Fitzpatrick F A, Lawson C F
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
J Pharmacol Exp Ther. 1988 Jun;245(3):839-44.
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.
白三烯B4通过一种依赖于促肌性环氧化酶代谢产物形成的间接机制使豚鼠肺实质条收缩。与普遍观点相反，我们的数据表明血栓素A2不一定是唯一或必需的参与介质。有几点支持这一结论。首先，血栓素B2释放的定量和时间方面与对白三烯B4的促肌性反应弱相关（r = 0.73）。其次，基于用白三烯B4收缩的肺条产生的血栓素B2量得出的血栓素A2剂量反应曲线，与用稳定的血栓素A2模拟物U - 46619或合成血栓素A2本身收缩的肺条的剂量反应曲线不一致。第三，以OKY - 1581和UK - 37248为代表的血栓素合成酶抑制剂，在血栓素B2形成减少80%至90%的条件下，并未抑制白三烯B4的促肌性活性。一种血栓素A2受体拮抗剂BM 13.177，在拮抗U - 46619作用的条件下，并未抑制白三烯B4的促肌性活性。除血栓素A2之外的环氧化酶代谢产物必定对白三烯B4的作用机制有贡献，或者白三烯B4的作用可能直接作用于某些细胞或受体。
