Giembycz M A, Rodger I W
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, U.K.
Can J Physiol Pharmacol. 1987 Jul;65(7):1467-77. doi: 10.1139/y87-230.
The role that thromboxane A2 plays in contractions induced by leukotriene D4 in guinea-pig isolated lung parenchyma was investigated under equilibrium conditions. Lung tissue generated thromboxane A2 and prostacyclin spontaneously as evidenced by the slow accumulation of their biologically inactive metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, in the bathing buffer. Challenge of guinea-pig lung parenchyma with a high concentration (EC90 for tension generation) of leukotriene D4 (200 nM) produced a biphasic contraction of the tissue that consisted of an initial rapid increase in isometric tension followed by a slowly developing, well-sustained contracture. In addition, leukotriene D4 (200 nM) effected a transient increase (over basal) in the generation of thromboxane A2 and prostacyclin that lagged significantly behind the tension response. Kinetic analysis of the mechanical and eicosanoid-generating effect of leukotriene D4 revealed that tension development could be suitably fitted to a biexponential function, whilst the release of both eicosanoids from the lung occurred monoexponentially. Pretreatment of the lung with the cyclooxygenase inhibitor, flurbiprofen, which effectively abolished both the spontaneous and the leukotriene D4-stimulated eicosanoid biosynthesis, significantly reduced both the first order rate coefficient of the first exponent and the maximum amplitude of this function with respect to control. This change in the kinetics describing leukotriene D4-induced contractions was explained by the fact that the initial rate of tension development was markedly reduced following pretreatment of the lung with flurbiprofen. Neither the inhibitor of thromboxane synthetase, dazmegrel, which selectively inhibited (by 95%) leukotriene D4-stimulated thromboxane A2 formation, nor blockade of 11 alpha,9 alpha-epoxymethano-prostaglandin H2 (U-46619)-sensitive (thromboxane A2) receptors with either AH 23848 or EP 092 affected the profile of leukotriene D4-induced tension development in guinea-pig lung. It is concluded that a high concentration of leukotriene D4 (200 nM) contracts guinea-pig lung by both a direct and indirect mechanism. Initially, a rapid short-lived contraction of the lung is manifest which is dependent, in part, upon the synthesis and release of cyclooxygenase product(s) other than thromboxane A2. This initial response occurs coincidently with, and is subsequently followed by, the development of a tonic well-sustained contracture that is the result of a direct action of leukotriene D4 on the contractile cells that comprise the lung.
在平衡条件下，研究了血栓素A2在白三烯D4诱导的豚鼠离体肺实质收缩中所起的作用。肺组织自发产生血栓素A2和前列环素，其生物学上无活性的代谢产物血栓素B2和6-酮-前列腺素F1α在浴液缓冲液中缓慢积累，证明了这一点。用高浓度（产生张力的EC90）的白三烯D4（200 nM）刺激豚鼠肺实质，可使组织产生双相收缩，包括等长张力的初始快速增加，随后是缓慢发展、持续良好的挛缩。此外，白三烯D4（200 nM）使血栓素A2和前列环素的生成出现短暂的（相对于基础水平）增加，且这一增加明显滞后于张力反应。对白三烯D4的机械作用和类花生酸生成作用的动力学分析表明，张力发展可很好地拟合为双指数函数，而肺中两种类花生酸的释放均呈单指数形式。用环氧化酶抑制剂氟比洛芬预处理肺，可有效消除自发的和白三烯D4刺激的类花生酸生物合成，相对于对照组，显著降低了该函数第一个指数的一级速率系数和最大振幅。描述白三烯D4诱导收缩的动力学变化是由于用氟比洛芬预处理肺后，张力发展的初始速率明显降低。血栓素合成酶抑制剂达唑米雷选择性抑制（95%）白三烯D4刺激的血栓素A2形成，用AH 23848或EP 092阻断11α,9α-环氧甲撑-前列腺素H2（U-46619）敏感的（血栓素A2）受体，均不影响豚鼠肺中白三烯D4诱导的张力发展情况。得出结论，高浓度的白三烯D4（200 nM）通过直接和间接机制使豚鼠肺收缩。最初，肺出现快速短暂的收缩，这部分依赖于除血栓素A2之外的环氧化酶产物的合成和释放。这种初始反应与强直性持续良好的挛缩同时发生，随后出现挛缩，这是白三烯D4对构成肺的收缩细胞直接作用的结果。
