Phospholipase A2-induced hypotension in the rat and its pharmacological modulation

1. An increase in circulating levels of extracellular group II phospholipase A2 (PLA2) has been detected in patients with septic shock as well as in rats, rabbits and human volunteers following intravenous endotoxin administration. 2. Group II PLA2 from Naja mocambique mocambique (NajaPLA2) snake venom (1-10 micrograms i.v.) induced a dose-dependent hypotension and leucopenia in the rat similar to that induced by intravenous administration of endotoxin. 3. NajaPLA2 did not aggregate rat platelet, but did aggregate purified rat neutrophils in vitro. However intravenous PLA2 caused rat platelets to aggregate in vivo. 4. The hypotensive effect was reduced either by inactivating NajaPLA2 in vitro with para-bromophenacyl bromide or by infusing in vivo polyclonal rabbit antiPLA2 antisera. Neither the hypotension nor the leucopenia was affected by several agonists and inhibitors. 5. The leukotriene D4 antagonist L-649,923 produced a dose-related (5-20 mg/kg i.v.) inhibition of NajaPLA2-induced hypotension while the dual inhibitor of lipo- and cyclooxygenase BW755c (5-50 mg/kg i.v.) was ineffective. 6. In rats rendered leucopenic with methotrexate the L-649,923 was ineffective implying that the L-649,923 effect could be partially mediated through its action on neutrophils.