Inhibition by leukotriene inhibitors, and calcium and platelet-activating factor antagonists, of acute gastric and intestinal damage in arthritic rats and in cholinomimetic -treated mice

The leukotrienes, platelet activating factor and intracellular calcium have been implicated in the development of gastro-intestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) but the relative significan ce of these inflammatory mediators in lesion formation has not been establi shed in sensitive and specific models of gastro-intestinal ulceration. In t he present study the effects of drugs affecting 5-lipoxygenase activity, th e actions of platelet activating factor and intracellular calcium on the de velopment of gastric and intestinal ulceration induced by NSAIDs were inves tigated in highly sensitive models of ulcerogenicity induced by treatment w ith either the cholinomimetic, acetyl-beta-methyl choline chloride, in mice (gastric mucosal lesions) or adjuvant-induced polyarthritis in rats (gastr ic and intestinal mucosal lesions) as well as in normal mice (intestinal mu cosal lesions). The 5-lipoxygenase inhibitors, such as MK-886 (3-[1-(4-chlorobenzyl)-3-t-bu tyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), given at doses shown to reduce the indomethacin-induced increase in mucosal leukotriene B -4 concentrations were found to partially prevent the development of gastri c and intestinal lesion induced by indomethacin and gastric lesions from as pirin, but the same doses of MK-886 did not affect gastric lesions from dic lofenac. Pretreatment with these inhibitors at both 3-5 h and 0-0.25 h was required to achieve protection against gastric mucosal damage from indometh acin. Immediate prior administration of platelet activating factor antagoni sts (e.g. WEB-2086) with the 5-lipoxygenase inhibitors did not affect gastr ic or intestinal lesions induced by indomethacin. The calcium antagonist, v erapamil, was slightly protective against gastric and intestinal lesions in duced by indomethacin. Gastric lesions were further prevented by combinatio ns of a single dose of verapamil with a platelet activating factor antagoni st but not combined with a 5-lipoxygenase inhibitor; other combinations of verapamil with lipoxygenase inhibitors or platelet-activating factor antago nists being without inhibitory effects on gastric or intestinal lesions com pared with the drugs alone. These results show that 5-lipoxygenase products and intracellular calcium p lay a major role in acute gastric and intestinal damage by the NSAIDs, but platelet-activating factor has little or no appreciable involvement.