Myotropic activity of leukotriene B4 on lung parenchyma strips is not necessarily attributable to thromboxane A2 release.
Leukotriene B4 contracts guinea pig lung parenchymal strips by an indirect mechanism dependent upon formation of myotropic cyclooxygenase metabolites. In contrast to the prevailing notion, our data indicate that thromboxane A2 is not necessarily the sole or essential mediator involved. Several points support this conclusion. First, the quantitative and temporal aspects of thromboxane B2 release and the myotropic response to leukotriene B4 were weakly correlated (r = 0.73). Second, the dose-response curve for thromboxane A2, based on the amount of thromboxane B2 generated by lung strips contracted with leukotriene B4, was inconsistent with dose-response curves for lung strips contracted with a stable thromboxane A2 mimetic, U-46619 or with synthetic thromboxane A2 itself. Third, thromboxane synthetase inhibitors, typified by OKY-1581 and UK-37248, did not inhibit the myotropic activity of leukotriene B4 under conditions in which thromboxane B2 formation was reduced by 80 to 90%. A thromboxane A2 receptor antagonist, BM 13.177, did not inhibit the myotropic activity of leukotriene B4 under conditions in which it antagonized the effects of U-46619. Cyclooxygenase metabolites other than thromboxane A2 must contribute to the mechanism of action of leukotriene B4 or leukotriene B4 effects may be mediated directly on certain cells or receptors.
Fitzpatrick
F A
FA
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
Lawson
C F
CF
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D008689:Methacrylates; D007975:Leukotriene B4; D013929:Thromboxane B2; D013928:Thromboxane A2; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D013930:Thromboxane-A Synthase