Angiotensin converting enzyme (ACE) inhibition improves endothelial function and reduces the risk of acute myocardial infarction in patients with risk factors for coronary artery disease. The current proposal is based on data from this laboratory that suggest that bradykinin contributes to the favorable cardiovascular effects of ACE inhibitors by increasing tissue-type plasminogen activator (t-PA) release and improving fibrinolytic balance. For example, we have shown that endogenous bradykinin contributes to the hemodynamic effects of acute ACE inhibition. Bradykinin stimulates t-PA release from human vasculature through a B2 receptor-dependent, but nitric oxide synthase- and cyclooxygenase-independent pathway. This response is similar in black and white Americans, but preliminary data suggest that the t-PA response to bradykinin is greater in women compared to men. Bradykinin-stimulated t-PA release is impaired in smokers, while ACE inhibition increases constitutive vascular t-PA release in smokers through endogenous bradykinin. Conversely the ACE deletion allele, associated with increased ACE activity and cardiovascular mortality, is also associated with increased degradation of bradykinin; preliminary data suggest that this polymorphism interacts with B 2 receptor polymorphisms to modulate bradykinin-stimulated vasodilation and t-PA release. The central hypothesis of the mechanistic studies presented in this proposal is that genetic or environmental factors that decrease ACE activity and bradykinin degradation or that increase bradykinin receptor sensitivity favorably alter cardiovascular morbidity and mortality by enhancing the effect of bradykinin on fibrinolytie balance.
In Specific Aim 1, we will test the hypothesis that female gender enhances the effect of endogenous bradykinin on vascular t-PA release during ACE inhibition through effects of estrogen.
In Specific Aim 2, we will test the hypothesis that 58C/T and BE1 polymorphisms in the B 2 receptor affect constitutive and bradykinin-stimulated t-PA release during ACE inhibition, and interact with the ACE insertion/deletion polymorphism in the absence of ACE inhibition.
In Specific Aim 3, we will extend our prior studies to test the hypothesis that simultaneous inhibition of ACE and neutral endopeptidase (NEP) potentiates the vasodilator and fibrinolytic effects of bradykinin to a greater extent than ACE inhibition alone. It is expected that these pharmacogenetic studies will yield critical new information and strategies for enhancing the favorable effect of the kallikrein-kinin system on fibrinolysis and the risk of thrombotic cardiovascular events.
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