The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and beta(2) Adrenergic Receptor Agonist Navafenterol in Human Small Airways

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of beta(2) adrenergic receptor (beta(2)AR) 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 beta(2)AR 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(2) (TxA(2)) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and beta(2)AR antagonist propranolol reversed this inhibitory effect. TxA(2) 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(2) analog-induced bronchoconstriction. In the presence of histamine or TxA(2) analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by beta(2)AR agonism of navafenterol.