Endothelin‐induced contraction and mediator release in human bronchus

Douglas W.P. Hay, Walter C. Hubbard, Bradley J. Undem

Research output: Contribution to journalArticlepeer-review

Abstract

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. ET‐1 was a potent and effective contractile 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 μm pre‐carbachol): ET‐1 = 103.8 ± 17.4, n = 7; LTD4 = 95.5 ± 9.3, n = 7; P > 0.6. The cyclo‐oxygenase inhibitor, sodium meclofenamate (1 μm) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 μm) were without significant effect on ET‐1 concentration‐response curves. In the presence of sodium meclofenamate (1 μm), the muscarinic receptor antagonist, atropine (1 μm), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 μm) or the combination of the H1‐histamine receptor antagonist, mepyramine (10 μm) and the leukotriene receptor antagonist, SK&F 104353 (10 μm), 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. ET‐1 (0.3 μm) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus. ET‐1 (0.3 μm) significantly stimulated the release of prostaglandin D2 (PGD2), 9α, 11β PGF2 (PGD2 metabolite), PGE2, 6‐keto PGF (PGI2 metabolite), PGF and thromboxane B2 (TxB2) a lower concentration, 10 nm, was without effect on prostanoid release. The production of PGD2 was increased 7.5 fold, whereas the release of the other prostanoids was stimulated only about 1.6 to 2.7 fold. 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. 1993 British Pharmacological Society

Original languageEnglish (US)
Pages (from-to)392-398
Number of pages7
JournalBritish Journal of Pharmacology
Volume110
Issue number1
DOIs
StatePublished - Sep 1993

Keywords

  • Endothelin‐1
  • SK&F 104353
  • SQ 29,548
  • WEB 2086
  • histamine release
  • human bronchus
  • mepyramine
  • peptidoleukotriene release
  • prostanoid release
  • sodium meclofenamate

ASJC Scopus subject areas

  • Pharmacology

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