PHOSPHOLIPASE A2-INDUCED HYPOTENSION IN THE RAT AND ITS PHARMACOLOGICAL MODULATION

1. An increase in circulating levels of extracellular group II phospho lipase A2 (PLA2) has been detected in patients with septic shock as we ll as in rats, rabbits and human volunteers following intravenous endo toxin administration. 2. Group II PLA2 from Naja mocambique mocambique (NajaPLA2) snake venom (1-10 mug i.v.) induced a dose-dependent hypot ension and leucopenia in the rat similar to that induced by intravenou s administration of endotoxin. 3. NajaPLA2 did not aggregate rat plate let, but did aggregate purified rat neutrophils in vitro. However intr avenous PLA2 caused rat platelets to aggregate in vivo. 4. The hypoten sive effect was reduced either by inactivating NajaPLA2 in vitro with para-bromophenacyl bromide or by infusing in vivo polyclonal rabbit an tiPLA2 antisera. Neither the hypotension nor the leucopenia was affect ed by several agonists and inhibitors. 5. The leukotriene D4 antagonis t L-649,923 produced a dose-related (5-20 mg/kg i.v.) inhibition of Na jaPLA2-induced hypotension while the dual inhibitor of lipo- and cyclo oxygenase BW755c (5-50 mg/kg i.v.) was ineffective. 6. In rats rendere d leucopenic with methotrexate the L-649,923 was ineffective implying that the L-649,923 effect could be partially mediated through its acti on on neutrophils.