Pharmacological study of the effects of leukotrienes C4, D4, E4 & F4 on guinea pig trachelis: Interaction with FPL-55712

doi:10.1016/0090-6980(83)90066-7

Prostaglandins

Volume 26, Issue 5, November 1983, Pages 833-843

Prostaglandins

https://doi.org/10.1016/0090-6980(83)90066-7 Get rights and content

Abstract

Leukotrienes D₄ ⩾ C₄ > E₄ ⩾ F₄ produced qualitatively similar contractions of guinea-pig trachealis, which were antagonized by the SRS-antagonist FPL-55712. Schild analyses indicated that FPL-55712 when tested in a low concentration range (0.57–5.7 × 10⁻⁶M) competitive antagonist of LTC₄, LTE₄ and LTF₄ (slope not significantly different from one). The interaction of FPL-55712 with LTD₄ may be noncompetitive (slope < 1). Comparison of the calculated dissociation constants (−log K_B) indicated that FPL-55712 was more effective at blocking LTE₄ and LTF₄ compared to LTC₄ and LTD₄. In the presence of higher concentrations of FPL-55712 (1.9 × 10⁻⁵M) the antagonism of LTC₄ became noncompetitive. These findings indicate that important differences exist in the interaction of FPL-55712 with the various peptido leukotrienes in guinea pig trachealis. Discovery of more selective antagonists will be needed to determine if multiple receptor subtypes are present in this tissue.

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Cited by (20)

Does leukotriene F4 play a major role in the infection mechanism of Candida sp.?
2020, Microbial Pathogenesis
Citation Excerpt :
Like all other CysTLs, LTF4 alone does not increase the migration of cells through the endothelium [38]. In the evaluation of these four leukotrienes in relation to tracheal smooth muscle contraction, LTD4 was shown as the highest power CysTL, demonstrating approximately 1.5, 5.0 and 8.0 times more potency than LTC4, LTE4, LTF4 respectively [37]. Despite the fact that the exact activity of CysLTs vary according to the tissue and species in question [38], it is evident that in studies where the function of CysLTs has been evaluated, LTF4 has the lowest biological activity [38,71], which may be the reason why patients who presented positive blood culture for Candida albicans also presented LTF4.
Candidiasis is the most common fungal infection affecting hospitalized patients, especially immunocompromised and critical patients. Limitations regarding the assertive diagnosis of both Candidemia and Candidiasis not only impairs the introduction of effective treatments but also lays a heavy financial burden over the health system. Furthermore, it is still challenging to ascertain whether diagnostic methods are accurate and whether treatment is effective for patients with Candidemia. These constraints come from the uncertainty of the pathophysiological mechanism by which the pathogen establishes the opportunistic infection. Additionally, it is the reason why some patients present positive blood culture results, and others do not, and why it is very difficult during clinical routines to prove Candidemia or invasive candidiasis. Taking into account the current situation, this contribution proposes two markers that may help to understand the mechanisms of infection by the pathogen: Leukotriene F4 and 5,6-dihydroxy-eicosatetraenoic. These two lipids putatively modulate the host's immune response, and the initial data presented in this contribution suggest that these lipids allow the opportunistic infection to be installed. The study was carried out using an omics-based platform using direct-infusion high-resolution mass spectrometry and allied with bioinformatics tools to provide accurate and reliable results for biomarker candidates screening.
Functional characteristics of cysteinyl-leukotriene receptor subtypes
2002, Life Sciences
Cysteinyl-leukotrienes, i.e. leukotriene (LT) C₄, D₄ and E₄, are inflammatory mediators and potent airway- and vasoconstrictors. Two different cysteinyl-leukotriene receptors, CysLT₁ and CysLT₂, have been cloned and functionally characterised using potent CysLT₁ receptor antagonists and the dual CysLT₁/CysLT₂ receptor antagonist BAY u9773. However, the rank order of potency of the cysteinyl-leukotrienes at the CysLT receptors differs between tissues and studies, and a CysLT receptor classification based on agonist selectivity has not been established. In addition, the existence of more than two receptor subtypes for cysteinyl-leukotrienes has been suggested.
Inhibitory effects of a lipoxygenase inhibitor nordihydroguaiaretic acid on antagonism of leukotriene C<inf>4</inf>-induced contractions of isolated guinea-pig trachea
1988, Prostaglandins
We have studied the effects of a lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) on antagonim of leukotriene (LT) C₄-induced contractions of isolated guinea-pig trachea and the results were compared to that of a cycloocygenase inhibitor indomethacin, NDGA (30 μM) as well as idomethacin (5 μM) inhibited LTC₄-iduced contraction. But in the presence of indomethacin NDGA was ineffective to inhibit the LTC₄ response, whereas two other lipoxygenase inhibitors, phenidone (3–30 μM) and 5,8,11,14-eicostatetraynoic acid (ETYA, 10 μM), markedly inhibited it. The antagonist action of an LTD₄ receptor antagonist FPL55712 against LTC₄-induced contractions was significantly reduced by NDGA (10–30 μM), but indomethacin had no effect on it. NDGA possessed the same inhibitory effect n the LTC₄ antagonism in the presence of indomethacin, but 0.3 μM phenidone and 1 μM ETYA which did not inhibit the LTC₄ response had no effect on it. NDGA also inhibited the relaxant response of isoproterenol on the contraction elicited by 30 nM LTC₄, but did not affect those of forskolin and aminophylline. The relaxant response of isoproterenol on the LCT₄ response was not inhibited by indomethacin, 0.3 μM phenidone and 1 μM ETYA. In the presence of a γ-glutamyltranspeptidase inhibitor, L-serine borate (SB, 45 mM), NDGA had no effect on the LTC₄ antagonism and the relaxant response of isoproterenol. In contrast, NDGA significantly inhibited the relaxant response of isoproterenol on 30 μM histamine- and 30 μM acetylcholine-induced contractions, but it did not affect the histamine antagonism by a histamine H₁-blocker pyrilamine. These results suggest that some putative nonprostanoids are involved in LTC₄-induced contractions of guinea-pig trachea and which regulate the effects of LTD₄ antagonism and β-adrenoceptor activation.
Leukotrienes cause eosinophil emigration into conjunction tissue
1986, Prostaglandins
The ability of LTB₄, LTC₄, the 5S,6R and 5R,6S LTD₄ stereoisomers, and LTE₄ to evoke leukocyte infiltration into the conjunctiva was demonstrated in the guinea pig by histological andl ight microscopy techniques. LTD₄ and LTE₄ demonstrated a dose-dependent and predominantly eosinophilic infiltrate over the selected dose range (10ng to 1000ng), while there was only a minimal response to LTC₄. LTB₄ produced marked eosinophil inflitrates only at the highest dose; scattered neutrophil infiltrates were also noted at the high dose of LTB₄. The 5R,6S LTD₄ stereoisomer did not evoke any leukocyte infiltrantion. The SRS-A antagonist, FPL 55712, abolished pre-treatment had no inhibitory effect, indicating direct mediation of this response by LTs. Histamine caused a comparable eosinophilia over a dose range of 10μg to 1000μg. LT-induced eosinophil emigration was directed to the conjunctival epithelium; the cells appeared intact and no tissue damage was observed. These results may have relevance in the areas of allergic conjunctivitis and asthma research.
Contractile responses of the guinea-pig esophageal muscularis mucosae in vitro to arachidonic acid and its metabolites
1985, European Journal of Pharmacology
The responsiveness of the guinea-pig esophageal muscularis mucosae to arachidonic acid (AA) and its cyclooxygenase and lipoxygenase metabolites was examined in vitro. AA (0.1–30 μM) produced a concentration-dependent contraction of the muscularis mucosae (ean EC₅₀ ± S.E.M. = 5.1 ± 1.0 μM). The contractions in response to low concentrations of AA (0.1–3 μM) were prevented by pretreatment of the tissue with indomethacin (1–10 μM), while those in response to high concentrations (10–100 μm) were prevented by BW755C (10–100 μM). The contractile response to AA was antagonized by polyphloretin phosphate (PPP, 1–10 μg/ml) and by FPL 55712 (1–10 μM). All cyclooxygenase and lipoxygenase metabolites of AA tested also produced a sustained contraction of the muscularis mucosae with the following order of sensitivity; leukotriene (LT) D₄ > LTC₄ > prostaglandin (PG) E₂ > PGF_2α > PGI₂ > thromboxane B₂. The responses to LTC₄ and LTD₄ were antagonized by FPL 55712 (0.1–1 μM), while those to PGE₂ and PGF_2α were antagonized by PPP (3–100 μg/ml). The present results indicate that exogenously applied AA contracts the isolated muscularis mucosae of the guinea-pig esophagus by an indirect action via its metabolism to both PGs and LTs. The putative PG and LT receptors located in this tissue are probably similar to those in the ileal longitudinal muscle, but differ from those in the airway smooth muscle.
Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pig
1985, Prostaglandins
Pulmonary responses to intravenous leukotrienes C₄, D₄ and E₄ administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD₄, LTC₄ and LTE₄ (respective ED₅₀ of 0.21 ± .1, 0.64 ± .2 and 2.0 ± .1 μg kg⁻¹) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-Rössler). Bronchoconstriction was antagonized by FPL-55712 (50–200 μg kg⁻¹), and indomethacin (50–200 μg kg⁻¹) but was not significantly altered by mepyramine (1.0 mg kg⁻¹), methysergide (0.1 mg kg⁻¹), intal (10 mg kg⁻¹) mepacrine (5 mg kg⁻¹) or dexamethasone (10 mg kg⁻¹). The beta adrenoceptor blocker, timolol (5 μg kg⁻¹) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE₄ but not LTD₄ or LTC₄ were partially antagonized by atropine (100 μg kg⁻¹) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD₄ and LTE₄ (2.8–3.2 μg kg⁻¹ min⁻¹) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE₄ and LTD₄ was partly reversed by intravenous FPL-55712 (1.0 mg kg⁻¹) and atropine (100 μg kg⁻¹) but was almost completely reversed by FPL-55712 (3 – 10 mg kg⁻¹). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE₄ as well as a small part of the initial response to continuous infusion of LTD₄ and LTE₄. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.

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Pharmacological study of the effects of leukotrienes C4, D4, E4 & F4 on guinea pig trachelis: Interaction with FPL-55712

Abstract

Biochem. Biophys. Res. Comm.

Prostaglandins

Tetrahedron Lett.

Prostaglandins

Prostaglandins

Life Sciences

Prostaglandins

Eur. J. Pharmacol.

The liberation of slow-reacting smooth muscle-stimulating substance in anaphylaxis

Quart. J. Exp. Physiol.

The release of histamine and formation of a slow reacting substance (SRS-A) during anaphylactic shock

J. Physiol.

Leukotriene C: a slow-reacting substance from murine mastocytoma cells

Structure of slow-reacting substance of anaphylaxis from guinea pig lung

Nature

Slow reacting substances of anaphylaxis: Identification of leukotrines C-I. and D from human and rat sources

Pharmacological study of the effects of leukotrienes C₄, D₄, E₄ & F₄ on guinea pig trachelis: Interaction with FPL-55712