Abstract
The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B4 releaseex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B4 antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin.
Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.
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References
J. L. Wallace, C. M. Keenan and D. N. Granger,Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil dependent process. Am. J. Physiol.259, G462-G467 (1990).
J. L. Wallace, K. E. Arfors and G. W. McKnight,A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology100, 878–883 (1991).
M. Lee, K. Aldred, E. Lee and M. Feldman,Aspirin-induced acute gastric mucosal injury is a neutrophil dependent process in rats. Am. J. Physiol.263, G920-G926 (1992).
J. L. Wallace and D. N. Granger,Pathogenesis of NSAID-gastropathy: Are neutrophils the culprits? TIPS13, 129–131 (1992).
M. A. Bray, The pharmacology and pathophysiology of leukotriene B4. Br. Med. Bull.39, 249–254 (1983).
S. H. Roth and R. E. Bennett,Non steroidal anti inflammatory drug gastropathy: Recognition and response. Arch. Intern. Med.147, 2093–2100 (1987).
K. P. Stock and G. L. Bach,Ulcer healing with ranitidine and antacids despite continued treatment with non steroidal antiinflammatory drugs. Z. Rheumatol.47, 177–181 (1988).
N. Hudson, M. Balsitis, S. Everitt and C. J. Hawkey, Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut34, 742–747 (1993).
M. A. Trevethick, N. M. Clayton, P. Strong and I. Harman,Do infiltrating neutrophils contribute to the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum? Gut34, 156–160 (1993).
J. Gillard, A. W. Ford-Hutchinson, C. Chan, S. Charleson, D. Denis and A. Foster et al.,L663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2-2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can. J. Physiol. Pharmacol.67, 456–464 (1989).
S. Djuric, P. W. Collins, P. H. Jones, R. L. Shone, B. S. Tai and D. J. Fretland et al.,7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid: An orally active, selective leukotriene B 4 receptor antagonist. J. Med. Chem.32, 1145–1147 (1989).
R. D. Krell, R. E. Giles, Y. K. Yee and D. W. Synder,In vivo pharmacology of ICI198,615: A novel, potent and selective peptide leukotriene antagonist. J. Pharmac. Exp. Ther.243, 557–564 (1987).
J. L. Wallace,Gastric ulceration: Critical events at the neutrophil-endothelium interface. Can. J. Physiol. Pharmacol.71, 98–102 (1993).
B. Peskar, Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach. Gastroenterology100, 619–626 (1991).
M. Lee and M. Feldman,Nonessential role of leukotrienes as mediators of acute gastric mucosal injury induced by aspirin in rats. Dig. Dis. Sci.37, 1282–1287 (1993).
K. D. Rainsford,The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal anti-inflammatory drugs in mice. Agents and Actions21, 316–319 (1987).
J. L. Wallace and B. J. R. Whittle,Role of prostanoids in the protective actions of BW755C on the gastric mucosa. Eur. J. Pharmacol.115, 45–52 (1985).
S. J. Konturek, T. Brzozowski, D. Drozdowicz and G. Beck,Role of leukotrienes in acute gastric lesions induced by ethanol, taurocholate, aspirin, platelet activating factor and stress in rats. Dig. Dis. Sci.33, 806–813 (1988).
P. M. Vaananen, C. M. Keenan, M. B. Grisham and J. L. Wallace,Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID-gastropathy. Inflammation16, 227–240 (1992).
Z. Kapui, K. Boer, I. Rozsa, G. Blasko and I. Hermecz,Investigations of indomethacin-induced gastric ulcer in rats. Arzneimittel-Forschung/Drug Res.43, 767–771 (1993).
B. M. Peskar, K. Larnge, W. Hoppa and B. A. Peskar, Ethanol stimulates formation of leukotriene C4 in rat gastric mucosa. Prostaglandins31, 283–294 (1986).
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Trevethick, M.A., Clayton, N.M., Bahl, A.K. et al. Leukotrienes do not contribute to the pathogenesis of indomethacin-induced ulceration of the gastric antrum in the re-fed rat. Agents and Actions 41, 179–183 (1994). https://doi.org/10.1007/BF02001913
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DOI: https://doi.org/10.1007/BF02001913