The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs.
Leukotrienes (LT) C4, D4, and E4 are major contributors to the pathobiology of human bronchial asthma. Therefore, it is likely that compounds that antagonize the action or inhibit the formation of LTs will be useful therapeutic agents. We have studied the effects of LT antagonists, 5-lipoxygenase inhibitors and selected standards in a model of LT-mediated allergic bronchospasm in guinea pigs. Sensitized animals were pretreated with mepyramine, indomethacin and propranolol to eliminate the influence of histamine, prostaglandins, thromboxanes and circulating catecholamines. In these animals, inhalation of antigen resulted in a bronchospasm consistent with a LT-mediated response that was slow in onset, of long duration and was inhibited by the selective LTD4, antagonists FPL-55712, LY-171,883 and ICI-198,615. ICI-198,615 was approximately 50-times more potent than FPL-55712 by the intravenous and intratracheal routes. However, of thirteen compounds known to inhibit 5-lipoxygenase and LT biosynthesis in vitro only phenidone, piriprost and AA-861 were active in this in vivo model. The allergic bronchospasm was inhibited by bronchodilators (e.g. PGE2, aminophylline and forskolin) and by some mast cell stabilizers, but was otherwise insensitive to other pharmacological classes of compounds including calcium channel blockers and antagonists of serotonin, acetylcholine and platelet-activating factor. This model seems useful and reasonably selective for the evaluation of new antianaphylactic compounds that are LT antagonists. The inactivity of many 5-lipoxygenase inhibitors in this model suggests they do not inhibit LT formation in vivo.
Kreutner
W
W
Department of Allergy and Inflammation, Schering-Plough, Bloomfield, NJ 07003.
Sherwood
J
J
Rizzo
C
C
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D012898:Autacoids / Q000037:antagonists & inhibitors; D001986:Bronchial Spasm / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004195:Disease Models, Animal; D006168:Guinea Pigs; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008297:Male; D010276:Parasympatholytics / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000503:physiopathology
D001095:Arachidonic Acids; D012898:Autacoids; D002121:Calcium Channel Blockers; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010276:Parasympatholytics; D016718:Arachidonic Acid