Endotoxin Induced Fall In Plasma Prekallikrein: Prevention By Prostacyclin And Lignocained

Abstract

The infusion of lipopolysaccharide (E.Coli 0111-B4) at a level of l00ng/kg body wt/min for 100 minutes caused a decrease in plasma prekallikrein levels of anaesthetized minipigs. Plasma prekallikrein (PK) in normal pig plasma was measured after cold activation by dextran sulphate using chromogenic substrate S2302. Blood samples were taken into a mixture of EDTA, indomethacin at 20 minute intervals for 3 hours. When infused with endotoxin the PK level decreased to 85% of the preinfusion level after 1 hour (p<0.05) and up to 76% after 2 hours (p<0.05). Significance levels were calculated in relation to the comparable sample in anaesthetized pigs received saline alone. Five pigs were included in each group. Blood pressure, platelet and white cell count also showed significant falls upon infusion of endotoxin.Infusion of lignocaine (20mg followed by 2mg/minute during the course of infusion), an endothelial stabiliser or prostacyclin (125ng/kg/min - a dosage not found to lower blood pressure by more than 5%) prevented the endotoxin induced decrease of PK levels completely as well as the fall in blood pressure. However the thrombocytopenia and leucopenia still occurred. Infusion of a potent thromboxane synthetase inhibitor (7.5mg/min) partially prevented a fall in blood pressure and PK levels.When endotoxin was added to plasma in vitro at concentrations up to lmg/ml no activation of prekallikrein was observed. This observation together with those above suggests that the activation of factor XII by endotoxin in vivo is mediated by primary interaction of endotoxin with endothelium or other vascular cellular elements presumably with the release of procoagulants and/or formation of activating surfaces. Infusion of lignocaine or prostacyclin by stabilizing cell membranes may therefore act to prevent this effect of endotoxin and thereby preclude factor XII activation and bradykinin formation.