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

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-PGF_1α, 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.
• 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.
• 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.
• 4 Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastointest Liver Physiol 2003; 284: G15-G26.
• 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.
• 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.
• 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.
• 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.
• 9 Dray A. Inflammatory mediators of pain. Br J Anaesth 1995; 75: 125-31.
• 10 Szallasi A, Blumberg PM. Vanilloid receptors: new insights enhance potential as a therapeutic target. Pain 1996; 68: 195-208.
• 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.
• 12 Fields HL. Pain. New York: McGraw-Hill; 1987
• 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.
• 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.
• 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.
• 16 Perkins MN, Campbell EA. Capsazepine reversal of the antinociceptive action of capsaicin in vivo. Br J Pharmacol 1992; 107: 329-33.
• 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.
• 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.
• 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.
• 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.
• 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.
• 22 Lee SM, Clemens MG. Effect of α -tocopherol on hepatic mixed function oxidases in hepatic ischemia/ reperfusion. Hepatology 1992; 15: 176-81.
• 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.
• 24 Liu L, Simon SA. Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia. Neurosci Lett 1997; 228: 29-32.
• 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.
• 26 Torry RJ, Labarrere CA, Nelson D. et al Localization and characterization of antithrombin in human kidney. J Histchem Cytochem 1999; 47: 313-21.
• 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.
• 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.
• 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.
• 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.
• 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.
• 32 Holzer P. Neural emergency system in the stomach. Gastroenterology 1998; 114: 823-39.
• 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.
• 34 van Nieuw Amerongen GP, van Hinsbergh VW. Targets for pharmacological intervention of endothelial hyperpermeability and barrier function. Vascular Phamacol 2003; 39: 257-72.
• 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.
• 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.
• 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.
• 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.
• 39 Granger DN, Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 1994; 55: 662-75.
• 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.
• 41 Tominaga M, Caterina MJ, Malmberg AB. et al The cloned capsaicin receptor integrates multiple painproducing stimuli. Neuron 1998; 21: 531-43.
• 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.
• 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.
• 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.
• 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.