Download PDF
Thromb Haemost 2005; 93(01): 48-56
DOI: 10.1160/TH04-02-0106
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats

Naoaki Harada
1   Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
,
Kenji Okajima
1   Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
,
Mehtap Yuksel
1   Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
,
Hirotaka Isobe
1   Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
› Author Affiliations
Further Information

Publication History

Received 18 February 2004

Accepted after resubmission 19 October 2004

Publication Date:
14 December 2017 (online)

Also available at
   Permissions and Reprints

Summary

We previously reported that antithrombin (AT) reduced ischemia/ reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicinsensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2 , the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8–37), a CGRP antagonist.AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin.AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin.Taken together,these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons,thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.

Keywords

Antithrombin - ischemia/reperfusion - capsaicin-sensitive sensory neurons - calcitonin gene-related peptide - prostacyclin
 

  • References

  • 1 Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiological role of this natural anticoagulant mechanism. Am J Med 1989; 87 suppl 3B 2S-9S.
    CrossrefPubMedSearch in Google Scholar
  • 2 Okajima K, Ueyama H, Hashimoto Y. et al Homozygous variant of antithrombin III that lacks affinity for heparin: AT III Kumamoto. Thromb Haemost 1989; 61: 20-24.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Okajima K, Abe H, Maeda S. et al Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with defective heparin binding associated with thrombosis. Blood 1993; 81: 1300-5.
    CrossrefPubMedSearch in Google Scholar
  • 4 Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastointest Liver Physiol 2003; 284: G15-G26.
    PubMedSearch in Google Scholar
  • 5 Harada N, Okajima K, Kushimoto S. et al Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999; 93: 157-64.
    PubMedSearch in Google Scholar
  • 6 Kainoh M, Imai R, Umetsu T. et al Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol 1990; 39: 477-84.
    CrossrefPubMedSearch in Google Scholar
  • 7 Eisenhut T, Sinha B, Grottrup-Wolfers E. et al Prostacyclin analogs suppress the synthesis of tumor necrosis factor- α in LPS-stimulated human peripheral blood mononuclear cells. Immunopharmacology 1993; 26: 259-64.
    CrossrefPubMedSearch in Google Scholar
  • 8 Uchiba M, Okajima K. Antithrombin does not directly promote the endothelial production of prostacyclin in cultured endothelial cells. Thromb Haemost 2001; 86: 722-3.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Dray A. Inflammatory mediators of pain. Br J Anaesth 1995; 75: 125-31.
    CrossrefPubMedSearch in Google Scholar
  • 10 Szallasi A, Blumberg PM. Vanilloid receptors: new insights enhance potential as a therapeutic target. Pain 1996; 68: 195-208.
    CrossrefPubMedSearch in Google Scholar
  • 11 Crossman D, McEwan J, MacDermot J. et al Human calcitonin gene-related peptide activates adenylate cyclase and releases prostacyclin from human umbilical vein endothelial cells. Br J Pharmacol 1987; 92: 695-701.
    CrossrefPubMedSearch in Google Scholar
  • 12 Fields HL. Pain. New York: McGraw-Hill; 1987
    Search in Google Scholar
  • 13 Harada N, Okajima K, Uchiba M. et al Ischemia/ reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin- sensitive sensory neurons in rats. J Lab Clin Med 2002; 139: 218-26.
    CrossrefPubMedSearch in Google Scholar
  • 14 Borov Borovikova LV, Ivanova S, Zhang M. et al Vagus nerve stimulation attenuates the systemic in flammatory response to endotoxin. Nature 2000; 405: 458-62.
    CrossrefPubMedSearch in Google Scholar
  • 15 Uchiba M, Okajima K, Murakami K. et al Effect of antithrombin III (AT III) and Trp49-modified AT III on plasma level of 6-keto-PGF1 α in rats. Thromb Res 1995; 80: 201-8.
    CrossrefPubMedSearch in Google Scholar
  • 16 Perkins MN, Campbell EA. Capsazepine reversal of the antinociceptive action of capsaicin in vivo. Br J Pharmacol 1992; 107: 329-33.
    CrossrefPubMedSearch in Google Scholar
  • 17 Laszlo F, Whittle JR B, Moncada S. Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors. Br J Pharmacol 1994; 111: 1309-15.
    CrossrefPubMedSearch in Google Scholar
  • 18 Uno K, Iuchi Y, Fujii J. et al In vivo study on cross talk between inducible nitric-oxide synthase and cyclooxygenase in rat gastric mucosa: effect of cyclooxygenase activity on nitric oxide production. J Pharmacol Exp Ther 2004; 309: 995-1002.
    CrossrefPubMedSearch in Google Scholar
  • 19 Kaneko H, Kaunitz J, Taché Y. Vagal mechanisms underlying gastric protection induced by chemical activation of raphe pallidus in rats. Am J Physiol 1998; 275: G1056-1062.
    PubMedSearch in Google Scholar
  • 20 Arai I, Hamasaki Y, Futaki N. et al Effect of NS-398, a new nonsteroidal anti-inflammatory agent, on gastric ulceration and acid secretion in rats. Res Commun Chem Pathol Pharmacol 1993; 81: 259-70.
    PubMedSearch in Google Scholar
  • 21 Hayashi H, Chaudry IH, Clemens MG. et al Hepatic ischemia models for determining the effects of ATP-MgCl2 treatment. J Surg Res 1986; 40: 167-75.
    CrossrefPubMedSearch in Google Scholar
  • 22 Lee SM, Clemens MG. Effect of α -tocopherol on hepatic mixed function oxidases in hepatic ischemia/ reperfusion. Hepatology 1992; 15: 176-81.
    PubMedSearch in Google Scholar
  • 23 Harada N, Okajima K, Uchiba M. et al Contribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in rats. Am J Physiol Gastrointest Liver Physiol 2003; 285: G1214-G1224.
    CrossrefPubMedSearch in Google Scholar
  • 24 Liu L, Simon SA. Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia. Neurosci Lett 1997; 228: 29-32.
    CrossrefPubMedSearch in Google Scholar
  • 25 Akiyoshi H, Gonda T, Terada T. A comparative histochemical and immunohistochemical study of aminergic, cholinergic and peptidergic innervation in rat, hamster, guinea pig, dog and human livers. Liver 1998; 18: 352-9.
    CrossrefPubMedSearch in Google Scholar
  • 26 Torry RJ, Labarrere CA, Nelson D. et al Localization and characterization of antithrombin in human kidney. J Histchem Cytochem 1999; 47: 313-21.
    CrossrefPubMedSearch in Google Scholar
  • 27 Ito Y, Abril ER, Bethea NW. et al Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. Am J Physiol Gastrointest Liver Physiol 2004; 286: G60-67.
    CrossrefPubMedSearch in Google Scholar
  • 28 Shito M, Wakabayashi G, Ueda M. et al Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia- reperfusion in the rat. Transplantation 1997; 63: 143-8.
    CrossrefPubMedSearch in Google Scholar
  • 29 Warren JS, Yabroff KR, Remick DG. et al Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. J Clin Invest 1989; 84: 1873-82.
    CrossrefPubMedSearch in Google Scholar
  • 30 Kushimoto S, Okajima K, Uchiba M. et al Role of granulocyte elastase in ischemia/reperfusion injury of rat liver. Crit Care Med 1996; 24: 1908-12.
    CrossrefPubMedSearch in Google Scholar
  • 31 Tognetto M, Amadesi S, Harrison S. et al Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. J Neurosci 2001; 21: 1104-9.
    CrossrefPubMedSearch in Google Scholar
  • 32 Holzer P. Neural emergency system in the stomach. Gastroenterology 1998; 114: 823-39.
    CrossrefPubMedSearch in Google Scholar
  • 33 Harada N, Okajima K, Kushimoto S. Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/ reperfusion injury of rat liver by inhibiting leukocyte activation. Crit Care Med 1999; 27: 1958-64.
    CrossrefPubMedSearch in Google Scholar
  • 34 van Nieuw Amerongen GP, van Hinsbergh VW. Targets for pharmacological intervention of endothelial hyperpermeability and barrier function. Vascular Phamacol 2003; 39: 257-72.
    PubMedSearch in Google Scholar
  • 35 Koj A, Regoeczi E. Effect of experimental inflammation on the synthesis and distribution of antithrombin III and alpha-1-antitrypsin in rabbits. Br J Exp Pathol 1978; 59: 473-81.
    PubMedSearch in Google Scholar
  • 36 Bull HA, Hothersall J, Chowdhury N. et al Neuropeptides induce release of nitric oxide from human dermal microvascular endothelial cells. J Invest Dermatol 1996; 106: 655-60.
    CrossrefPubMedSearch in Google Scholar
  • 37 Armstrong JM, Chapple D, Dusting GJ. et al Cardiovascular actions of prostacyclin (PGI 2 ) in chloralose anesthetized dogs. Br J Pharmacol 1977; 61: 136-41.
    PubMedSearch in Google Scholar
  • 38 Gibbs LS, Lai L, Malik AB. Tumor necrosis factor enhances the neutrophil-dependent increase in endothelial permeability. J Cell Physiol 1990; 145: 496-500.
    CrossrefPubMedSearch in Google Scholar
  • 39 Granger DN, Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 1994; 55: 662-75.
    CrossrefPubMedSearch in Google Scholar
  • 40 Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1β , and IL-6 but not IL-8 in the development of heat hyper- algesia: Effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 2000; 20: 6289-93.
    CrossrefPubMedSearch in Google Scholar
  • 41 Tominaga M, Caterina MJ, Malmberg AB. et al The cloned capsaicin receptor integrates multiple painproducing stimuli. Neuron 1998; 21: 531-43.
    CrossrefPubMedSearch in Google Scholar
  • 42 Oelschlager C, Romisch J, Staubitz A. et al Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. Blood 2002; 99: 4015-20.
    CrossrefPubMedSearch in Google Scholar
  • 43 Uchiba M, Okajima K, Murakami K. et al Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III. Am J Physiol 1996; 270: L921-L930.
    PubMedSearch in Google Scholar
  • 44 Isobe H, Okajima K, Uchiba M. et al Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. Blood 2002; 99: 1638-45.
    CrossrefPubMedSearch in Google Scholar
  • 45 Mizutani A, Okajima K, Uchiba M. et al Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood 2003; 101: 3029-36.
    CrossrefPubMedSearch in Google Scholar