Effect of BAY u3405, a thromboxane A₂ receptor antagonist, on neuro-effector transmission in canine tracheal tissue

Thromboxane A₂ (TXA₂) is reported to potentiate vagal nerve neuro-effector transmission in airway smooth muscle tissue. We investigated the effects of BAY u3405 (3(R)-[[4-fluorophenyl)sulfonyl]amino]-1,2,3,4,-tetrahydro-9H-carbazole- 9-propanoic acid), a potent and selective TXA₂ receptor antagonist, on the increase in vagal nerve neuro-effector transmission induced by a TXA₂ mimetic, U-46619, in the canine trachea. We measured the contractions of canine tracheal smooth muscle evoked by electrical field stimulation (EFS) and by acetylcholine (ACh) in the presence and absence of a subthreshold dose of U-46619 (the highest dose that did not induce any smooth muscle contraction). We then examined whether BAY u3405 inhibited the effect of U-46619 on tracheal smooth muscle. The following results were obtained: (i) subthreshold doses of U-46619 (10^-10 M and 10^-9 M) significantly increased the amplitude of the contractions evoked by EFS; (ii) by contrast, U-46619 had no effect on the contractile response of smooth muscle to exogenously applied ACh; (iii) the contraction evoked by EFS was completely abolished by the application of atropine (10^-6 M) or tetrodotoxin (10^-7 M), indicating that EFS caused the smooth muscle contraction through the release of ACh from vagal nerve terminals; and (iv) pretreatment with BAY u3405 (10^-6 M) abolished the excitatory action of U-46619 on the amplitude of twitch contraction evoked by EFS in the trachea. These results indicate that U-46619, at low concentrations, has a prejunctional action stimulating neuro-effector transmission, presumably increasing ACh release from vagal nerve terminals through TXA₂ receptors. The inhibitory action of BAY u3405 on the TXA₂-induced enhancement of vagal nerve neuro-effector transmission may be useful in the treatment of bronchial asthma.