Possible involvement of 5-HT2 receptor activation in aggravation of diet-induced acute pancreatitis in mice.
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.
Yoshino
T
T
Basic Research Group, Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-26, Japan.
Yamaguchi
I
I
D000208:Acute Disease; D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D003533:Cyproheptadine / Q000494:pharmacology; D005001:Ethionine / Q000008:administration & dosage*; D005260:Female; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010195:Pancreatitis / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003533:Cyproheptadine; D012701:Serotonin; D007650:Ketanserin; D005001:Ethionine