leukotriene-c4 and Ear-Diseases

We have investigated the effects of actinomycin D on mouse ear oedema induced by capsaicin, neuropeptides, and established inflammatory mediators. Actinomycin D (0.5 mg/kg, i.v.) significantly (P < 0.01) inhibited ear oedema induced by topical application of capsaicin, while adriamycin (6.0 mg/kg, i.v.) and cycloheximide (6.0 mg/kg, i.v.) had no effect on oedema. The ear oedema induced by intradermal injection of neuropeptides such as mammalian tachykinins, calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP), was markedly (P < 0.05, P < 0.01 or P < 0.001) suppressed by actinomycin D. The drug was also effective (P < 0.01 or P < 0.001) in inhibiting bradykinin (BK)- and compound 48/80-induced ear oedema, but did not inhibit oedema induced by histamine, 5-HT, leukotriene C4 (LTC4), and platelet activating factor (PAF) at a dose of 1 mg/kg. In mast cell-deficient W/WV mice, actinomycin D (1.0 mg/kg, i.v.) failed to inhibit substance P (SP)-induced ear oedema whereas spantide (0.5 mg/kg, i.v.) was an effective (P < 0.01) inhibitor of oedema formation. Furthermore, actinomycin D (10-100 microM) dose-dependently prevented histamine release from rat peritoneal mast cells evoked by SP, compound 48/80, and the ionophore A23182, respectively. These results strongly suggest that an inhibitory effect of actinomycin D on neurogenic inflammation is due primarily to the prevention of mast cell activation mediated by neuropeptides, rather than an interaction with DNA or receptors of neuropeptides.

Topics: Animals; Bradykinin; Calcimycin; Calcitonin Gene-Related Peptide; Capsaicin; Cycloheximide; Dactinomycin; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Ear Diseases; Edema; Histamine; Injections, Intravenous; Leukotriene C4; Male; Mast Cells; Mice; p-Methoxy-N-methylphenethylamine; Platelet Activating Factor; Rats; Rats, Wistar; Serotonin; Substance P; Tachykinins; Vasoactive Intestinal Peptide

This study was performed to establish a useful method for monitoring the effects of inhibitors of 5-lipoxygenase (5-LO) and/or cyclooxygenase (CO) and for differential evaluation of these inhibitors. After oral dosing, CO inhibitors such as indomethacin (20-40 mg/kg) and ketoprofen (40-80 mg/kg), zileuton (5-LO inhibitor, 20-80 mg/kg) and MK886 (5-LO-activating-protein inhibitor, 640 mg/kg) potently suppressed arachidonic acid (AA, 0.25 mg)-induced ear edema in mice. Methysergide (serotonin antagonist, 20 mg/kg) showed a slight anti-edematous effect, while mepyramine (160 mg/kg) and bromelain (320 mg/kg) had no effect. The anti-edematous effects of indomethacin and ketoprofen were reduced by concomitant topical application of prostaglandin E2 (PGE2, 1 micrograms/ear), but not by concomitant intradermal application of leukotriene C4 (LTC4, 0.1 micrograms/ear). On the contrary, the anti-edematous effects of zileuton and MK886 were reduced by LTC4, but not by PGE2. Dual (5-LO and CO) inhibitors such as phenidone (80-160 mg/kg) and BW755C (40-80 mg/kg), which inhibited the biosynthesis of LTB4 13-15 times more potently than that of PGE2 in rat peritoneal exudate cells, also showed anti-edematous effects that were reduced by LTC4, but not by PGE2. These results suggest that the AA (0.25 mg)-induced ear edema in mice is mainly mediated by LTs and PGs and is suitable for evaluating inhibitors of 5-LO and/or CO, and that an application of LTC4 or PGE2 with AA is a useful method for differential evaluation of these inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Ascitic Fluid; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprostone; Ear Diseases; Edema; Leukotriene C4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; Rats; Rats, Wistar