title: Aprotinin, an antifibrinolytic drug, attenuates bradykinin-induced permeability in conscious rats via platelets and neutrophils.
abstract: Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surgery 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, and (iii) the effects of TXA or APR on BK responses in platelet- or neutrophil-depleted rats. Evans blue dye (EB) was used as the marker of extravasation. The animals were treated with antiplatelet serum for platelet depletion or with methotrexate for neutrophil depletion. In normal rats, BK increased VP in most tissues. Thrombocytopenia and neutropenia also increased basal VP. TXA had no significant effect whereas APR decreased basal VP. In the second series of experiments, APR significantly attenuated BK-induced increases in VP, whereas TXA was completely 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 series of experiments, TXA potentiated the effect of BK in the upper and lower bronchi of platelet-depleted rats, compared with the effects of TXA on BK in normal animals, except in the lung parenchyma, where TXA blocked the increase of VP induced by BK. APR also potentiated the effect 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 attenuated in platelet-depleted rats. Like TXA, APR blocked 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 response to BK. In those rats, the inhibitory effect of APR against BK increases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attributed to the inhibition of plasma exudation mediated, in part, by BK. In addition, 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 protective inhibitory effect of APR on BK-induced increases of VP involves, at least in part, platelets and neutrophils, since the inhibitory effect of APR is attenuated in thrombocytopenic and neutropenic rats. Both cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary bypass could enhance the protective effect of APR.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, QC, Canada.
authors.forename: J G
authors.initials: JG
authors.lastname: O'Brien
authors.forename: B
authors.initials: B
authors.lastname: Battistini
authors.forename: P
authors.initials: P
authors.lastname: Farmer
authors.forename: R J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: F
authors.initials: F
authors.lastname: Zaharia
authors.forename: G E
authors.initials: GE
authors.lastname: Plante
authors.forename: P
authors.initials: P
authors.lastname: Sirois
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D007611:Aprotinin / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000502:physiology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000097:blood; D008297:Male; D009503:Neutropenia / Q000097:blood; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013921:Thrombocytopenia / Q000097:blood; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid; D007611:Aprotinin; D001920:Bradykinin