EFFECT OF LIPOXYGENASE INHIBITORS AND LEUKOTRIENE ANTAGONISTS ON ACUTE AND CHRONIC GASTRIC HEMORRHAGIC 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 ch ronic gastritis (induced by 7 day treatment with iodoacetamide) in rat s to establish the role of leukotrienes (LTs) in the pathogenesis of t hese lesions. The protective effects of highly selective 5-lipoxygenas e (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 th e 5-LO inhibitor L-656 224 (50 mg/kg), whereas lower doses of this dru g were ineffective. Prior treatment with oral doses (5 and 10 mg/kg) o f the 5-LO inhibitor L-655 224 or the LT antagonists L-649 923 or L-66 0 711, failed to affect lesions induced by aspirin (100 mg/kg, p.o.) a nd indomethacin (400 mg/kg, s.c.), whereas higher doses of all three d rugs (50 mg/kg) showed protective effects. Repeated prior dosing up to 5 h with the novel ve lipoxygenase activating protein (FLAP) inhibito r, MK886 (50 and 100 mg/kg), reduced the lesions developed by indometh acin (30 mg/kg, s.c.). Twice daily dosing with the 5-LO inhibitor L-65 6 224 (5 mg/kg) or the LT antagonist L-649 923 (2 or 5 mg/kg) for 7 da ys significantly reduced the development of iodoacetamide-induced gast ritis during the period of induction of this condition, but higher dos es of these inhibitors were not; protective. We conclude that 5-LO pro ducts partially mediate the production of gastric mucosal lesions indu ced by damaging agents, which varies according to the ulcer model empl oyed; the limited protective effects of the respective 5-LO inhibitors and LT antagonists depend on their individual pharmacokinetics and th eir time of dosing.