Thromboxane A2 mimetic (U-46619) induces hyperresponsiveness of smooth muscle in the canine bronchiole, but not in the trachea.

It has been reported that cholinergic agonists induce bronchoconstriction by directly stimulating M3 muscarinic receptors on the surfaces of smooth muscle cells. Although thromboxane A2 (TXA2) has been demonstrated to induce airway hyperresponsiveness to cholinergic agonists in vivo, it does not affect the contractile response of smooth muscle to cholinergic agonists in vitro. To investigate the causes for the discrepancy between the in vivo and in vitro data, we compared the effects exerted by a TXA2 mimetic, U-46619, on the smooth muscle of canine trachea and bronchiole. We measured the contractile response to exogenously applied acetylcholine (ACh) before and after the application of a subthreshold dose of U-46619. The subthreshold dose was determined as that dose which did not induce smooth muscle contraction, this being 10(-9) M in the present study. The contractile responses of tracheal strips to ACh were not affected by the subthreshold dose of U-46619. By contrast, the responses of bronchiolar rings were significantly enhanced by this subthreshold dose. The excitatory effect of U-46619 on the ACh-induced contraction was completely prevented by treatment with a TXA2 antagonist, BAY u3405. These results indicate that TXA2 directly increases the responsiveness of smooth muscle in the bronchiole, and suggest that increases in the responsiveness of small airways may play an important role in the development of the airway hyperresponsiveness induced by TXA2.