神经激肽A引起的豚鼠离体气管收缩：hepoxilins的增强作用

Neurokinin A-induced contraction of guinea-pig isolated trachea: potentiation by hepoxilins.

Laneuville O, Couture R, Pace-Asciak C R

Research Institute, Hospital for Sick Children, Toronto, Canada.

Br J Pharmacol. 1992 Nov;107(3):808-12. doi: 10.1111/j.1476-5381.1992.tb14528.x.

Abstract

Hepoxilin A3 (8R and 8S isomers) (HxA3), hepoxilin A3-C (8R and 8S isomers) (HxA3-C) and trioxilin A3 (8S isomer) (TrXA3, the stable derivative of HxA3) were tested for their effects on helicoidal strips of guinea-pig isolated tracheae. 2. None of the compounds (10(-9)-10(-6) M) tested had a direct effect on resting tension of trachea. 3. HxA3 (8S) and HxA3-C (8R) (10(-8) M) produced a significant leftward shift of the log concentration-response curves to neurokinin A (NKA) (EC50 (nM), control = 29.0 +/- 2.8, HxA3 (8S) = 21.7 +/- 3.7, HxA3-C (8R) = 13.8 +/- 3.8, n = 6 for each). Also the maximal response to NKA was significantly increased when the tissues were exposed to these hepoxilins (% of the maximal response to NKA, control = 100, HxA3 (8S) = 114.5 +/- 5.3, HxA3-C (8R) = 139.0 +/- 6.2, n = 6 for each). The threshold concentrations for both hepoxilins was 10(-8) M and their effects were dose-related. 4. Stereochemical specificity was observed. The 8S-isomer of HxA3 was active in potentiating the NKA-induced contraction of the trachea while the 8R isomer was inactive. In contrast, the 8R isomer of HxA3-C was active while the 8S isomer was inactive. The trihydroxy metabolite of the active isomer of HxA3 (8S), i.e. TrXA3 (8S) (10(-6) M), was inactive in potentiating the NKA-induced contraction of the trachea. 5. It is concluded that hepoxilins sensitize the guinea-pig isolated trachea to the potent bronchoconstrictor, NKA.

摘要

对肝氧素A3（8R和8S异构体）（HxA3）、肝氧素A3-C（8R和8S异构体）（HxA3-C）和三羟素A3（8S异构体）（TrXA3，HxA3的稳定衍生物）对豚鼠离体气管螺旋条的作用进行了测试。2. 所测试的化合物（10⁻⁹ - 10⁻⁶ M）均对气管的静息张力无直接影响。3. HxA3（8S）和HxA3-C（8R）（10⁻⁸ M）使神经激肽A（NKA）的对数浓度-反应曲线显著左移（EC50（nM），对照组 = 29.0 ± 2.8，HxA3（8S） = 21.7 ± 3.7，HxA3-C（8R） = 13.8 ± 3.8，每组n = 6）。当组织暴露于这些肝氧素时，对NKA的最大反应也显著增加（对NKA最大反应的百分比，对照组 = 100，HxA3（8S） = 114.5 ± 5.3，HxA3-C（8R） = 139.0 ± 6.2，每组n = 6）。两种肝氧素的阈浓度均为10⁻⁸ M，且其作用呈剂量相关。4. 观察到立体化学特异性。HxA3的8S异构体在增强NKA诱导的气管收缩方面具有活性，而8R异构体无活性。相反，HxA3-C的8R异构体具有活性，而8S异构体无活性。HxA3（8S）活性异构体的三羟基代谢产物，即TrXA3（8S）（10⁻⁶ M），在增强NKA诱导的气管收缩方面无活性。5. 得出结论：肝氧素使豚鼠离体气管对强效支气管收缩剂NKA敏感。