Possible involvement of endogenous 5-HT in aggravation of cerulein-induced acute pancreatitis in mice.
The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT2A agonist (DOI), but not by the preferential 5-HT2B agonist (BW723C86) or the preferential 5-HT2C agonist (mCPP). Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT2C receptor as well, paralleled their reported pKi values at the 5-HT2A receptor. Selective 5-HT2B (SB204741) and 5-HT2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT2A/2B/2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pKi values at the 5-HT2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT2A antagonists may provide a new therapy for acute pancreatitis.
Hamada
Kentaro
K
UMN Pharma, Inc., Department of Pharmacology, 1-15-8 Jinnan, Shibuya-ku Tokyo 150-0041, Japan.
Yoshida
Masanori
M
Isayama
Hiroyuki
H
Yagi
Yoshiki
Y
Kanazashi
Shuichi
S
Kashihara
Yasunari
Y
Takeuchi
Koji
K
Yamaguchi
Isamu
I
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide / Q000633:toxicity*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology
D044402:Receptor, Serotonin, 5-HT2A; D011949:Receptors, Cholecystokinin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D012701:Serotonin; C003338:spiramide; D002108:Ceruletide; D000681:Amylases