Vol. 283, Issue 3, 1102-1109, 1997

Absence of Tachykinin Involvement in Leukotriene D₄ and Antigen-Induced Contraction of Guinea Pig Isolated Bronchus¹

Susan M. Cibulsky and David C. Thompson

Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Denver, Colorado

In guinea pig airways, contractions induced by leukotriene D₄ or antigen are thought to be mediated primarily by an action of the agonist or of released mast cell-derived mediators directly on the airway smooth muscle cell. An indirect contractile action mediated by endogenous tachykinins also has been described for both of these stimuli. The present study evaluated the contribution of endogenous tachykinins to ovalbumin- and leukotriene D₄-induced contractions in the guinea pig bronchus by modulating the concentrations of tachykinins within the tissues and by using neurokinin receptor antagonists. Acute depletion of tachykinins with capsaicin had no effect on responses elicited by either stimulus. Similarly, tetrodotoxin treatment failed to influence leukotriene D₄-induced contractions. Inhibitors of neutral endopeptidase (thiorphan) and angiotensin-converting enzyme (lisinopril) enhanced neurally mediated tachykininergic responses and potentiated leukotriene D₄. The latter effect persisted in the presence of tetrodotoxin or the neurokinin antagonists CP99994 and SR48968 and in tissues treated acutely with capsaicin. The potentiation was absent, however, from bronchi incubated with L-cysteine. Ovalbumin-induced contractions were unaltered by inhibition of neutral endopeptidase and angiotensin-converting enzyme. These observations suggest that tachykinins are not involved in mediation of leukotriene D₄- or antigen-induced contractions of the guinea pig bronchus. The ability of protease inhibitors to potentiate leukotriene D₄ but not antigen-induced responses is therefore ascribed to inhibition of bioinactivation of leukotriene D₄ to leukotriene E₄.