Leukotriene-induced contraction and thromboxane production in guinea-pig lung parenchymal strips

Creese, Brian R.; Bach, Michael K.; Fitzpatrick, F. A.; Bothwell, W

doi:10.1016/0014-2999(84)90251-6

Cited by 27 publications

(3 citation statements)

References 29 publications

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“…As in the case of antigen challenge, the inhibition by the methylation inhibitors of the contraction of the sensitized tissues induced by Paf-acether and by LTD4 cannot be explained by a direct effect on the cyclo-oxygenase pathway. Indeed, LTD4- (Austen et al, 1983;Creese et al, 1984), Paf-acether - (Stimler & O'Flaherty, 1983;Detsouli et al, 1985) and histamine - (Mitchell & Denborough, 1979;Stimler-Gerard, 1985) induced lung strip contractions are not blocked by cyclooxygenase inhibitors.…”

Section: Chemicals Andstatistical Analysismentioning

confidence: 99%

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Randon

Lefort

Vargaftig

1987

British J Pharmacology

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The combination of two methylation inhibitors 3‐deazaadenosine (10−4 or 4 × 10−4 m) plus l‐homocysteine (2 × 10−4 m) caused a time‐dependent inhibition of antigen‐induced contraction, formation of thromboxane B2 (TxB2) and release of histamine from lung parenchyma strips taken from guinea‐pigs actively sensitized with ovalbumin (OA). The methylation inhibitors also prevented the lung strip contractions induced by the mediators platelet‐activating factor (Paf‐acether, 10−6 m), leukotriene D4 (LTD4, 10−8 and 3 × 10−8 m), and in part to arachidonic acid (10−6 and 10−5 m), under conditions where the contractions to histamine (10−6‐10−4 m) were virtually unaffected. TxB2 formation induced by these mediators or by OA was more affected by the methylation inhibitors than the lung strip contractions, indicating that prostaglandin formation is more sensitive to these inhibitors than the myotropic activity. In contrast, the suppressive effect of the methylation inhibitors on histamine secretion by parenchyma lung strips induced by OA followed the inhibition of the contraction. These results show that inhibitors of methyltransferases interfere with the myotropic responses and with the release of mediators by actively sensitized guinea‐pig lung strips stimulated with antigen, and suggest a major role for a methylation process in mediating the contraction of and mediator release by the lung parenchyma.

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Section: Chemicals Andstatistical Analysismentioning

confidence: 99%

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Randon

Lefort

Vargaftig

1987

British J Pharmacology

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“…In view ofthe evidence, at least in the guinea-pig trachea, that the postulated inhibitory influence may involve a prostanoid , the effects ofa cyclo-oxygenase inhibitor, indomethacin, on leukotriene-induced contractions were investigated. 5-Hydroxytryptamine (5-HT) and thromboxane A2 are potent bronchoconstrictors (Creese et al, 1984;Cohen et al, 1985), and the present study was extended therefore to examine the effects ofepithelium removal on responses produced by 5-HT and the thromboxane mimetic, U-44069. Preliminary accounts of the findings have been presented previously (Hay et al, 1986c;Farmer et al, 1986a).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of epithelium removal on the responsiveness of guinea‐pig tracheal smooth muscle to bronchoconstrictors

Hay¹,

Farmer

Raeburn

et al. 1987

British J Pharmacology

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The influence of the epithelium on contractions produced by the peptidoleukotrienes, 5‐hydroxytryptamine (5‐HT) and the thromboxane mimetic, U‐44069, was examined in trachea from control and ovalbumin‐sensitized guinea‐pigs. In control tissues removal of the epithelium produced an approximately 2 to 4 fold leftward shift in leukotriene C4 (LTC4) and LTD4 concentration‐response curves, but no effect on LTE4‐induced contractions. Similar results were obtained in preparations from ovalbumin‐sensitized animals. Responses produced by 5‐HT or U‐44069 were similar in the presence and absence of the epithelium in control guinea‐pigs. Indomethacin produced contrasting effects on leukotriene‐induced contractions in control guinea‐pigs: an increase in sensitivity to LTC4 in the presence but not absence of the epithelium, no effect on LTD4‐induced contractions and a decrease in sensitivity to LTE4 in both epithelium‐containing and epithelium‐free preparations. These results indicate that there is selectivity in the effects of epithelium removal on agonist‐induced contractions of the guinea‐pig trachea. This provides further evidence for the modulatory influence of the epithelium on the reactivity of mammalian airway smooth muscle and supports the postulated existence of an epithelium‐derived inhibitory factor. The observation that in intact trachea indomethacin mimics the effects of epithelium removal on LTC4‐induced responses, suggests the involvement of a prostanoid(s) in this phenomenon.

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“…However, antagonism of leukotriene effects by FPL-55,712 or inhibition of eicosanoid formation by BW-755C reduced the overall amplitude and dura tion of the late contractile response. We used the dual eicosanoid synthesis inhibitor BW-755C rather than the leukotriene receptor antagonist FPL-55,712 in further experiments, because the latter was shown to act preferentially on LTD4 receptors [14] and exoge nous leukotrienes are known to release thromboxane A2 in guinea pig pulmonary tissue [15]. Thus, BW-755C inhibited the release of leukotrienes and cy clooxygenase products simultaneously [16], and effec tively isolated all the major eicosanoids from the ana phylactic response.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Platelet Activating Factor Mediated Component of Guinea Pig Anaphylaxis by Receptor Antagonists

Darius¹,

Jb²,

Am³

1986

Int Arch Allergy Immunol

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The role of platelet activating factor (PAF) and its inhibition by specific receptor antagonists was studied in hypersensitivity reactions in guinea pig lung parenchymal strips and in guinea pigs in vivo. Immunological challenge of isolated lung parenchymal strips with ovalbumin resulted in a contractile response of 184 ± 16 mg (n = 38). Pretreatment of the strips with a combination of the antihistamine diphenhydramine, the dual lipoxygenase and cyclooxygenase product synthesis inhibitor BW-755C, and the PAF receptor antagonist kadsurenone totally inhibited the increase in tension. The bronchoconstrictor effects induced by immunological challenge were also totally inhibited when the leukotriene receptor antagonist FPL-55,712 was used to replace BW-755C or another PAF receptor antagonist, alprazolam was used to replace kadsurenone. Ovalbumin challenge in sensitized guinea pigs in vivo resulted in airway constriction, circulatory failure and an abrupt fall in continuously measured platelet count by 75 ± 12%, followed by death of all animals within 5–8 min. Pretreatment with diphenhydramine, BW-755C and kadsurenone (or alprazolam) improved survival to 64% (i.e., 7 of 11 animals) compared to a survival rate of 0% (i.e., 0 of 8 vehicle treated controls). Despite the improved survival, the severe thrombocytopenia was unaltered with the combined therapy. PAF, histamine and peptide leukotrienes appear to act in concert in mediating the anaphylaxis-induced airway constriction and circulatory failure in guinea pigs, but are not apparently responsible for the accompanying thrombocytopenia.

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Leukotriene-induced contraction and thromboxane production in guinea-pig lung parenchymal strips

Cited by 27 publications

References 29 publications

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Blockade by methylation inhibitors of the anaphylactic response of guinea‐pig lung strips

Differential effects of epithelium removal on the responsiveness of guinea‐pig tracheal smooth muscle to bronchoconstrictors

Inhibition of the Platelet Activating Factor Mediated Component of Guinea Pig Anaphylaxis by Receptor Antagonists

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