Effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal mucus secretion in ovalbumin-sensitized guinea-pigs in vitro

Abstract

1. We investigated the inhibitory effects of the cysteinyl leukotriene (CysLT₁) receptor antagonists, pranlukast and zafirlukast, on ³⁵SO₄ labelled mucus output, in vitro, in guinea-pig trachea, induced by leukotriene D₄ (LTD₄) or by antigen challenge of sensitized animals. Agonists and antagonists were administered mucosally, except in selected comparative experiments where drugs were administered both mucosally and serosally to assess the influence of the epithelium on evoked-secretion.

2. LTD₄ increased ³⁵SO₄ output in a concentration-related manner with a maximal increase of 23 fold above controls at 100 μM and an approximate EC₅₀ of 2 μM. Combined mucosal and serosal addition of LTD₄ did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC₄ nor LTE₄ (10 μM each) affected ³⁵SO₄ output. Pranlukast or zafirlukast significantly inhibited 10 μM LTD₄-evoked ³⁵SO₄ output in a concentration-dependent fashion, with maximal inhibitions of 83% at 10 μM pranlukast and 78% at 10 μM zafirlukast, and IC₅₀ values of 0.3 μM for pranlukast and 0.6 μM for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 μM each) gave degrees of inhibition of mucosal-serosal 10 μM LTD₄-evoked ³⁵SO₄ output similar to those of the drugs given mucosally. Pranlukast (0.5 μM) caused a parallel rightward shift of the LTD₄ concentration-response curve with a pK_B of 7. Pranlukast did not inhibit ATP-induced ³⁵SO₄ output.

3. Ovalbumin (10–500 μg ml⁻¹) challenge of tracheae from guinea-pigs actively sensitized with ovalbumin caused a concentration-related increase in ³⁵SO₄ output with a maximal increase of 20 fold above vehicle controls at 200 μg ml⁻¹. The combination of the antihistamines pyrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induced ³⁵SO₄ output in sensitized guinea-pigs. Neither mucosal (10 μM or 100 μM) nor mucosal-serosal (100 μM) histamine had any significant effect on ³⁵SO₄ output.

4. Pranlukast or zafirlukast (5 μM each) significantly suppressed ovalbumin-induced secretion in tracheae from sensitized guinea-pigs by 70% and 65%, respectively.

5. We conclude that LTD₄ or ovalbumin challenge of sensitized animals provokes mucus secretion from guinea-pig trachea in vitro and this effect is inhibited by the CysLT₁ receptor antagonists pranlukast and zafirlukast. These antagonists may be beneficial in the treatment of allergic airway diseases in which mucus hypersecretion is a clinical symptom, for example asthma and allergic rhinitis.

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