Muscarinic receptor reserve and β-adrenergic sensitivity in tracheal smooth muscle

The possibility that differences in β-adrenergic sensitivity among canine trachealis muscles contracted with different contractile agonists are related to differences in the receptor-occupancy characteristics of the contractile agonists was investigated. Relaxation to isoproterenol was compared in muscles contracted with the muscarinic agonists McN-A-343 and acetylcholine (ACh). The apparent dissociation constant (pK(B)) values for the M₁-antagonist, pirenzepine, against ACh (6.96 ± 0.18) and McN-A-343 (6.84 ± 0.08) were similar. The pK(B) values for the M₃-antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) against ACh (8.76 ± 0.13) and McN-A-343 (8.71 ± 0.10) were also similar, suggesting that these agonists were activating the same subtype of muscarinic receptor, probably M₃. However, the contractile response to ACh was associated with a greater receptor reserve than that for McN-A-343. Isoproterenol relaxed muscles contracted with McN-A-343 much more effectively than those contracted with an equieffective concentration of ACh. The results suggest that the relative resistance of ACh-induced contractions to relaxation by isoproterenol may not be an inherent quality of muscarinic receptor stimulation. The large receptor reserve available to ACh may act to buffer the contractile response from the inhibitory effects of β-adrenergic stimulation. Alternatively, ACh may be able to initiate subcellular mechanisms that are unavailable to agonists of lower efficacy.