Histamine and leukotriene-independent guinea-pig anaphylactic shock unaccounted for by Paf-acether

Ovalbumin induced dose-dependent contractions of lung parenchyma strips from sensitized guinea-pigs, whereas Paf-acether (1-alkyl-2-acetyl-sn-glycero-3-phosphoryl choline), a potential mediator of immediate hypersensitivity, induced a single contraction, followed by specific desensitization to a second exposure. Lung strips desensitized to Paf-acether contracted to ovalbumin as did non-desensitized controls, even in the presence of inhibitors of other mediators of anaphylaxis. Contractions by Paf-acether and by ovalbumin were reduced by nordihydroguaiaretic acid (NDGA) and by the phospholipase A2 inhibitor p-bromophenacyl bromide (0.1-0.3 mM). Three other anti-lipoxygenase agents (diethylcarbamazine, 5 mM; eicosatetraynoic acid and BW755c, 0.1 mM), reduced the contractions by ovalbumin but also those due to acetylcholine, indicating non-specific effects. Neither the anti-allergic compound sodium cromoglycate (3 mM) nor the anti-leukotriene agent, FPL 55712 (0.01 mM), inhibited the contractions by ovalbumin or by Paf-acether. A sensitized strip stimulated with ovalbumin released substances which contracted a non-sensitized strip mounted in the same organ bath. The contractions of the non-sensitized strip were abolished by FPL 55712 (0.01 mM), by NDGA and BW755c, (0.1 mM), whereas those of the sensitized one were unaffected. Leukotrienes are formed by the lung strips during shock but alone, they do not explain the contractile activity. The intravenous administration of ovalbumin (1 mg kg-1) led to bronchoconstriction and thrombocytopenia, which were not modified by the anti-leukotriene substance FPL 55712 nor by aspirin. Bronchoconstriction was suppressed if FPL 55712 was used in combination with aspirin (20 mg kg-1), mepyramine and methysergide (200 micrograms kg-1 of either). Pretreatment of the guinea-pigs with propranolol reduced this inhibition to approximately 60%. In no instance was thrombocytopenia prevented. In vitro contractions of the actively sensitized lung strip are not fully accounted for by histamine, FPL 55712-inhibitable leukotrienes or Paf-acether, whereas in systemic anaphylaxis histamine and leukotrienes (inhibited respectively by mepyramine and by FPL 55712) have a significant role.