Endothelin-induced contraction and mediator release in human bronchus.
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 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 microM 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 microM) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 microM) were without significant effect on ET-1 concentration-response curves. 4. In the presence of sodium meclofenamate (1 microM), the muscarinic receptor antagonist, atropine (1 microM), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 microM) or the combination of the H1-histamine receptor antagonist, mepyramine (10 microM) and the leukotriene receptor antagonist, SK&F 104353 (10 microM), 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 microM) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus. 6. ET-1 (0.3 microM) 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 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.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.
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
D000109:Acetylcholine / Q000378:metabolism / Q000502:physiology; D001381:Azepines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008469:Meclofenamic Acid / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D013189:SRS-A / Q000037:antagonists & inhibitors; D013050:Spectrometry, Fluorescence; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003998:Dicarboxylic Acids; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D015289:Leukotrienes; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D013189:SRS-A; D014230:Triazoles; C052518:WEB 2086; D008469:Meclofenamic Acid; D013928:Thromboxane A2; C045749:SQ 29548; D000109:Acetylcholine; C052393:pobilukast; D007213:Indomethacin