Correlation between the myotropic activity of leukotriene A 4 on guinea-pig lung, trachea and ileum and its biotransformation in situ

Abstract

Leukotrienes A 4 and D 4 displayed equivalent myotropic activity on guinea pig lung parenchyma strips. However, on the trachea, the activity of LTD 4 was much higher than that of LTA 4. The potencies of these two leukotrienes were also different on strips of longitudinal muscles of the ileum where LTD 4 was very active whereas LTA 4 was inactive. Since the activities of both leukotrienes were blocked by FPL-55712, our results suggested that the transformation of LTA 4 by the smooth muscle preparations was a prerequisite to its biological activity. LTA 4 was then incubated for 10 min with homogenates of guinea pig lung parenchyma, trachea and longitudinal muscles of ileum, and the metabolites were analysed by bioassay using strips of guinea pig ileum and lung parenchyma in a cascade superfusion system and also by reversed phase high performance liquid chromatography (RP-HPLC). Homogenates of lung parenchyma rapidly transformed LTA 4 to LTB 4, LTC 4, LTD 4 and LTE 4. Incubation of LTA 4 with homogenates of trachea or of the longitudinal muscles of ileum showed the formation of LTB 4 and its isomers but no significant amount of peptido-leukotrienes were detected. These findings reveal that LTA 4 undergoes distinctly different metabolic transformations in these tissues which correspond to the biological activites of the products recovered. These results strongly suggest that the myotropic activity and potency of LTA 4 is related to the tissue levels of enzymes which catalyse its biotransformation.