Modification of endotoxin‐induced haemodynamic and haematological changes in the rabbit by methylprednisolone, F(ab′)2 fragments and rosmarinic acid

Abstract

The effects of methylprednisolone, F(ab′)2 fragments of human gamma globulins and rosmarinic acid, an inhibitor of complement activation, were tested on endotoxin‐induced haemodynamic and haematological changes in the rabbit. Their effects were compared with complement depletion by cobra venom factor (CVF) pretreatment. The results provide further evidence for the role of complement activation and the concomitant triggering of the arachidonic acid cascade in the early phase of shock. The formation of vasoactive prostanoids (prostacyclin and thromboxane A2), the arterial hypotension and the thrombocytopenia were largely dependent on the presence of the intact complement system. F(ab′)2 fragments (150 mg kg−1, i.v.) diminished the second fall in blood pressure to some extent but failed to alter any of the other endotoxin‐induced changes. Methylprednisolone (40 mg kg−1, i.v.) given 10 min before endotoxin significantly reduced the activation of complement, the second rise of prostacyclin and the secondary hypotension, but was without effect on the early thromboxane peak of the haematological features of endotoxin shock. Rosmarinic acid (20 mg kg−1, i.v.) may be of potential interest for treatment of septic shock, since the drug suppressed the endotoxin‐induced activation of complement, the formation of prostacyclin, both hypotensive phases, the thrombocytopenia and the concomitant release of thromboxane A2. The role of leukocytes and their arachidonic acid metabolites in plasma exudation deserves further investigation, because leukopenia and pulmonary oedema were not complement‐dependent and were not affected by any of the treatments. Our results indicate that drugs, interfering with complement activation and/or prostaglandin biosynthesis, may be beneficial in endotoxin shock, provided that they are administered at an early stage. 1985 British Pharmacological Society