The RAS, KKS and inflammation. Activation of the RAS exerts proinflammatory effects. For example, Ang II activates the transcription factor nuclear factor (NF)-kB, which in turn regulates genes involved in cellular recruitment and the inflammatory cytokine cascade. Ang II induces the synthesis and secretion of the inflammatory interleukin (IL)-6. As mentioned above, bradykinin produces many of the characteristics of the inflammatory state and upregulates IL-1b and TNFa-stimulated IL-8 and stimulates the release of IL-6. Thus, both Ang II and bradykinin stimulates the release of IL-6. ACE inhibitor treatment is associated with a reduction in IL-6 response to CPB. In a randomized non-blinded study, Trevelyan and colleagues20 demonstrated that ACE inhibition produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan had a similar but less marked effect. Potential mechanisms for this variation in IL-6 response between ACE inhibitors and angiotensin receptor blocker may be due to their differential effect on Ang II formation and bradykinin degradation. Furthermore, bradykinin-induced increases in IL-6 protein and total mRNA are inhibited by the selective B2 receptor antagonist HOE-140 but not by a selective B1 receptor antagonist. In Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and angiotensin II type 1 (AT1) receptor antagonist modulate the fibrinolytic and inflammatory response to CPB differently.