Differences in Ca²⁺ mobilization by muscarinic agonists in tracheal smooth muscle

The muscarinic agonists acetylcholine (ACh) and McN-A-343 activate a homogeneous population of M₃ receptors in canine tracheal smooth muscle. However, ACh is much more efficacious than McN-A-343 both at stimulating force development and active shortening and at antagonizing relaxation induced by isoproterenol. In other tissues, the same muscarinic receptor may be coupled to multiple subcellular pathways, but activate different pathways depending on the efficacy of the agonist. The present study investigated mechanisms of excitation-contraction coupling in canine tracheal smooth muscle by muscarinic agonists of different efficacy. ACh was more effective at stimulating inositol phosphate production and elicited a large initial transient increase in intracellular Ca²⁺ concentration ([Ca²⁺](i)), whereas McN-A-343 elicited only a slow gradual rise in [Ca²⁺](i). Extracellular Ca²⁺ influx through voltage-operated channels played a minor role in contractions induced by either agonist. Results suggest that contractions by ACh and McN-A-343 may be mediated by the same subcellular pathways; however, the greater potency of ACh at stimulating those pathways results in very different kinetics of Ca²⁺ activation.