Bradykinin receptor antagonism could reduce the inflammatory response to CPB. During CPB, exposure of blood to bioincompatible surfaces of the extracorporeal circuit, as well as tissue ischemia and reperfusion associated with the procedure, induce the activation of several major humoral pathways of inflammation. Bradykinin produces many of the characteristics of the inflammatory state, such as changes in local blood pressure, edema, and pain, resulting in vasodilation and increased microvessel permeability. Bradykinin activates NF-kB and upregulates interleukin(IL)-1b and TNFa-stimulated IL-8 production through the B2 receptor. In addition, bradykinin stimulates the release of IL-6 from a variety of cells. The growing knowledge of the biological role of kinins, in particular in inflammation, has fueled the development of potent and selective kinin receptor antagonist as potential therapeutics. For example, the bradykinin antagonist, deltibant (CP-0127) showed a significant improvement in the 28-day risk-adjusted survival of patients with gram-negative sepsis. In an animal model of intestinal ischemia-reperfusion injury, B2 receptor antagonism inhibited reperfusion induced increases in vascular permeability, neutrophil recruitment and expression of B1 receptor mRNA. The role of B2 receptor antagonist in myocardial ischemia-reperfusion injury is more controversial. Kumari et al demonstrated a protective effect of HOE 140 during in vivo ischemia-reperfusion injury, whereas in isolated rabbit heart studies, CP-0127 impaired recovery from acute coronary ischemia. This contradictory results may be the result of different antagonist used, differences in species sensitivity or different experimental protocols. The role of B1 receptor antagonist in inflammation is unclear. In contrast to the constitutively expressed bradykinin B2 receptor, bradykinin B1 receptor expression is upregulated following an inflammatory insult or ischemia-reperfusion injury. It appears that each kinin receptor subtype mediates different aspects of the inflammatory response. However, B1 receptor antagonism administered prior to CPB may be detrimental. For example, Siebeck et al demonstrated that B2 receptor blockade attenuates endotoxin-induced mortality in pigs, whereas additional B1 receptor blockade seemed to reverse these beneficial effects. Taken together, B2 receptor antagonism may decrease the acute inflammatory response whereas additional B1 receptor blockade may be harmful. These studies, and also the fact that aprotinin exerts part of its beneficial effects through a reduction in bradykinin concentrations, suggest the hypothesis that pharmacological strategies to block the bradykinin B2 receptor may be superior to reducing bradykinin concentrations in modulating the inflammatory response to CPB.