indices of hypertrophy, we concluded that caerulein produced both hyperplasia and hypertrophy of rat pancreatic acinar cells. Secretin markedly augmented the hypertrophic action of caerulein but did not alter its hyperplastic action.
The effect of a synthetic analogue of CCK (Thr4,Nle7CCK-9) on growth of SW-1990 human pancreatic cancer was examined in two experimental models. Nude mice bearing SW-1990 pancreatic cancer xenografts were injected with CCK (5, 15, or 25 micrograms/kg) or vehicle twice daily for 20 days. Animals were then sacrificed and tumor volume, weight, protein, and deoxyribonucleic acid (DNA) content were evaluated. SW-1990 cells were grown in vitro and the effects of CCK, secretin, vasoactive intestinal peptide (VIP), and proglumide (a CCK-receptor antagonist) on cell number and DNA synthesis were determined. The highest dose of CCK, 25 micrograms/kg, significantly increased tumor weight, protein content, and DNA content (P less than 0.005). In vitro, CCK caused significant increases in cell counts of up to 47% at six days and 66% at 12 days compared to control. Graded concentrations of CCK had a biphasic effect on DNA synthesis with significant increases of up to 65% (P less than 0.005). CCK-induced cell proliferation was inhibited by proglumide. Secretin slightly increased cancer cell growth, although not as potently as CCK, VIP or secretin in combination with CCK did not show potentiation. These results indicate that growth of some human pancreatic cancers may be influenced by gastrointestinal peptides, of which CCK is the most potent.
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