Possible Involvement of Endogenous 5-HT in Aggravation of Cerulein-Induced Acute Pancreatitis in Mice

Journal of Pharmacological Sciences

Isamu Yamaguchi²  Shuichi Kanazashi²  Kentaro Hamada²  Koji Takeuchi³  Yoshiki Yagi²  Hiroyuki Isayama¹  Masanori Yoshida⁴  Yasunari Kashihara² 

[1] Department of Gastroenterology, Faculty of Medicine, The University of Tokyo, Japan;UMN Pharma, Inc., Department of Pharmacology, Japan;Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Japan;Department of Pharmacology, Graduate School of Medicine, Osaka City University, Japan

关键词: serotonin (5-HT);    5-HT2A-receptor activation;    cerulein-induced acute pancreatitis;    hyperenzymemia;    histological alteration;   

DOI  :  10.1254/jphs.FP0071049

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(43)Cited-By(3)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.

【 授权许可】

Unknown