Abstract
Acute pancreatitis was induced in mice by feeding with a choline-deficient ethionine-supplemented diet. All the mice developed acute pancreatitis, and approximately 80% of them died within 4 days. Stereomicroscopic and light microscopic examinations revealed that pancreatic necrosis and circulatory disturbance that were not apparent on day 1 were increased markedly on days 2 and 3. Serum levels of pancreatic enzymes were normal or reduced on day 1 but then increased to peak on day 3. Plasma 5-hydroxyindoleacetic acid levels, which may indicate serotonin release, were significantly increased on days 1 through 3. Pretreatment with d,l-p-chlorophenylalanine methylester hydrochloride (200–400 mg/kg) significantly attenuated the mortality of the mice with pancreatitis. Dose-dependent attenuation was also obtained with ketaserin (0.01–10 mg/kg), cyproheptadine (0.01–10 mg/kg), pindolol (0.1–100 mg/kg) and NAN-190 (0.1–100 mg/kg), but not with 0.01 to 10 mg/kg of ICS205-930 or M-840, and the activities were significantly correlated with the binding affinities for serotonin2 receptor on the rat cerebral cortex. In addition, ketanserin or cyproheptadine attenuated the morphologic changes in the choline-deficient ethionine-supplemented diet mice at a dose (3.2 mg/kg) that hardly affected the serum enzyme levels. We propose that serotonin2 receptor activation plays an important role in the aggravation of diet-induced acute pancreatitis.
Footnotes
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Send reprint requests to: Takako Yoshino, Department of Biological Sciences, Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., 5-2-3 Tokodai, Tsukuba, Ibaraki 300-26, Japan.
- Abbreviations:
- CDE
- choline-deficient ethionine-supplemented
- 5-HT
- serotonin
- 5-HIAA
- 5-hydroxyindoleacetic acid
- p-CPA
- d,l-p-chlorophenylalanine methyl ester hydrochloride
- HPLC-ECD
- high-performance liquid chromatography-electrochemical detection
- Received September 4, 1996.
- Accepted August 1, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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