D'Agostino_2008_Br.J.Pharmacol_154_1611

BACKGROUND AND PURPOSE: In human airways, muscarinic acetylcholine receptors (mAChRs) exert a predominant role in the control of airways resistance and anti-muscarinic agents are currently included in the pharmacological treatment of chronic obstructive pulmonary disease (COPD). However, the development of more effective mAChR antagonists is hampered by considerable species variability in the ultrastrucural and functional control of airway smooth muscle, making extrapolation of any particular animal model questionable. This study was designed to characterize the mAChRs in a bronchial preparation from pigs, animals considered to provide close models of human biology. EXPERIMENTAL APPROACH: Smooth muscle bronchial strips were examined by electron microscopy in order to compare their neuromuscular structure with that of human bronchi and used to study the affinity of a series of selective mAChR antagonists, estimated as pKis in competition binding assays with NMS and pA2, by Schild analysis, in contractile experiments. KEY
RESULTS: Pharmacodynamic binding parameters and affinity profiles of a series of antagonists were consistent with the presence of a majority of M2 mAChRs along with a minor population of M3 mAChRs. Functionally, the highly significant correlation between postjunctional pA2 affinities and corresponding affinity constants at human recombinant M1-M5 subtypes indicated that smooth muscle contraction in porcine bronchi, as in human bronchi, was dependent on the M3 subtype. CONCLUSION AND IMPLICATIONS: Based on the characterization of mAChRs, isolated porcine bronchi provide an additional experimental model for development of mAChR antagonists for the treatment of human airway dysfunctions.