Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Rutgers Institute for Translational Medicine & Science (RITMS), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Cells. 2023 Jan 6;12(2):240. doi: 10.3390/cells12020240.
Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β adrenergic receptor (βAR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and βAR agonist functions, currently in development as a COPD therapeutic. In precision-cut human lung slices (hPCLS), we investigated the bronchoprotective effect of navafenterol against two non-muscarinic contractile agonists, histamine and thromboxane A (TxA) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and βAR antagonist propranolol reversed this inhibitory effect. TxA analog-induced bronchoconstriction was attenuated by navafenterol pre-treatment, albeit to a lesser magnitude than that of histamine-induced bronchoconstriction. Propranolol completely reversed the inhibitory effect of navafenterol on TxA analog-induced bronchoconstriction. In the presence of histamine or TxA analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by βAR agonism of navafenterol.
支气管扩张剂和抗炎药是慢性阻塞性肺疾病（COPD）和哮喘的主流治疗方法。β肾上腺素能受体（βAR）激动剂和毒蕈碱拮抗剂的联合应用比这些药物单独使用具有更好的支气管保护作用。Navafenterol（AZD8871）是一种单分子、双重药理学药物，结合了毒蕈碱拮抗剂和βAR 激动剂的功能，目前正在开发作为 COPD 的治疗药物。在精确切割的人肺切片（hPCLS）中，我们研究了 navafenterol 对两种非毒蕈碱收缩激动剂组胺和血栓烷 A（TxA）类似物（U46619）的支气管保护作用。Navafenterol 预处理显著减轻了组胺诱导的支气管收缩，βAR 拮抗剂普萘洛尔逆转了这种抑制作用。TxA 类似物诱导的支气管收缩被 navafenterol 预处理减轻，但减轻程度小于组胺诱导的支气管收缩。普萘洛尔完全逆转了 navafenterol 对 TxA 类似物诱导的支气管收缩的抑制作用。在存在组胺或 TxA 类似物的情况下，navafenterol 在人类气道中表现出支气管保护作用，主要是通过 navafenterol 的βAR 激动作用介导的。
