Prehypertension (systolic blood pressure: 120-139 mm Hg and/or diastolic blood pressure: 80-89 mm Hg) affects ~30% of the US adult population and is associated with increased atherothrombotic vascular disease risk. The underlying mechanisms responsible for this heightened risk are unclear. The capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of the fibrinolytic system, is an important endogenous defense mechanism against intravascular fibrin deposition and thrombosis. As part of an ongoing study, we are determining whether the capacity of the endothelium to release t-PA is impaired in adults with prehypertension. To date, 22 sedentary, non-obese middle-aged men have been studied: 12 normotensive (age: 53±2 yr; BP: 113/72±2/2 mm Hg) and 10 prehypertensive (age: 55±2 yr; BP: 133/85±2/1 mm Hg). All subjects were free of overt cardiometabolic disease. Net endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2-8 μg/min). Endothelial t-PA release in response to each dose of BK was significantly lower (~50%) in the prehypertensive (from -1.7±0.7 to 34.1±5.7 ng/100 mL tissue/min) vs the normotensive (from 0.6±1.4 to 54.1±5.7 ng/100 mL tissue/min) adults. Total amount of t-PA released (area under the BK curve) was ~40% less (P<0.05) in the prehypertensive compared with normotensive group (210±32 vs 336±45 ng/100 mL tissue). There was no effect of SNP on t-PA release in either group. In the overall study population, there was a significant inverse relation between both systolic (r=-0.44) and mean arterial (r=-0.42) blood pressure and total t-PA release. No other anthropometric, hemodynamic or metabolic variable was associated with t-PA release. These initial results indicate that the capacity of the endothelium to release t-PA is impaired in prehypertensive men. Diminished endothelial fibrinolytic capacity may contribute to the increased atherothrombotic risk with prehypertension.