INHIBITION OF CHEMICALLY INDUCED MICROV ASCULAR LEAKAGE BY ONO-1078,A LEUKOTRIENE ANTAGONIST,IN RAT SKIN

This study is to determine whether ONO-1078, a potent leukotriene antagonist,influences chemically induced rat skin microvascular leakage which is considered to be , at least inpart ,due to stimulation of sensory nerve ending and release of sensory neuropeptides. Evans blue dyewas used as a tracer for plasma leakage, Intradermal injections of chemical stimuli, histamine(10μg),capsaicin(10μg) and formalin(0. 5 mg) , evoked Evans blue dye extravasation in rat Skin. Intraperitoneal ONO-l078 dose-dependently inhibited the dye extravasation induced by these stimuli, with ID₅0values of l.98 mg·kg^-1 for histamine,1. 78 mg· kg”^-1 for capsaicin, and 2. 23 mg· kg^-1 forformalin, In contrast to chlorpheniramine,a H₁ receptor antagoiiist , the inhibitory effect of ONO-1078 was weaker on histamine ,but more potent on capsaicin and formalin. The inhibitory effect ofdexamethasone was more potent than that of ONO-l078 on these stimuli. On the other hand, ONO-1078 inhibited the dye extravasation induced by leukotriene D₄(0.05μg), but showed no effect onthose induced by substance P.5μg, a sensory neuropeptide), a larger dose of histamine(100μg),and bradykinin(1μg). These results suggest that inhibition of chemically induced skin microvascularleakage by ONO-1078 may be mediated by inhibiting the release of sensory neuropeptides fromcapsaicin-sensitive sensory fibers.