Isolated porcine bronchi provide a reliable model for development of bronchodilator anti-muscarinic agents for human use.
OBJECTIVE
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.


METHODS
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.


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.


CONCLUSIONS
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.
Department of Experimental and Applied Pharmacology, University of Pavia, Italy. dagg@unipv.it
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G
D'Agostino
A M
AM
Condino
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L
Gioglio
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F
Zonta
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M
Tonini
A
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Barbieri
D000818:Animals; D001667:Binding, Competitive; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D008854:Microscopy, Electron; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013045:Species Specificity; D013552:Swine
D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic