ENDOTHELIN-INDUCED CONTRACTION AND MEDIATOR RELEASE IN HUMAN BRONCHUS

1 To elucidate the role of acetylcholine and various autacoids in endo thelin-1 (ET-1)-induced contraction in human bronchus, the effects of various receptor antagonists were examined. In addition, the ability o f ET-1 to stimulate the release of histamine, peptidoleukotrienes and prostanoids was determined. 2 ET-1 was a potent and effective contract ile agonist in human bronchus, possessing similar potency and efficacy to leukotriene D4 (LTD4); EC50 (- log M): ET-1 = 7.76 +/- 0.09, n = 7 ; LTD4 = 8.46 +/- 0.53, n = 7; P > 0.2; maximum response (% 10 muM pre -carbachol): ET-1 = 103.8 +/- 17.4, n =7; LTD4 = 95.5 +/- 9.3, n = 7; P > 0.6. 3 The cyclo-oxygenase inhibitor, sodium meclofenamate (1 muM) or the potent and selective thromboxane receptor antagonist, SQ 29,54 8 (1 muM) were without significant effect on ET-1 concentration-respon se curves. 4 In the presence of sodium meclofenamate (1 muM), the musc arinic receptor antagonist, atropine (1 muM), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 muM) or the combination of the H-1-histamine receptor antagonist, mepyramine (10 muM) and the leukotriene receptor antagonist, SK&F 104353 (10 muM), were without ma rked effect on ET-1 concentration-response curves. In addition, the co mbination of all four receptor antagonists did not antagonize ET-1-ind uced contraction. 5 ET-1 (0.3 muM) did not stimulate the release of hi stamine or immunoreactive leukotrienes from human bronchus. 6 ET-1 (0. 3 muM) significantly stimulated the release of prostaglandin D2 (PGD2 ), 9alpha, 11beta PGF2 (PGD2 metabolite), PGE2, 6-keto PGF1alpha (PGI2 metabolite), PGF2alpha and thromboxane B2 (TxB2) a lower concentratio n, 10 nM, was without effect on prostanoid release. The production of PGD2 was increased 7.5 fold, whereas the release of the other prostano ids was stimulated only about 1.6 to 2.7 fold. 7 These data provide ev idence that ET-1 elicits contraction of human isolated bronchus predom inantly via a direct mechanism with no significant involvement of the release of acetylcholine, leukotrienes, histamine or PAF. Although ET- 1 increased the release of several prostanoids they did not have a sig nificant modulatory effect on the smooth muscle contraction.