Endogenous NO regulates plasminogen activator inhibitor-1 during angiotensin-converting enzyme inhibition.

Brown NJ, Muldowney JA, Vaughan DE
Hypertension. 2006 47 (3): 441-8

PMID: 16432054 · DOI:10.1161/01.HYP.0000202478.79587.1a

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-NG-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-NG-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-NG-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.

MeSH Terms (22)

Adult Aldosterone Angiotensin-Converting Enzyme Inhibitors Arginine Double-Blind Method Drug Combinations Enzyme Inhibitors Female Fibrinolysis Hemodynamics Humans Infusions, Intravenous Male Middle Aged NG-Nitroarginine Methyl Ester Nitric Oxide Nitric Oxide Synthase Plasminogen Activator Inhibitor 1 Prodrugs Ramipril Reference Values Renin-Angiotensin System

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