Pure enzymes in a test hierarchy for antibronchoconstrictory lipoxygenase inhibitors.
A test hierarchy for potential antibronchoconstrictive drugs acting as lipoxygenase inhibitors was developed which includes a purified mammalian lipoxygenase/leukotriene A4 synthase, purified cyclooxygenase, arachidonic acid metabolism of polymorphonuclear leukocytes, arachidonic acid-induced contraction of lung strips, isolated human bronchi, and ovalbumin-induced bronchoconstriction with sensitized guinea pigs. The lipoxygenase from rabbit reticulocytes turned out to be superior to a variety of other animal and plant lipoxygenases. Among the various test systems with respiratory tract preparations, the arachidonic acid-induced contraction of guinea pig lung strips gave the most reliable results in the search for new antiasthmatic drugs. The validity of the test hierarchy was ascertained in screening investigations. Novel classes of antibronchoconstrictory lipoxygenase inhibitors were found.
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001985:Bronchial Provocation Tests; D001986:Bronchial Spasm; D004796:Clinical Enzyme Tests; D016861:Cyclooxygenase Inhibitors; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008084:Lipoxygenase; D016859:Lipoxygenase Inhibitors; D009119:Muscle Contraction / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D010047:Ovalbumin / Q000494:pharmacology; D011817:Rabbits
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D010047:Ovalbumin; D001091:Arachidonate Lipoxygenases; D008084:Lipoxygenase