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Endothelin‐induced contraction and mediator release in human bronchus
Author(s) -
Hay Douglas W.P.,
Hubbard Walter C.,
Undem Bradley J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13822.x
Subject(s) - mepyramine , chemistry , endocrinology , histamine , medicine , receptor antagonist , antagonist , leukotriene d4 , prostaglandin , histaminergic , leukotriene , agonist , autacoid , pharmacology , receptor , biology , asthma
1 To elucidate the role of acetylcholine and various autacoids in endothelin‐1 (ET‐1)‐induced contraction in human bronchus, the effects of various receptor antagonists were examined. In addition, the ability of ET‐1 to stimulate the release of histamine, peptidoleukotrienes and prostanoids was determined. 2 ET‐1 was a potent and effective contractile agonist in human bronchus, possessing similar potency and efficacy to leukotriene D 4 (LTD 4 ); EC 50 (−log m ): ET‐1 = 7.76 ± 0.09, n = 7; LTD 4 = 8.46 ± 0.53, n = 7; P > 0.2; maximum response (% 10 μ m pre‐carbachol): ET‐1 = 103.8 ± 17.4, n = 7; LTD 4 = 95.5 ± 9.3, n = 7; P > 0.6. 3 The cyclo‐oxygenase inhibitor, sodium meclofenamate (1 μ m ) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 μ m ) were without significant effect on ET‐1 concentration‐response curves. 4 In the presence of sodium meclofenamate (1 μ m ), the muscarinic receptor antagonist, atropine (1 μ m ), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 μ m ) or the combination of the H 1 ‐histamine receptor antagonist, mepyramine (10 μ m ) and the leukotriene receptor antagonist, SK&F 104353 (10 μ m ), were without marked effect on ET‐1 concentration‐response curves. In addition, the combination of all four receptor antagonists did not antagonize ET‐1‐induced contraction. 5 ET‐1 (0.3 μ m ) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus. 6 ET‐1 (0.3 μ m ) significantly stimulated the release of prostaglandin D 2 (PGD 2 ), 9α, 11β PGF 2 (PGD 2 metabolite), PGE 2 , 6‐keto PGF 1α (PGI 2 metabolite), PGF 2α and thromboxane B 2 (TxB 2 ) a lower concentration, 10 n m , was without effect on prostanoid release. The production of PGD 2 was increased 7.5 fold, whereas the release of the other prostanoids was stimulated only about 1.6 to 2.7 fold. 7 These data provide evidence that ET‐1 elicits contraction of human isolated bronchus predominantly 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 significant modulatory effect on the smooth muscle contraction.