sq-29548 and zileuton

This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B(4) antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D(4) antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester, the H(2) histamine-receptor antagonist cimetidine, the H(1) histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT(1/2) serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 microM) did not affect high K(+)-induced increase in intracellular Ca(2+) concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B(4) and cysteinyl leukotrienes are involved in mosquito allergy-associated itching.

Topics: Animals; Arachidonate 5-Lipoxygenase; Betamethasone Valerate; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Chromones; Cimetidine; Culicidae; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Hydroxyurea; Hypersensitivity; Indoles; Indomethacin; Ketoprofen; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Phenylpropionates; Phospholipid Ethers; Propionates; Pruritus; Quinolines; Terfenadine

The i.v. administration of leukotriene (LT)D4 to anesthetized guinea pigs produced dose-dependent increases in pulmonary microvascular permeability, as measured by extravasation of Evans blue dye into the trachea, main bronchi, and small airways, with an ED50 of approximately 0.05 microgram/kg. When LTD4 was administered at 0.3 microgram/kg, the resulting plasma extravasation into all three airway sections was markedly reduced by pretreatment with a cyclooxygenase inhibitor, meclofenamic acid (2.5 mg/kg, i.v.), a thromboxane (TX) receptor antagonist, SQ 29,548 (0.1 or 1 mg/kg, i.v.), or a peptidoleukotriene receptor antagonist, pranlukast (SB 205312) (0.1 or 1 mg/kg, i.v.), but not by the H1 histamine receptor antagonist, pyrilamine. When LTD4 was administered at 1.0 microgram/kg, meclofenamate (2.5 or 5 mg/kg, i.v.) or SQ 29,548 slightly attenuated plasma extravasation only in the small airway, whereas pranlukast was effective in all three airway segments. Administration of the 5-lipoxygenase inhibitor, zileuton (10 mg/kg, i.v.), or the PAF antagonist, L-659,989 (5 mg/kg, i.v.), did not affect the microvascular leakage response to 1.0 microgram/kg LTD4. In addition, i.v.-administered LTD4 (0.3 or 1.0 microgram/kg) or the prostaglandin (PG)/TXA2 receptor agonist, U-46619 (3.0 micrograms/kg), produced significant bronchoconstriction as measured by increases in pulmonary insufflation pressure. The bronchoconstrictor responses to LTD4 were markedly attenuated by the same inhibitors, namely meclofenamic acid, SQ 29,548, and pranlukast, that reduced the 0.3 microgram/kg LTD4-induced plasma extravasation throughout the airways and the 1.0 microgram/kg LTD4-induced extravasation into the small airways. U-46619-induced bronchoconstriction was blocked only by SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Bronchoconstriction; Capillary Permeability; Chromones; Fatty Acids, Unsaturated; Furans; Guinea Pigs; Hydrazines; Hydroxyurea; Leukotriene D4; Lipoxygenase Inhibitors; Lung; Male; Meclofenamic Acid; Plasma; Prostaglandin Endoperoxides, Synthetic; Pyrilamine; Receptors, Thromboxane; SRS-A; Thromboxane A2; Trachea; Vasoconstrictor Agents