EFFECT OF BAY U3405, A THROMBOXANE A(2) RECEPTOR ANTAGONIST, ON NEUROEFFECTOR TRANSMISSION IN CANINE TRACHEAL TISSUE

Thromboxane A(2) (TXA(2)) 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 TXA(2) receptor antagonist, on the increase in vagal nerve neuro-effector transmission induced by a TXA(2) 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 TXA(2) receptors, The inhibitory action of BAY u3405 on the TXA(2)-induced enhancement of vagal nerve neuro-effector transmission may be useful in the treatment of bronchial asthma.