The Cannabinoid 1 Receptor Antagonist, AM251, Prolongs the Survival of Rats with Severe Acute Pancreatitis
KAZUHISA MATSUDA, YUKIO MIKAMI, KAZUNORI TAKEDA, SHOJI FUKUYAMA, SHINICHI EGAWA, MAKOTO SUNAMURA, IKUROU MARUYAMA1 and SEIKI MATSUNO
Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan, and 1Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana). Anandamide is mainly produced by macrophages. Cannabinoid 1 (CB1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB1 receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis.
keywords ——severe acute pancreatitis; septic shock; anandamide; endocannabinoids; AM251
© 2005 Tohoku University Medical Press
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Tohoku J. Exp. Med., 2005, 207, 99-107
Correspondence: Kazuhisa Matsuda, M.D., Ph.D., Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
e-mail: k_matsuda@surg1.med.tohoku.ac.jp