The RAS, Fibrinolysis and Cardiopulmonary Bypass

Each year over a million patients worldwide undergo cardiac surgery requiring
cardiopulmonary bypass (CPB).1 CPB is associated with significant morbidity including
hemodynamic instability, the transfusion of allogenic blood products, and inflammation.
Blood product transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis
contributes to increased blood product transfusion requirements in the perioperative period.
CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin
concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric
oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data
indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients
with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While
interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB,
ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change
in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor
antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism.

Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced
increases in vascular permeability and neutrophil recruitment.A randomized, placebo
controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on
survival in patients with systemic inflammatory response syndrome and gram-negative sepsis.
In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular
t-PA release during ACE inhibition. The current proposal derives from data from our
laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and
fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and
that ACE inhibition and smoking further increases bradykinin concentrations. During CPB,
bradykinin concentrations correlate inversely with mean arterial pressure and directly with
t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates
protamine-related hypotension following CPB. The current proposal tests the central
hypothesis that the fibrinolytic and inflammatory response to cardiopulmonary bypass differ
during angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor
antagonism.