Dr. Brown's investigative efforts have been focused on the cardioprotective effects of bradykinin and on the interaction of the renin-angiotensin-aldosterone and fibrinolytic systems in humans. In particular, studies completed in Dr. Brown's laboratory have examined the contribution of endogenous bradykinin to the hypotensive effects of acute ACE inhibition in humans. Using biochemical techniques and LC/MS methodology, Dr. Brown's laboratory has identified a stable metabolite of systemic bradykinin in the human circulation, bradykinin 1-5. Studies indicate that an insertion/deletion polymorphism in the angiotensin-converting enzyme determines bradykinin metabolism to bradykinin 1-5 in humans. Measurement of bradykinin 1-5 concentrations has allowed for the elucidation of the role of bradykinin in a range of common human diseases including hypertension, diabetes, and sepsis. In addition, Dr. Brown and co-workers have demonstrated that bradykinin stimulates tissue plasminogen activator (t-PA) release from the human endothelium through a B2 receptor- dependent, nitric oxide synthase- and cyclooxygenase- independent, pathway.

The observation that bradykinin stimulates endothelial t-PA release complements studies indicating that angiotensin (Ang) II stimulates PAI-1 (plasminogen activator inhibitor-1), the major physiological inhibitor of t-PA in vivo. Work performed in Dr. Brown's laboratory in collaboration with Dr. Douglas Vaughan has demonstrated that activation of the renin-angiotensin-aldosterone system (RAAS), which has been associated with increased risk of myocardial infarction, is associated with increased circulating PAI-1 concentrations, whereas interruption of the RAAS by ACE inhibition decreases PAI-1 concentrations and the molar ratio of PAI-1 to t-PA. In addition, studies by Dr. Brown and co-workers indicate that aldosterone, as well as Ang II, regulates the expression of PAI-1 both in vitro and in vivo.

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