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(Hypertension. 2006;47:441.)
© 2006 American Heart Association, Inc.

Original Articles

Endogenous NO Regulates Plasminogen Activator Inhibitor-1 During Angiotensin-Converting Enzyme Inhibition

From the Divisions of Clinical Pharmacology (N.J.B.) and Cardiovascular Medicine (J.A.S.M., D.E.V.), the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Nancy J. Brown, MD, 560 Robinson Research Building, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.j.brown{at}vanderbilt.edu

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-arginine+ramipril. 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 (mean±SD 0.7±0.5 ng angiotensin I/mL per hour). In contrast, L-arginine+ramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8±9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1:t-PA (2.3±1.6) compared with placebo (13.5±10.8 ng/mL, P=0.006; ratio 2.9±2.1, P=0.015) or ramipril alone (15.2±13.2 ng/mL, P=0.009; ratio 3.7±3.3, P=0.005). L-arginine and ramipril synergistically increased D-dimers (23.1±31.5, 29.7±50.0, 35.1±50.0, and 57.1±144.8 ng/mL during placebo, L-arginine, ramipril, and L-arginine+ramipril, respectively; P<0.05 for L-arginine+ramipril versus any other group). 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 9.4±8.6 ng/mL during vehicle to 13.5±11.0 ng/mL during L-N^G-nitro-arginine-methyl-ester; P=0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0.4±0.3 to 0.5±0.4 IU/mL; P=0.031), consistent with an effect on release. Both effects of L-N^G-nitro-arginine-methyl-ester were reversed by L-arginine. During angiotensin-converting enzyme inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance in normotensive salt-replete subjects.

Key Words: nitric oxide • nitric oxide synthase • angiotensin • renin • plasminogen

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