A relationship may exist between endothelial-mediated vasodilation and tissue-type plasminogen activator (t-PA) release. However, the existing evidence is mainly based upon exogenous agonist administration, and needs testing under more physiological conditions. We evaluated the link between t-PA, the key fibrinolytic factor in man, and forearm reactive hyperemia, a model of endogenous endothelial-mediated vasodilation, in 13 uncomplicated hypertensive subjects and six elderly hypertensive patients with atherosclerotic peripheral vascular disease and hypercholesterolemia (i.e a group in whom post-ischemic hyperemia was probably defective because of dysfunctional endothelium). To characterize further the phenomenon, 29 additional uncomplicated hypertensive patients underwent intra-arterial drug infusions. Study variables were forearm blood flow (strain-gauge plethysmography), arterial and venous concentrations of t-PA mass concentrations, and calculated net release (forearm plasma flow × veno-arterial differences). Reactive hyperemia was induced by inflating a cuff midway between systolic and diastolic pressure for 10 min; blood and forearm blood flow were sampled before and after cuff release. Post-ischemic t-PA release increased in uncomplicated hypertensives, and did not change in hypercholesterolemic atherosclerotic patients in whom post-ischemic vasodilation was negligible. Local adenosine (n= 9), acetylcholine (n= 12) and bradykinin (n= 8) vasodilated similarly, but only bradykinin increased t-PA release. Thus, reactive hyperemia stimulates t-PA release, and that relationship is altered when endothelium is dysfunctional. Release of t-PA is independent of forearm vasodilatationper se, adenosine or biological products of muscarinic stimulation and may, perhaps, be related to the activity of the endogenous kininogen/kinin system.