The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and β<sub>2</sub> Adrenergic Receptor Agonist Navafenterol in Human Small Airways
2023
Joseph Antony Jude | Ian Dainty | Nikhil Karmacharya | William Jester | Reynold Panettieri
Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β<sub>2</sub> adrenergic receptor (β<sub>2</sub>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 β<sub>2</sub>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<sub>2</sub> (TxA<sub>2</sub>) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and β<sub>2</sub>AR antagonist propranolol reversed this inhibitory effect. TxA<sub>2</sub> 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<sub>2</sub> analog-induced bronchoconstriction. In the presence of histamine or TxA<sub>2</sub> analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by β<sub>2</sub>AR agonism of navafenterol.
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