Qian Y, Girard V, Martin C A, Molimard M, Advenier C
Faculté de Médicine Paris-Ouest Laboratoire de Pharmacologie, France.
Eur Respir J. 1994 Feb;7(2):306-10. doi: 10.1183/09031936.94.07020306.
Theophylline has been reported to inhibit excitatory noncholinergic but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might exert this effect through an inhibition of phosphodiesterases (PDE), and since many types of PDE have now been described, the aim of this study was to investigate the effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazodan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, respectively. Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10(-6) M and propranolol 10(-6) M. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. Rolipram (10(-9) to 10(-6) M) but not siguazodan or zaprinast, inhibited the peptidergic contraction in a concentration-dependent manner. Conversely, the cholinergic response was unaffected. Contractile responses induced by exogenous acetylcholine (10(-8) to 10(-3) M) or [Nle10]NKA(4-10) (10(-10) to 10(-6) M) were also unaffected by rolipram, siguazodan and zaprinast (10(-7) M). These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is specifically involved in this effect, as in other anti-inflammatory effects.
据报道，茶碱可抑制豚鼠支气管中的兴奋性非胆碱能神经传递，但不抑制胆碱能神经传递。由于茶碱可能通过抑制磷酸二酯酶（PDE）发挥这种作用，且目前已描述了多种类型的PDE，因此本研究的目的是在体外研究三种特异性PDE抑制剂对豚鼠离体主支气管电场刺激（EFS）的影响。所用药物分别是西呱唑旦、咯利普兰和扎普司特，它们分别特异性抑制III型、IV型和V型PDE。在10⁻⁶ M消炎痛和10⁻⁶ M普萘洛尔存在的情况下，用双相脉冲（16 Hz，1 ms，320 mA，持续10 s）对豚鼠支气管进行透壁刺激。观察到两个连续的收缩反应：快速的胆碱能收缩，随后是由于C纤维末梢局部释放神经肽引起的持久收缩。咯利普兰（10⁻⁹至10⁻⁶ M）而非西呱唑旦或扎普司特以浓度依赖性方式抑制肽能收缩。相反，胆碱能反应未受影响。罗利普兰、西呱唑旦和扎普司特（10⁻⁷ M）也不影响外源性乙酰胆碱（10⁻⁸至10⁻³ M）或[Nle10]NKA(4 - 10)（10⁻¹⁰至10⁻⁶ M）诱导的收缩反应。这些结果表明，与抑制PDE的浓度相似的咯利普兰浓度可减少C纤维末梢感觉神经肽的释放，并表明IV型环磷酸腺苷（AMP）PDE特别参与了这一效应，如同在其他抗炎效应中一样。
