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Airway generation-dependent induction of muscarinic hyperresponsiveness by thromboxane mimetic in vitro.

We compared the potentiating effect of U46619, a stable thromboxane analogue, on muscarinic contractile responses of rat trachealis and large and small intrapulmonary bronchi. Cylindrical proximal and distal bronchi and midtracheal strips were excised and mounted on an isometric force transducer in a physiologic tissue bath. Dose-response curves to the muscarinic agonist bethanechol (BCh) alone were compared with responses to BCh plus U46619. Airways were incubated for 2 h prior to and during second BCh curves with a noncontractile dose of U46619. U46619 induced a left shift of the dose-response curve in all airways. This was significant only at the ED10 level in trachealis, and at the ED10, ED20, and ED50 levels in large and small bronchi. Muscarinic hyperresponsiveness induced by U46619 was significantly greater in small airways than in large bronchi or trachealis. Stabilization of endogenously released acetylcholine (ACh) with physostigmine did not alter the responses to BCh plus U46619; therefore, this mechanism does not fully explain the induction of hyperresponsiveness by U46619. Our findings demonstrate the induction of a graded increase in muscarinic responsiveness in isolated airways, and they suggest that results of studies of trachealis or proximal bronchi may not necessarily be generalized to the distal resistance airways.