Abstract-To test the hypothesis that NO contributes to effects of angiotensin-converting enzyme inhibitors on fibrinolysis, fibrinolytic balance was assessed in 17 normal subjects during placebo and after randomized, double-blind 4-week treatment with the NO precursor L-arginine (3 g TID), ramipril (10 mg QD), or L-arginineϩramipril. Neither L-arginine nor ramipril alone affected basal plasminogen activator inhibitor-1 or tissue-type plasminogen activator (t-PA) antigen in these salt-replete subjects in whom plasma renin activity was suppressed (meanϮSD 0.7Ϯ0.5 ng angiotensin I/mL per hour). In contrast, L-arginineϩramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8Ϯ9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1: During ramipril, the NO synthase inhibitor L-N G -nitro-arginine-methyl-ester (2 mg/kg) significantly increased plasminogen activator inhibitor-antigen after 2 hours (from 9.4Ϯ8.6 ng/mL during vehicle to 13.5Ϯ11.0 ng/mL during L-N G -nitro-arginine-methyl-ester; Pϭ0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0. Key Words: nitric oxide Ⅲ nitric oxide synthase Ⅲ angiotensin Ⅲ renin Ⅲ plasminogen P lasminogen activators play a critical role in the regulation of vascular fibrinolysis and the degradation of extracellular matrix. Plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of plasminogen activators, promotes thrombosis and fibrosis. 1 PAI-1 expression is increased in atherosclerotic lesions and at sites of vascular injury. 2,3 Circulating PAI-1 concentrations are increased in patients with risk factors for atherosclerosis, particularly in those with insulin resistance. 4 Furthermore, increased PAI-1 concentrations are associated with increased risk of myocardial infarction. 5 In addition to glucose and insulin, other growth factors, cytokines, and hormones regulate PAI-1 expression, including transforming growth factor-, tumor necrosis factor-␣, and angiotensin II (Ang II). 1 Increasing evidence suggests that the deleterious vascular effects of activation of the renin-angiotensin-aldosterone system (RAAS) derive in part from Ang II and aldosterone-induced PAI-1 expression. 6 On the other hand, studies in vitro and in animal models suggest that NO inhibits PAI-1 release and expression. For example, NO donors reduce PAI-1 release from platelets. 7,8 Feener et al reported that NO diminishes Ang II or plateletderived growth factor-stimulated PAI-1 expression in vascular smooth muscle cells via a cGMP-dependent pathway. 9 In rodents, NO synthase (NOS) inhibition using L-N G -nitroarginine-methyl-ester (L-NAME) induces vascular PAI-1 expression. 10,11 Coadministration of an angiotensin-converting enzyme (ACE) inhibitor abolishes L-NAME-induced PAI-1 expression and vascular injury, further suggesting that NO modulates Ang II-stimulated PAI-1 expression in vivo. 10 The role of NO in the regulation of PAI-1 expression in humans has not been established. Korbut et al reported that intravenous infusion of the NO ...