Effect of lipoxygenase inhibitors and leukotriene antagonists on acute and chronic gastric haemorrhagic mucosal lesions in ulcer models in the rat.
Studies were performed in three models of acute gastric mucosal damage (induced by oral ethanol, aspirin and indomethacin) and a model of chronic gastritis (induced by 7 day treatment with iodoacetamide) in rats to establish the role of leukotrienes (LTs) in the pathogenesis of these lesions. The protective effects of highly selective 5-lipoxygenase (5-LO) inhibitors and leukotriene antagonists were thus examined in rats given these ulcerogens. Ethanol (1 mL, p.o.)-induced haemorrhagic lesions were significantly reduced by prior oral administration of the 5-LO inhibitor L-656224 (50 mg/kg), whereas lower doses of this drug were ineffective. Prior treatment with oral doses (5 and 10 mg/kg) of the 5-LO inhibitor L-655224 or the LT antagonists L-649923 or L-660711, failed to affect lesions induced by aspirin (100 mg/kg, p.o.) and indomethacin (400 mg/kg, s.c.), whereas higher doses of all three drugs (50 mg/kg) showed protective effects. Repeated prior dosing up to 5 h with the novel five lipoxygenase activating protein (FLAP) inhibitor, MK886 (50 and 100 mg/kg), reduced the lesions developed by indomethacin (30 mg/kg, s.c.). Twice daily dosing with the 5-LO inhibitor L-656224 (5 mg/kg) or the LT antagonist L-649923 (2 or 5 mg/kg) for 7 days significantly reduced the development of iodoacetamide-induced gastritis during the period of induction of this condition, but higher doses of these inhibitors were not protective. We conclude that 5-LO products partially mediate the production of gastric mucosal lesions induced by damaging agents, which varies according to the ulcer model employed; the limited protective effects of the respective 5-LO inhibitors and LT antagonists depend on their individual pharmacokinetics and their time of dosing.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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Gyömber
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Vattay
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Szabo
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Rainsford
D000818:Animals; D001241:Aspirin; D001572:Benzofurans / Q000627:therapeutic use; D000431:Ethanol; D005260:Female; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D007213:Indomethacin; D007460:Iodoacetamide; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D010438:Peptic Ulcer Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D010654:Phenylbutyrates / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy
D001572:Benzofurans; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010654:Phenylbutyrates; D011422:Propionates; D011804:Quinolines; C055868:L 656224; D000431:Ethanol; C059141:verlukast; D017998:Leukotriene D4; C050033:L 649923; D001241:Aspirin; D007213:Indomethacin; D007460:Iodoacetamide