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Anti-tussive and bronchodilator mechanisms of action for the enaminone E121.

机译：烯胺酮E121的镇咳和支气管扩张剂作用机制。

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AIMS: In this study, we investigated whether the enaminone, E121, has anti-tussive effects in a guinea pig model of cough, and if so, whether this effect is mediated via a central or peripheral site of action. We also assessed whether E121 has bronchodilator effects and the molecular mechanisms underlying any anti-tussive and/or bronchodilator effects. MAIN METHODS: Whole body plethysmography was used to assess both cough and airway obstruction. A stereotaxic apparatus was used to administer drugs intracerebroventricularly (i.c.v.). Effects of E121 were examined in vitro on contractile effects in guinea pig bronchioles. KEY FINDINGS: Pre-treatment of animals with E121 resulted in a significant inhibition in the citric acid-induced cough and airway obstruction compared to vehicle-pretreated animals. The K(ATP) antagonist, glibenclamide, significantly inhibited the anti-tussive and bronchoprotective effects of E121. Also, intra-tracheal administration of E121 resulted in a significant inhibition of both the citric acid-induced cough response and airway obstruction compared to vehicle-pretreated animals. By contrast, i.c.v. administration had no effect. Finally, E121 significantly inhibited carbachol-induced airway smooth muscle contractions, an effect that was reduced by both glibenclamide and propranolol. Interestingly, E121 enhanced histamine-induced cAMP release in human eosinophils although it did not directly elevate cAMP levels. SIGNIFICANCE: The enaminone, E121, has anti-tussive and bronchodilatory effects and is topically, but not centrally, active. The anti-tussive mechanism of action of E121 seems to be K(ATP) channel dependent, whereas its bronchodilatory effects appear to be mediated via activation of both K(ATP) channels and beta(2) receptors. Therefore, E121 may potentially represent a novel therapy for cough, particularly cough associated with airway obstruction.
机译：目的：在这项研究中，我们调查了烯胺酮E121在豚鼠咳嗽模型中是否具有镇咳作用，如果有，这种作用是通过中枢还是外周作用介导的。我们还评估了E121是否具有支气管扩张药作用以及任何抗咳嗽和/或支气管扩张药作用的分子机制。主要方法：全身体积描记法用于评估咳嗽和气道阻塞。使用立体定向装置来脑室内（i.c.v.）施用药物。在体外检查了E121对豚鼠细支气管收缩作用的作用。主要发现：与媒介物预处理的动物相比，用E121进行动物预处理可显着抑制柠檬酸引起的咳嗽和气道阻塞。 K（ATP）拮抗剂格列本脲显着抑制E121的镇咳和支气管保护作用。同样，与载体预处理的动物相比，气管内施用E121导致柠檬酸诱导的咳嗽反应和气道阻塞的显着抑制。相比之下，i.c.v。管理没有效果。最后，E121显着抑制了卡巴胆碱引起的气道平滑肌收缩，但格列苯脲和普萘洛尔均减弱了这种作用。有趣的是，E121增强了组胺诱导的嗜酸性粒细胞中cAMP的释放，尽管它​​并未直接提高cAMP的水平。重要性：烯胺酮E121具有镇咳和支气管扩张作用，局部但非中央活跃。 E121的镇咳作用机制似乎是K（ATP）通道依赖性的，而其支气管扩张作用似乎是通过K（ATP）通道和beta（2）受体的激活介导的。因此，E121可能代表了一种新的咳嗽疗法，特别是与气道阻塞相关的咳嗽。

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