Cardiovascular disease is an emerging problem in human immunodeficiency virus (HIV)-1-infected adults. Indeed, individuals infected with HIV-1 represent one of the most rapidly growing cohorts with atherothrombotic vascular disease. Rates of atherosclerotic lesion development, myocardial infarction and restenosis are significantly higher in HIV-1-seropositive compared with the general population. The mechanisms responsible for the heightened cardiovascular risk with HIV-1 infection are not completely understood. Impaired fibrinolytic function is recognized to play a central role in the initiation and progression of atherothrombotic vascular disease and has been linked to HIV-1 infection. However, the underlying mechanisms responsible for the apparent hypofibrinolytic state with HIV-1 infection are not well understood. It is currently unknown whether the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA) is impaired in HIV- 1-infected adults. This is critically important because it is the local endothelial release rate of t-PA, the key enzyme in initiating fibrinolysis, and not circulating plasma fibrinolytic concentrations that determines endogenous thrombolysis potential. Accordingly, the specific aims of the present proposal will be to determine: 1) if the capacity of the vascular endothelium to release t-PA is reduced in HIV-1-seropositive treatment na[unreadable]ve adult humans; 2) if the postulated decrease in endothelial t-PA release with HIV-1 infection is due to increased oxidative stress; and 3) if the postulated decrease in endothelial t-PA release with HIV-1 infection is associated with is associated with systemic inflammation. To address these aims, HIV-1-seronegative and untreated HIV- 1-seropositive adults ranging in age from 21-50 years will be studied. Capacity of the vascular endothelium to locally release t-PA will be assessed, in vivo, in response to intrabrachial infusions of bradykinin (12.5-50 ng/100 mL tissue/min) and sodium nitroprusside (1.0-4.0 [unreadable]g/100 ml tissue/min). Net release/uptake of t-PA across the forearm vasculature to each pharmacological stimulus will be calculated as the product of the arteriovenous concentration gradient and forearm plasma flow. To determine the effects of oxidative stress on endothelial t-PA release, the bradykinin and sodium nitroprusside dose response curves will be repeated with a co-infusion of the antioxidant vitamin C (12 mg/100 mL tissue/min). The relation between plasma biomarkers of inflammation and t-PA release will also be examined. The expected results should provide mechanistic insight into the excess risk of atherothrombotic vascular disease observed in HIV-1 infected adults, and experimental support for future antioxidant supplementation trials aimed at reducing/preventing cardiovascular complications associated with HIV-1 infection. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]