Morbidity of cardiopulmonary bypass. Each year more than a million patients worldwide undergo cardiac surgery. Nearly all cardiac surgeries are performed on unbeating hearts supported by CPB. Although the use of off-pump coronary artery bypass surgery procedures are increasing, concerns regarding incomplete revascularization and reduced venous graft patency limit the use of this technique to specific patients. CPB activates various humoral cascades including the coagulation cascade, the KKS, the fibrinolytic cascade, and causes a systemic inflammatory response syndrome. Activation of these systems can lead to hypotension, fever, disseminated intravascular coagulation, diffuse tissue edema, or, in extreme cases, to multiple organ failure. Activation of the KKS contributes to the hemodynamic perturbations, fibrinolysis and inflammatory response observed in patients undergoing CPB. Aprotinin, a non-specific serine protease inhibitor, that works in part by decreasing bradykinin generation, decreases fibrinolysis, hypotension and the systemic inflammatory response associated with CPB. Aprotinin decreases blood loss and transfusion requirements, however, its use is mainly limited to redo-cardiac surgery because of cost. Other factors that may limit the widespread use of aprotinin include an increased risk for renal dysfunction, allergic reaction and non-specificity of the drug. Bradykinin mediates most of the effects of the KKS. Thus, bradykinin receptor antagonism has the potential to modulate the effects of KKS activation during CPB. The purpose of this proposal is to test the hypothesis that endogenous bradykinin contributes to the hemodynamic, fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will reduce hypotension, inflammation and transfusion requirements. The proposed studies promise to lead to novel therapies to reduce morbidity associated with CPB.