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  • Meeting abstract
  • Open Access

Antithrombin reduces the ischemia/reperfusion-induced hepatic injury by increasing hepatic levels of prostacyclin through activation of capsaicin-sensitive sensory neurons in rats

  • 1,
  • 2 and
  • 2
Critical Care20026(Suppl 1):P118

Published: 1 March 2002


  • PGI2
  • CGRP Receptor
  • Hepatic Level
  • Induce Liver Injury
  • Capsazepine

We have previously demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation through the promotion of hepatic production of prostacyclin (PGI2) [1]. However, AT does not directly promote the endothelial production of PGI2 in cultured endothelial cells [2]. Capsaicin-sensitive sensory neurons (CSSN) are nociceptive neurons that release calcitonin gene-related peptide (CGRP) upon activation. Since CGRP increases the endothelial production of PGI2, it is possible that AT may increase the hepatic PGI2 production in rats subjected to I/R through the activation of CSSN. Recent studies have demonstrated that CGRP increases the endothelial production of nitric oxide (NO). Since NO has been shown to activate endothelial cyclooxygenase-1 (COX-1) activity, we further examined whether AT-induced increase in hepatic level of PGI2 can be mediated by nitric oxide synthase (NOS) activation. Male Wistar rats were subjected to 60-min ischemia and subsequent reperfusion. Both tissue levels of CGRP and the expression of immunohistochemical CGRP in the liver were significantly increased in rats subjected to I/R 1 hour after reperfusion. AT (250 U/kg, i.v.) significantly enhanced the I/R-induced increase in both hepatic levels of CGRP and the expression of immunohisto-chemical CGRP. AT-induced increase in hepatic level of CGRP and CGRP expression were completely inhibited by capsazepine (CPZ), a vanilloid receptor-1 antagonist. Furthermore, AT-induced increase in hepatic level of 6-keto-PGF1a, a stable metabolite of PGI2, were significantly inhibited by CPZ, CGRP (8-37), a CGRP receptor antagonist, and L-nitro-arginine-methyl-ester (L-NAME), a non-selective inhibitor of NOS. AT reduced the I/R-induced liver injury by inhibiting the I/R-induced increase in hepatic tumor necrosis factor (TNF)-a. Pretreatment of rats with CPZ, CGRP (8-37), and L-NAME completely abrogated such preventive effects of AT. Administration of rat a-CGRP produced effects similar to those of AT. These results strongly suggest that AT might reduce the I/R- induced liver injury by increasing the hepatic level of PGI2 through the activation of CSSN. Thus, AT might sensitize hepatic CSSN in rats subjected to hepatic I/R, leading to the increase in the hepatic tissue level of PGI2. In this process, CGRP-induced activation of endothelial NOS and COX-1 could be critically involved.

Authors’ Affiliations

Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, Japan
Department of Laboratory Medecine, Kumamoto University School of Medicine, Kumamoto, Japan


  1. Harada N, et al.: Blood 1999, 93: 157-164.PubMedGoogle Scholar
  2. Uchiba M, Okajima K: Thromb Haemost 2001, 86: 722-723.PubMedGoogle Scholar


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