thromboxane-a2 and pobilukast

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.

Topics: Acetylcholine; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Dicarboxylic Acids; Endothelins; Fatty Acids, Unsaturated; Histamine Release; Humans; Hydrazines; In Vitro Techniques; Indomethacin; Inflammation; Leukotrienes; Lung; Meclofenamic Acid; Muscle Contraction; Muscle, Smooth; Platelet Aggregation Inhibitors; Prostaglandins; Spectrometry, Fluorescence; SRS-A; Thromboxane A2; Triazoles

Thromboxane A2/prostaglandin H2 (TP)-receptor activation has been reported to participate in some of the responses to peptide leukotrienes (LT). We examined the effect of TP-receptor antagonism on LT-induced mesenteric vasoconstriction and hemoconcentration in anesthetized rats. The antagonist used in these studies, SQ 30,741, was shown to have high selectivity and potency for vascular TP-receptors in the rat. Arterial (i.a.) injection of LTC4 and D4 elicited dose-dependent and transient reductions in mesenteric blood flow without changes in arterial blood pressure. These responses were unaffected by a dose of SQ 30,741 which produced approximately 99% inhibition of similar responses to U-46,619. In contrast, LT-induced mesenteric vasoconstriction was inhibited approximately 90% by two LT antagonists, LY 171,883 and SKF 104,353. In other experiments i.v. infusion of LTD4 caused increases in hematocrit and reductions in arterial blood pressure that were not influenced by SQ 30,741. These data suggest that increases in mesenteric vascular resistance and hemoconcentration in response to LTs are not the result of TP-receptor activation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetophenones; Angiotensin II; Animals; Blood Pressure; Dicarboxylic Acids; Dinoprost; Hematocrit; Male; Mesenteric Arteries; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Tetrazoles; Thromboxane A2; Vasoconstriction