Evidence that phospholipase A2 (PLA2) inhibitors can selectively block PLA2-mediated contractions of guinea pig lung pleural strips

DW Snyder, CD Sommers, JL Bobbitt and ED Mihelich

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

We have demonstrated previously that porcine pancreatic phospholipase A2 (PLA2)-induced contractions of guinea pig lung pleural strips can be abated by inhibitors of cyclooxygenase and 5-lipoxygenase pathways, suggesting the liberation of arachidonic acid. To validate further the involvement of a PLA2-related mechanism, the effects of three known inhibitors of PLA2 were evaluated. Manoalogue, an irreversible inhibitor of PLA2, parabromophenacyl bromide, an irreversible, active site directed inhibitor and a transition-state analog, a competitive inhibitor of PLA2 were used. Transition-state analog (3-30 microM), added to the tissues for 30 min before PLA2, shifted the PLA2 curves to the right in a concentration-related manner. In contrast, the reported inactive enantiomer of transition-state analog failed to alter the PLA2 curves. Manoalogue and para-bromophenacyl bromide, at concentrations up to 40- and 50-fold higher than the enzyme concentration, respectively, were incubated in Krebs' buffer with the enzyme for 24 hr before challenging the tissues. Under these conditions, the PLA2-induced contractions were suppressed markedly. In contrast, neither reduced nor methylated manoalogue, incubated at a 20-fold molar excess with PLA2 for 24 hr, suppressed the maximal PLA2-induced responses. These results demonstrate that inhibitors of secretory PLA2, acting by different mechanisms, can alter the contractile responses induced by PLA2 on pleural strips from guinea pig lung.

Volume 262, Issue 3, pp. 1147-1153, 09/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				E. Williams, J Furness, F. Walsh, and P Doherty Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF Development, January 6, 1994; 120(6): 1685 - 1693. [Abstract] [PDF]