Bradykinin mediates acute inflammation by increasing microvascular permeability, vasodilation, leukocyte migration and accumulation, and the production of arachidonic acid via phospholipase A2 activation. Arachidonic acid metabolites, or eicosanoids, are potent modulators of biological functions, particularly inflammation. Bradykinin exerts its inflammatory effects via the bradykinin B2 receptor. The aim of this study was to evaluate the effect of a bradykinin B2 receptor antagonist, FR173657 (FR), on intestinal ischemia-reperfusion (I/R) injury. Twenty-eight mongrel dogs were divided into four groups (n = 7 per group). Group I underwent I/R alone, Group II underwent I/R and received FR treatment, Group III was sham operated, and Group IV was sham operated and received FR treatment. The FR treatment consisted of FR continuously from 30 min prior to ischemia to 2 hr after reperfusion. In the I/R procedure, the superior mesenteric artery (SMA) and vein were clamped for 2 hr and then released to permit reperfusion for 12 hr. The intramucosal pH (pHi), SMA blood flow, and mucosal tissue blood flow were measured during the reperfusion period. The serum thromboxane B2 and 6-keto-prostaglandin F1α levels were determined, and tissue samples were examined histologically. Results showed that tissue blood flow, pHi, and SMA blood flow after reperfusion were maintained in Group II in comparison with Group I. Histopathological examination showed less severe mucosal damage after reperfusion in Group II than in Group I. The serum thromboxane B2 and 6-keto-prostagland in F1α levels were significantly lower in Group II than in Group I (P < 0.05). We conclude that FR treatment appears to have clear protective effects on small bowel I/R injury by inhibiting the release of eicosanoids.
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Welbourn CRB, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB: Pathophysiology of ischemia-reperfusion injury: Central role of the neutrophil. Br J Surg 78:651–655, 1991
Nilsson UA, Schoenberg MH, Aneman A, Poch B, Magadum S, Berger HG, Lundgren O: Free radicals and pathogenesis during ischemia and reperfusion of the cat small intestine. Gastroenterology 100:629–636, 1994
Caty MG, Guice KS, Oldham KT, Remick DG, Kunkel SI: Evidence for tumor necrosis factor induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. Ann Surg 212:694–700, 1990
Kanwar S, Teppermean BL, Payne D, Sutherland LR, Kubes P: Time course of nitric oxide production and epithelial dysfunction during ischemia/reperfusion of the feline small intestine. Circ Shock 42:135–140, 1994
Mangino MJ, Anderson CB, Murphy MK, Brunt E, Turk J: Mucosal arachidonate metabolism and intestinal ischemia-reperfusion injury. Am J Physiol 257:G299–G307, 1989
Zimmerman BJ, Guillory DJ, Grisham MB, Gaginella TS, Granger DN: Role of leukotriene B$_{4}$ in the granulocyte infiltration into postischemic feline intestine. Gastroenterology 99:1358–1363, 1990
Ernster L: Biochemistry of reoxygenation injury. Crit Care Med 16:947–953, 1988
Bruch RM, Axelrod J: Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: Evidence for G-protein regulation of phospholipase A$_{2}$. Proc Natl Acad Sci USA 84:6374–6378, 1987
Ricupero D, Taylor L, Polgar P: Interactions of bradykinin, calcium, G-protein and protein kinase in the activation of phospholipase A$_{2}$ in bovine pulmonary artery endothelial cells. Agents Actions 40:110–118, 1993
Silvka SR, Insel PA: Phorbol ester and neomycin dissociate bradykinin receptor-mediated arachidonic acid release and polyphosphoinositide hydrolysis in Madin-Darby canine kidney cells: Evidence that bradykinin mediates noninterdependent activation of phospholipases A$_{2}$ and C. J Biol Chem 263:14640–14647, 1988
Bathon JM, Proud D: Bradykinin antagonists. Annu Rev Pharmacol Toxicol 31:129–162, 1991
Bloechle C, Kusterer K, Kuehn RM, Schneider C, Knoefel WT, Izbicki JR: Inhibition of bradykinin B2 receptor preserves microcirculation in experimental pancreatitis in rats. Am J Physiol 274:G42–G51, 1998
Hoffmann TF, Leiderer R, Waldner H, Messmer K: Bradykinin antagonists HOE-140 and CP-0597 diminish microcirculatory injury after ischaemia-reperfusion of the pancreas in rats. Br J Surg 83:189–195, 1996
Hashimoto N, Takeyoshi I, Tsutsumi H, Sunose Y, Tokumine M, Totsuka O, Ohwada S, Yokoe T, Matsumoto K, Morishita Y: Effects of a bradykinin B$_{2}$ receptor antagonist, FR173657, on pulmonary ischemia-reperfusion injury in dogs. J Heart Lung Transplant 21:1022–1029, 2002
Iwanami K, Takeyoshi I, Ohwada S, Kobayashi J, Kawata K, Matsumoto K, Morishita Y: Intramucosal pH and intestinal mucosal damage in ischemia-reperfusion injury. Transplant Int 11:401–407, 1998
Chiu C-J, McArdle AH, Brown R, Scott HJ, Gurd FN: Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 101:478–483, 1970
Parks DA, Bulkley GB, Granger DN, Hamilton SR, McCord JM: Ischemic injury in the cat small intestine: Role of superoxide radicals. Gastroenterology 82:9–15, 1982
Granger DN, Rutili G, McCord JM: Superoxide radicals in feline intestinal ischemia. Gastroenterology 81:22–29, 1981
Schoenberg MH, Muhl E, Sellin D, Younes M, Schildberg FW, Hagland U: Posthypotensive generation of superoxide free radicals: Possible role in the pathogenesis of the intestinal mucosal damage. Acta Chir Scand 150:301–309, 1984
Takahashi T, Kunimoto F, Ichikawa H, Ishikawa S, Sato Y, Hasegawa Y, Morishita Y: Gastric intramucosal pH and hepatic venous oximetry after cardiopulmonary bypass in valve replacement patients. Cardiovasc Surg 4:308–310, 1996
Wolfard A, Vangel R, Szalay L, Kaszaki J, Haulik L, Balogh A, Nagy S, Boros M: Endothelin-A receptor antagonism improves small bowel graft perfusion and structure after ischemia and reperfusion. Transplantation 68:1231–1238, 1999
Kubes P: Nitric oxide modulates epithelial permeability in the feline small intestine. Am J Physiol 262:G1138–G1142, 1992
Marceau F: Kinin B1 receptors: A review. Immunopharmacology 30:1–26, 1995
Asano M, Inamura N, Hatori C, Sawai H, Fujiwara T, Katayama A, Kayakiri H, Satoh S, Abe Y, Inoue T, Sawada Y, Nakahara K, Oku T, Okuhara M: The identification of an orally active, nonpeptide bradykinin B$_{2}$ receptor antagonist, FR173657. Br J Pharmacol 120:617–624, 1997
Ryan JW, Moffat JG, Thompson AG: Role of bradykinin in the development of acute pancreatitis. Nature 204:1212–1213, 1964
Ryan JW, Moffat JG, Thompson AG: Role of bradykinin system in acute hemorrhagic pancreatitis. Arch Surg 91:14–24, 1965
Yotsumoto F, Manabe T, Ohshio G: Bradykinin involvement in the aggravation of acute pancreatitis in rabbits. Digestion 54:224–230, 1993
Elliott DF, Horton EW, Lewis GP: Actions of pure bradykinin. J Physiol 153:473–480, 1960
Kunze H, Vogt W: Significance of phospholipase A for prostaglandin formation. Ann NY Acad Sci 180:123–125, 1971
Hamgerg M, Samuelsson B: Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 71:3400–3404, 1974
Moncada S, Vane JR: Arachidonic acid metabolites and interactions between platelets and blood vessel walls. N Engl J Med 300:1142–1147, 1979
Kaplan E, Diehl JT, Peterson MB, Somerville KH, Daly BDT, Connolly RJ, Cooper AG, Seiler SD, Cleveland RJ: Extended ex vivo preservation of the heart and lungs. Effects of acellular oxygen-carrying perfusates and indomethacin on the autoperfused working heart-lung preparation. J Thorac Cardiovasc Surg 100:687–698, 1990
Isozaki H, Okajima K, Hara H, Kobayashi M: The protective effect of thromboxane A$_{2}$ synthetase inhibitor against ischemic liver injury. Surg Today 24:435–440, 1994
Bunting S, Moncada S, Vane JR: The prostacyclin-thromboxane A$_{2}$ balance: Pathophysiological and therapeutic implications. Br Med Bull 39:271–276, 1983
Matsumoto S, Kuroda Y, Fujita H, Tanioka Y, Sakai T, Hamano M, Kim Y, Suzuki Y, Ku Y, Saitoh Y: Extending the margin of safety of preservation period for resuscitation of ischemically damaged pancreas during preservation using the two-layer (University of Wisconsin solution/perfluorochemical) method at 20$^{^}$ with thromboxane A$_{2}$ synthesis inhibitor OKY046. Transplantation 62:879–883, 1996
Okada Y, Marchevsky AM, Kass RM, Matloff JM, Jordan SC: A stable prostacyclin analog, beraprost sodium, attenuates platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation. Transplantation 66:1132–1136, 1998
Lehr HA, Guhlmann A, Nolte D, Keppler D, Messmer K: Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster. J Clin Invest 87:2036–2041, 1991
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Arakawa, K., Takeyoshi, I., Akao, Y. et al. Bradykinin B2 Receptor Antagonist FR173657 Ameliorates Small Bowel Ischemia–Reperfusion Injury in Dogs. Dig Dis Sci 50, 27–36 (2005). https://doi.org/10.1007/s10620-005-1273-1
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DOI: https://doi.org/10.1007/s10620-005-1273-1