Effect of Activation and Inhibition of the Renin-Angiotensin System on Plasma PAI-1 Nancy J. Brown, Mehmet A. Agirbasli, Gordon H. Williams, W. Reid Litchfield, Douglas E. Vaughan Abstract—Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P10 -7 ) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6.7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.74.6 versus 16.13.3 and 16.33.7 ng/mL, respectively; P0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1. (Hypertension. 1998;32:965-971.) Key Words: renin  angiotensin II  plasminogen activator inhibitor 1  fibrinolysis  tissue plasminogen activator  sodium  quinapril A ctivation of the renin-angiotensin system (RAS) has been associated with an increased risk of ischemic cardiovascu- lar events independent of effects on blood pressure. Retrospec- tive and prospective epidemiologic studies have provided evi- dence that hypertensive subjects with an increased renin-sodium profile are at increased risk for both myocardial infarction and stroke. 1,2 Similarly, activation of the RAS by diuretic use or low salt intake has been associated with an increased risk of myocardial infarction (MI). 3,4 Conversely, interruption of the RAS with an angiotensin-converting enzyme (ACE) inhibitor decreases progression of atherosclerosis in animal models 5,6 and appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. 7,8 The mechanisms through which activation of the RAS increases or ACE inhibition reduces the risk of ischemic cardiovascular events in selected populations are not known. One possible explanation involves an interaction between the RAS and fibrinolytic system. Accumulating data suggest that angiotensin II (Ang II) modulates fibrinolysis. For example, Ang II and its hexapeptide metabolite Ang IV stimulate plasminogen activator inhibitor-1 (PAI-1) expression in cul- tured endothelial cells in a dose-dependent manner. 9 Infusion of exogenous Ang II has been shown to increase PAI-1 antigen selectively in both normotensive and hypertensive subjects. 10 These findings may be of clinical significance because PAI-1 is the major inhibitor of tissue plasminogen activator (tPA) in vivo. 11 Increased PAI-1 expression has been observed in atherosclerotic plaques in humans 12 and may contribute to the progression of vascular disease. Elevated PAI-1 levels are observed in insulin-resistant states 13 and appear to be a risk factor for recurrent MI. 14 ACE inhibitors not only block the formation of Ang II but also prevent the degradation of bradykinin. 15,16 We have previously proposed that the prothrombotic effects of Ang II may be balanced by the antithrombotic effects of bradyki- nin. 17 Bradykinin is a potent stimulus for tPA secretion in ACE-pretreated bovine aorta endothelial cells, in animal models, and in humans. 17–19 Thus, ACE inhibitors would be expected to favorably alter fibrinolytic balance by decreasing Ang II and increasing bradykinin. The purpose of the present study was to test the hypothesis that activation of the RAS increases PAI-1 and that ACE Received May 8, 1998; first decision June 25, 1998; revision accepted July 21, 1998. From the Departments of Medicine and Pharmacology (N.J.B., M.A.A., D.E.V.), Vanderbilt University Medical Center, and the Veterans Affairs Medical Center (D.E.V.), Nashville, Tenn; and the Department of Medicine (G.H.W., W.R.L.), Brigham and Women’s Hospital, Boston, Mass. Reprint requests to Nancy J. Brown, MD, 560 Medical Research Building I, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.brown@mcmail.vanderbilt.edu © 1998 American Heart Association, Inc. Hypertension is available at http://www.hypertensionaha.org 965 Scientific Contributions by guest on March 16, 2016 http://hyper.ahajournals.org/ Downloaded from