Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea.
1. The present study was undertaken to determine the mechanism of action of endothelin-1 (ET-1)-induced contraction of the guinea-pig isolated trachea. 2. ET-1 (1 nM-0.3 microM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleukotriene receptor antagonist, SK&F 104353 (10 microM) and the H1-histamine receptor antagonist, mepyramine (10 microM), which abolishes antigen-induced contraction in guinea-pig trachea, was without effect on ET-1 concentration-response curves. Furthermore, the platelet-activating factor (PAF) receptor antagonist, WEB 2086, (1 or 10 microM) did not inhibit ET-induced contraction. 3. ET-1 (0.3 microM) did not stimulate histamine or immunoreactive peptidoleukotriene release from guinea-pig isolated trachea. 4. The release of various prostanoids from guinea-pig trachea was increased significantly by ET-1 (0.3 microM); the profile of release was prostaglandin D2 (PGD2) = PGE2 = 6-keto PGF1 alpha (PGI2 metabolite) > thromboxane B2 = PGF2 alpha >> 9 alpha, 11 beta PGF2 (PGD2 metabolite). ET-1-induced release of prostaglandins, which was about 30% of that elicited by antigen in sensitized tissues, was not affected by epithelium removal and was observed in tissues from which the smooth muscle had been removed. Previous studies in our laboratory indicated that indomethacin potentiated contraction produced by high concentrations of ET-1, whereas a thromboxane receptor antagonist was without appreciable effect on ET-1 concentration-response curves. 5. Pretreatment of tissues for 1 h with capsaicin (10 microM), which depletes different sensory neurones, produced a small, but significant, inhibitory effect on ET-1 concentration-response curves in the presence but not the absence of the epithelium. The combination of the NK1 tachykinin receptor antagonist,CP-96,345 (0.1 microM), and the NK2 tachykinin receptor antagonist, SR 48968 (0.1 microM), was without effect on ET-l concentration-response curves but substantially antagonized capsaicin-induced contraction.6. The present data suggest that in guinea-pig isolated trachea, ET- 1 produces contraction predominantly via a direct mechanism: there is no significant contribution of the release of histamine,leukotrienes, PAF, or tachykinins (acting on NK1 or NK2 receptors). Although ET-1 evokes the release of an array of prostanoids from the trachea they do not appear to have a major influence on the contractile response.
Hay
D W
DW
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Hubbard
W C
WC
Undem
B J
BJ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D020024:Leukotriene Antagonists; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D013189:SRS-A / Q000037:antagonists & inhibitors; D013779:Tetrodotoxin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
D001549:Benzamides; D001713:Biphenyl Compounds; D003998:Dicarboxylic Acids; D016232:Endothelins; D020024:Leukotriene Antagonists; D010880:Piperidines; D011453:Prostaglandins; D018039:Receptors, Tachykinin; D013189:SRS-A; D013779:Tetrodotoxin; C073839:SR 48968; D015288:Neurokinin A; C052393:pobilukast; D002211:Capsaicin; C066892:CP 96345