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.(ABSTRACT TRUNCATED AT 250 WORDS)
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000294:innervation*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002227:Carbazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D013779:Tetrodotoxin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001285:Atropine; D000109:Acetylcholine; C063119:ramatroban