APROTININ, AN ANTIFIBRINOLYTIC DRUG, ATTENUATES BRADYKININ-INDUCED PERMEABILITY IN CONSCIOUS RATS VIA PLATELETS AND NEUTROPHILS

Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surger y while reducing blood Loss. Their mechanisms of action have yet to be fully understood. To investigate their possible mechanisms of action during cardiopulmonary bypass, we examined (i) the effects of TXA and APR on bradykinin (BK) induced vascular permeability (VP) in conscious rats, (ii) the roles of platelets and neutrophils in this reaction, a nd (iii) the effects of TXA or APR on BK responses in platelet-or neut rophil-depleted rats. Evans blue dye (EB) was used as the marker of ex travasation. The animals were treated with antiplatelet serum for plat elet depletion or with methotrexate for neutrophil depletion. In norma l rats, BK, increased VP in most tissues. Thrombocytopenia and neutrop enia also increased basal VP. TXA had no significant effect whereas AP R decreased basal VP. In the second series of experiments, APR signifi cantly attenuated BK-induced increases in VP, whereas TXA was complete ly ineffective. Platelet depletion did not affect BK-induced increases of VP, except for a massive plasma exudation in the lung parenchyma. Neutrophil depletion also had no effect on BK-induced increases of VP, except for an attenuation in the duodenum. In the third and last seri es of experiments, TXA potentiated the effect of BK in the upper and l ower bronchi of platelet-depleted rats, compared with the effects of T XA on BK in normal animals, except in the lung parenchyma, where TXA b locked the increase of VP induced by BK. APR also potentiated the effe ct of BK in the lower bronchi of platelet-depleted rats. Overall, the inhibitory effect of APR on the VP induced by BK in normal rats was at tenuated in platelet-depleted rats. Like TXA, APR blacked the increase of VP induced by BK in the lung parenchyma of platelet-depleted rats. In neutrophil-depleted rats, TXA did not affect the permeabilizing re sponse to BK. In those rats, the inhibitory effect of APR against BK i ncreases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attribute d to the inhibition of plasma exudation mediated, in part, by BK. In a ddition, platelets and neutrophils do not appear to be involved in BK- mediated plasma exudation. However, both cell types are essential for the regulation of basal VP. Finally, the mechanism underlying the prot ective inhibitory effect of APR on BK-induced increases of VP involves , at least in part, platelets and neutrophils, since the inhibitory ef fect of APR is attenuated in thrombocytopenic and neutropenic rats. Bo th cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary b ypass could enhance the protective effect of APR.