Studies on the arachidonic acid cascade—I: Inhibition of phospholipase A2in vitro and in vivo by several novel series of inhibitor compounds

A series of compounds have been discovered which are potent inhibitors in vitro of hog pancreas, cobra venom, and bee venom phospholipase A₂. Collagen-induced aggregation of human platelets was prevented by representatives of this series. The inhibition was reversed by aggregatory concentrations of arachidonate, indicating the hydrolysis of esterified arachidonate had been prevented. In the isolated perfused guinea pig lung sensitized to ovalbumin, the release of prostanoids, resulting from a challenge dose of the antigen, was prevented by exemplars of these compounds. Subsequent administration of arachidonate in the presence of the inhibitor resulted in full prostanoid synthesis and secretion, again indicating that the block was at the phospholipase level. Administration of some of these compounds to guinea pigs by subcutaneous or intraperitoneal routes delayed the onset, and decreased the severity, of erythema induced in depilitated skin by the controlled application of ultraviolet light. This result was, also, consistent with phospholipase A₂ inhibition. Kinetic experiments with hog pancreas phospholipase A₂ demonstrated that, with representatives of this series, the inhibition induced was noncompetitive, and appropriate dissociation constants have been calculated.