| Co-Investigator(Kenkyū-buntansha) |
KANDA Fumio KOBE UNIV MED,ASSISTANT PROFESSOR, 医学部, 助手 (70252765)
MATSUI Toshimitsu KOBE UNIV MED,LECTURER, 医学部・附属病院, 講師 (10219371)
KAJI Hidesuke KOBE UNIV MED,LECTURER, 医学部, 講師 (90224401)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Research Abstract |
Cholecystokinin (CCK)-B/gastrin receptors belonging to the seven membrane-spanning G protein-coupled receptor family are thought to play a significant role not only in acid secretion but also in cell proliferation of the gastric mucosa. In our previous report, CCK-B/gastrin receptors were demonstrated to be essential for physiological cell growth of the gastric mucosa by generating CCK-B/gastrin receptor-deficient mice (CCKBR-/-). Here, we focused on water-immersion and restraint stress-induced gastric lesions and gastric acid secretion in CCKBR-/- mice. In spite of hypergastrinemia, stress-induced gastric lesions were not observed in CCKBR-/- mice as much as in the wild-littermates. In addition to the decreased basal gastric acid output, the gastric acid secretion of CCKBR-/- mice in response to histamine was significantly less than that of the wild-type mice. These results indicate that CCK-B/gastrin receptors play an important role in stress-induced gastric lesions through physiolog
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ical gastric acid secretion in vivo. Thus, chronic suppression of the CCK-B/gastrin receptor function by specific antagonists might be useful for intervening stress-induced gastric ulcer formation.
Pancreatic exocrine function and bile secretion were examined in CCK-B receptor gene targeted mice, and compared among different genotypes. The histology and protein concentrations in the pancreas were also examined. Amylase release from the dispersed acini was examined in vitro using the various doses of CCK-8, carbachol and secretin. In vivo, the bile and pancreatic juice were collected and the concentrations of amylase and bile acid were measured in anesthetized mice. The responses to CCK (100 pmol/kg) or acctyl-betamethylcholinc (500 nmol/kg) were examined. In vitro studies showed that the maximal effective concentrations of CCK-8 (0.1 nM), carbachol (10 muM) and secretin (0.5 muM) were comparable for all genotypes. Fluid, amylase and bile acid outputs in vivo were also comparable for all genotypes. Pancreatic wet weight and protein concentrations were not significantly different, and no abnormal findings were observed on histological examination in any genotype. These results indicated that the CCK-B receptor has no role in pancreatic growth or exocrine secretion, nor in bile secretion in adult mice.
Now, we are investigating some behavioural (pharmacological responses, anxiety studies, locomotor activity) as well as neurochemical chages of the receptor deficient mice with collaborators in several countries. Less
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