McAlexander M A, Myers A C, Undem B J
Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1998 May;285(2):602-7.
The role of endogenous 5-lipoxygenase products in modulating tachykinergic neurotransmission in guinea pig isolated trachea was investigated. Tachykinin-containing afferent nerve fibers were stimulated with either electrical field stimulation or antidromic stimulation of the right vagus nerve. This resulted in contractions of the isolated caudal trachea and bronchus that could be blocked with either tetrodotoxin or a combination of neurokinin-1 and neurokinin-2 receptor antagonists. The 5-lipoxygenase inhibitor ZD 2138 (1 microM) significantly inhibited these neurally mediated tachykinergic contractions, by approximately 50%, yet had no effect on the contractions evoked by stimulating tachykinergic fibers in an action potential-independent fashion with capsaicin or by exogenously applied neurokinin A. The effect of ZD 2138 on action potential-driven tachykinergic contractions was mimicked by pobilukast, pranlukast, montelukast and zafirlukast, four structurally unrelated antagonists of the cysteinyl leukotriene 1 receptor subtype. Pobilukast had no effect on the tachykinergic contraction in tissues pretreated with ZD 2138. Likewise, ZD 2138 had no effect on the tachykinergic contractions in tissues pretreated with pobilukast. Intracellular electrophysiological recording of the membrane properties of jugular ganglion neurons, the source of tachykinins in the guinea pig trachea/bronchus, demonstrated that leukotriene D4 caused a membrane depolarization of vagal afferent C-fiber neurons and an increase in input impedance, both of which were abolished by zafirlukast. Taken together, these data indicate that in the resting guinea pig isolated trachea/bronchus, endogenous 5-lipoxygenase activity leads to the production of cysteinyl leukotrienes that amplify action potential-dependent release of tachykinins from airway afferent nerve fibers.
研究了内源性5-脂氧合酶产物在调节豚鼠离体气管速激肽能神经传递中的作用。含速激肽的传入神经纤维通过电场刺激或右侧迷走神经的逆向刺激进行刺激。这导致离体尾段气管和支气管收缩，而这种收缩可被河豚毒素或神经激肽-1和神经激肽-2受体拮抗剂的组合所阻断。5-脂氧合酶抑制剂ZD 2138（1微摩尔）显著抑制这些神经介导的速激肽能收缩，抑制率约为50%，但对辣椒素以与动作电位无关的方式刺激速激肽能纤维或外源性应用神经激肽A所诱发的收缩没有影响。ZD 2138对动作电位驱动的速激肽能收缩的作用被泊比司特、普仑司特、孟鲁司特和扎鲁司特所模拟，这四种药物是半胱氨酰白三烯1受体亚型的结构不相关拮抗剂。泊比司特对用ZD 2138预处理的组织中的速激肽能收缩没有影响。同样，ZD 2138对用泊比司特预处理的组织中的速激肽能收缩也没有影响。对豚鼠气管/支气管中速激肽来源的颈神经节神经元的膜特性进行细胞内电生理记录表明，白三烯D4导致迷走传入C纤维神经元的膜去极化和输入阻抗增加，而这两者都被扎鲁司特消除。综上所述，这些数据表明，在静息的豚鼠离体气管/支气管中，内源性5-脂氧合酶活性导致半胱氨酰白三烯的产生，这些半胱氨酰白三烯会放大气道传入神经纤维中动作电位依赖性速激肽的释放。
