Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongii University School of Medicine, Shanghai, 200065, China.
Division of Dysphagia Rehabilitation, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Eur J Pharmacol. 2021 Sep 15;907:174192. doi: 10.1016/j.ejphar.2021.174192. Epub 2021 May 16.
Our previous studies implicated the voltage-gated sodium channel subtype Na 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of Na 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the antitussive effects of the Na 1.7 selective blocker Compound 801 administered systemically in awake guinea pigs or administered topically in anesthetized guinea pigs. We also evaluated the antitussive effects of ambroxol, a low affinity Na blocker modestly selective for tetrodotoxin resistant Na subtypes. Both Compound 801 and ambroxol dose-dependently inhibited action potential conduction in guinea pig vagus nerves (assessed by compound potential), with ambroxol nearly 100-fold less potent than the Na 1.7 selective Compound 801 in this and other Na 1.7-dependent guinea pig and human tissue-based assays. Both drugs also inhibited citric acid evoked coughing in awake or anesthetized guinea pigs, with potencies supportive of an Na 1.7-dependent mechanism. Notably, however, the antitussive effects of systemically administered Compound 801 were accompanied by hypotension and respiratory depression. Given the antitussive effects of topically administered Compound 801, we speculate that the likely insurmountable side effects on blood pressure and respiratory drive associated with systemic dosing make topical formulations a viable and perhaps unavoidable therapeutic strategy for targeting Na 1.7 in cough.
我们之前的研究表明，电压门控钠离子通道亚型 Na 1.7 参与了调节咳嗽的迷走传入神经的动作电位的传递，因此将该通道鉴定为一种合理的止咳治疗靶点。但目前尚不清楚，是否可以通过全身给予 Na 1.7 电导率的小分子抑制剂，在不影响心血管功能、胃肠道动力或呼吸的情况下，实现治疗获益。为此，我们评估了全身性给予 Na 1.7 选择性阻断剂 Compound 801 在清醒豚鼠或麻醉豚鼠局部给予时的止咳作用。我们还评估了 ambroxol 的止咳作用，ambroxol 是一种对河豚毒素抗性 Na 亚型具有低亲和力的 Na 阻断剂，对 Na 1.7 具有适度选择性。Compound 801 和 ambroxol 均剂量依赖性地抑制豚鼠迷走神经的动作电位传导（通过复合电位评估），ambroxol 在这种和其他依赖于 Na 1.7 的豚鼠和人组织基础测定中，对 Na 1.7 的选择性几乎比 Na 1.7 选择性化合物 801 低 100 倍。这两种药物还抑制柠檬酸诱发的清醒或麻醉豚鼠咳嗽，其效力支持 Na 1.7 依赖性机制。然而，值得注意的是，全身给予 Compound 801 的止咳作用伴随着低血压和呼吸抑制。鉴于局部给予 Compound 801 的止咳作用，我们推测，全身给予时与血压和呼吸驱动力相关的不可克服的副作用使得局部制剂成为针对咳嗽的 Na 1.7 的可行且可能不可避免的治疗策略。
