Leukotriene and anti-IgE induced contractions of human isolated trachea: studies with leukotriene receptor antagonists and a novel 5-lipoxygenase inhibitor

Abstract

The pharmacological actions of three leukotriene D4 (LTD4) receptor antagonists, FPL-55712, L-648,051, and L-649,923, and a novel inhibitor of leukotriene biosynthesis, L-651,896, have been investigated on isolated human tracheal smooth muscle. In the order of potency L-648,051 greater than FPL-55712 greater than L-649,923, these agents antagonized contractions to LTD4 and produced parallel rightward shifts in the dose-response curves. Mean -log KB values against LTD4 were 6.9 +/- 0.1, 6.5 +/- 0.3, and 6.0 +/- 0.1 for L-648,051, FPL-55712, and L-649,923, respectively. FPL-55712 also antagonized contractions to LTC4 (-log KB value, 6.4 +/- 0.3) and this activity was not decreased by the gamma-glutamyl transpeptidase inhibitor, L-serine borate. In the presence of 1 x 10(-7) M atropine, 7 x 10(-6) M mepyramine, and 1.4 x 10(-6) M indomethacin, L-648,051 at 2 x 10(-5) and 2 x 10(-6) M produced complete and partial blockade, respectively, of the contraction to goat anti-IgE. L-649,923 and FPL-55712 produced partial but significant inhibition at 2 x 10(-5) M, whereas the 5-lipoxygenase inhibitor, L-651,896, produced almost complete inhibition at 3.5 and 35 x 10(-6) M. L-Serine borate (15 mM) did not alter the the activity of FPL-55712 versus anti-IgE. These findings indicate that LTD4 receptors mediate contraction of human trachea to exogenously applied and endogenously (anti-IgE) released leukotrienes. LTD4 antagonists, such as L-648,051, may be useful in assessing the role of leukotrienes in respiratory disease.