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(Hypertension. 2002;40:859.)
© 2002 American Heart Association, Inc.

Scientific Contributions

ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism

Differential Effects on PAI-1 Over Time

Nancy J. Brown; Sandeep Kumar; Corrie A. Painter; Douglas E. Vaughan

From the Divisions of Clinical Pharmacology, Department of Pharmacology (N.J.B., S.K.), and Cardiovascular Medicine, Department of Medicine (C.A.P.), Vanderbilt University Medical Center, Nashville; and the Veteran’s Administration Medical Center (D.E.V.), Nashville, Tenn.

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

	Abstract

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ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT₁) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m², or fasting serum triglyceride 2.8 mmol/L) hypertensive subjects (mean age, 47.9±2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019) pressure. Ramipril (from 133.6±5.1/94.5±2.4 to 127.0±3.1/91.4±3.3 mm Hg) or losartan (from 137.0±3.9/93.1±2.9 to 123.7±2.6/86.4±2.1 mm Hg) further reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013) but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT₁ receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT₁ receptor antagonism.

Key Words: fibrin • plasminogen • angiotensin • renin • angiotensin-converting enzyme

	Introduction

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Angiotensin-converting enzyme (ACE) inhibitors reduce the incidence of cardiovascular events in patients with left-ventricular dysfunction¹ and in high-risk patients with vascular disease.² Although there are numerous mechanisms whereby interruption of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibition could reduce cardiovascular mortality, a possible mechanism involves the interaction of the RAAS and fibrinolytic system. Angiotensin (Ang) II and aldosterone increase plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of fibrinolysis, in vitro and in vivo.^3–5 Increased PAI-1 expression has been demonstrated in conditioned media from arterial segments with atherosclerotic changes⁶ and in atherosclerotic plaques.⁷ Elevated levels of PAI-1 are seen in patients with insulin resistance,⁸ and both proinsulin and insulin stimulate PAI-1 expression.^9,10 Elevated levels of PAI-1 predict cardiovascular risk in middle-age men.¹¹ Studies indicate that activation of the RAAS by either salt depletion or diuretic use increases plasma PAI-1 antigen concentrations,^12–14 whereas ACE inhibition reduces PAI-1 antigen in salt-depleted normotensive subjects,¹² in postmenopausal women,¹⁵ in patients with hypertension,¹⁶ and in patients after myocardial infarction (MI).¹⁷

The effect of angiotensin type 1 (AT₁) receptor antagonism (AT₁RA) on fibrinolytic balance is uncertain. AT₁RA decreases PAI-1 expression in vascular smooth muscle cells¹⁸ but not in endothelial cells or proximal tubular epithelial cells.^19,20 This may be explained by the observation that in some cell types, the effect of Ang II on PAI-1 expression is mediated through the AT₄ receptor.^19,20 However, AT₁RA prevents Ang II–induced PAI-1 expression in rats.⁴ In humans, AT₁RA did not affect plasma PAI-1 antigen in salt-depleted normotensive subjects,²¹ in postmenopausal women,²² or in patients with essential hypertension.²³ On the other hand, it has been reported that AT₁RA lowers PAI-1 antigen in patients with essential hypertension¹⁶ or when given acutely in patients with congestive heart failure.²⁴

Differences in study populations, in the timing of sample collection relative to diurnal variation in PAI-1,¹² and in the duration of treatment likely contribute to the divergent findings as to the effect of AT₁RA on fibrinolytic balance in humans. For this reason, we compared the time-course of effect of ACE inhibition and AT₁RA on morning plasma PAI-1 antigen. Hypertensive patients with clinical evidence of insulin resistance were studied because PAI-1 antigen concentrations are known to be elevated in these patients, who are at increased risk for MI.⁸ To maximize pretreatment PAI-1 concentrations, we studied patients in whom the RAAS had been activated by treatment with hydrochlorothiazide (HCTZ), a commonly prescribed antihypertensive agent.

	Methods

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The study was approved by the Vanderbilt University Institutional Review Board. Informed consent was obtained, and subjects underwent a history and physical examination before study. Antihypertensive medications were then discontinued or tapered, and 2 weeks after subjects were off all vasoactive medications, screening blood pressure measurements and laboratory were obtained. Subjects were eligible for study if they had a seated diastolic blood pressure (DBP) 95 mm Hg and 115 mm Hg or systolic blood pressure (SBP) 180 mm Hg, and if they met one of the following clinical criteria for insulin resistance: fasting glucose >8.3 mmol/L (150 mg/dL), body mass index >28 kg/m², and fasting serum triglyceride concentration 2.8 mmol/L (250 mg/dL). Subjects with secondary forms of hypertension, with disease other than hypertension or who weighed >40% above their ideal body weight were excluded. Women on hormone replacement therapy and pregnant women were excluded.

After screening, a 24-hour ambulatory blood pressure monitor (Accutracker II ABPM device, Suntech Medical Instruments) was placed, and subjects were asked to collect their urine for 24 hours for measurement of sodium excretion. The blood pressure monitor was programmed to measure pressure every 20 minutes from 7:00 AM to 11:00 PM and every hour from 11:00 PM to 7:00 AM. The next day, subjects reported to the Vanderbilt General Clinical Research Center at 7:00 AM in a fasting state. Blood pressure and heart rate were measured in triplicate after subjects had been seated for 30 minutes. Blood was then drawn through an indwelling catheter for measurement of plasma renin activity (PRA), aldosterone, PAI-1 and tPA antigen, insulin, and glucose. On the first and last study days, blood was also obtained for hemoglobin A_1C and lipids. At the end of the first study day, subjects were given HCTZ (12.5 mg/d PO). Beginning on the sixth day of treatment, ambulatory blood pressure monitoring and urine collection were repeated, and on the seventh day of HCTZ, hemodynamic measurements and blood drawing were repeated.

At the end of the second study day, subjects were randomized to double-blind treatment with either ramipril (1.25 mg PO QD) or losartan (25 mg PO QD). The dose of each medication was escalated every 5 to 7 days (through 2.5, 5, and 10 mg/day for ramipril and through 50 and 100 mg/day for losartan) to achieve a DBP <90 mm Hg. Pill counts were completed at each study day. The doses of ramipril and losartan were chosen to be equipotent with respect to blood pressure lowering and maximal with respect to ACE inhibition and AT₁RA.^25,26 All subjects achieved the highest dose of study medication, except 1 subject who was randomized to losartan and who remained on 50 mg/day throughout the study. Hemodynamic measurements and analysis of fibrinolytic, endocrine, and metabolic parameters were repeated 1, 3, 4, and 6 weeks after randomization. Ambulatory blood pressure monitoring and 24-hour urine collection were repeated 1 day before the 6-week study visit. Body composition was also measured using an air displacement method (The Bod Pod Body Composition System, Life Measurements Instruments) on the first and last study days.

Laboratory Analysis
Blood samples were collected on ice and centrifuged immediately at 0°C for 20 minutes. All plasma or serum was separated and stored at -70°C until assay. Blood for measurement of PAI-1 and tPA antigen was collected in Vacutainer tubes containing 0.105 mmol/L acidified sodium citrate, and antigen levels were determined by using a 2-site enzyme-linked immunosorbent assay (Biopool AB). tPA activity was determined by using an immunofunctional assay (Chromolize, Biopool AB). Blood for PRA and aldosterone was drawn into chilled tubes containing EDTA. PRA was measured by radioimmunoassay for Ang I formation at pH 7.4 and 37°C. Aldosterone was measured by using a commercially available radioimmunoassay (Diagnostic Product Corp). Serum cholesterol and triglycerides were determined by using standard enzymatic methods on an automated system (ACE, Schiapparelli Bio Systems). Plasma glucose concentration was measured with a colorimetric assay (Johnson and Johnson Clinical Diagnostics), and serum insulin was measured by immunoassay (Tosoh Medics Inc). The homeostasis model assessment–insulin resistance (HOMA IR) index was calculated by using the following equation: [fasting glucose (mmol/L)xinsulin (mU/L)]/22.5.²⁷

Statistical Analysis
Data are presented as mean±SEM. The effect of treatment on pressure, endocrine and electrolyte parameters, and fibrinolytic balance was analyzed using a General Linear Model in which the within-subject variable was time and the between-subject variables included drug, gender, body mass index, ethnicity, PRA during HCTZ (designated renin status), and insulin. Data for tPA activity were square-root transformed before analysis. Probability values derived from general linear model analysis are presented in the text, unless otherwise specified. Post hoc comparisons were made using a paired or unpaired t test, as appropriate, and are shown in the tables. A 2-tailed probability value of <0.05 was the criterion for statistical significance.

	Results

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Subject Characteristics
Tables 1 through 4 provide baseline subject characteristics for the 2 treatment groups. There were no differences in age, gender, ethnicity, body mass index, blood pressure, 24-hour urine sodium and potassium excretion, cholesterol, triglycerides, glucose, insulin, hemoglobin A_1C, renin, aldosterone, duration of hypertension, number of antihypertensive medications, or history of ACE inhibitor or AT₁RA use between the treatment groups. Subjects randomized to losartan were significantly more likely to have been treated with a thiazide diuretic before washout.

View this table: [in this window] [in a new window]   TABLE 1. Subject Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Effect of Treatment on Blood Pressure

View this table: [in this window] [in a new window]   TABLE 3. Effect of Treatment on Plasma PAI-1 and tPA Antigen

View this table: [in this window] [in a new window]   TABLE 4. Effect of Treatment on Metabolic Parameters

Blood Pressure Effects
Treatment with HCTZ significantly decreased seated SBP (P=0.011), ambulatory SBP (P=0.023), and seated DBP (P=0.019), but not ambulatory DBP (P=0.273) (Table 2 and Figure 1). These blood pressure responses to HCTZ were similar in the 2 treatment groups (P>0.5 for effect of group for all). Addition of either ramipril or losartan caused a further decrease in seated SBP (P=0.009), seated DBP (P=0.037), and ambulatory SBP (P=0.016) and significantly decreased ambulatory DBP (P=0.004) compared with the levels for treatment with HCTZ alone. The effects of ramipril and losartan on blood pressure were statistically similar (P>0.24 for seated and ambulatory SBP and DBP) and sustained for the duration of the study.

View larger version (17K): [in this window] [in a new window]   Figure 1. Effect of treatment with HCTZ alone and in 6-week combination with ramipril (ACEI, A) or losartan (AT1RA, B) on ambulatory mean arterial pressure over 24 hours.

There were no significant differences in 24-hour urine sodium or potassium excretion between the groups throughout the study. Thus, 24-hour sodium excretion was 166±24 mmol in the ramipril group and 156±13 mmol in the losartan group at week 6. Twenty-four–hour urine potassium excretion was 54±7 and 56±17 mmol at week 6 in the ramipril and losartan groups, respectively.

RAAS Effects
Treatment with HCTZ tended to increase PRA (from 0.9±0.2 to 1.2±0.1 ng Ang I/mL per hour, P=0.069). PRA was similar in the ramipril (1.2±0.1 ng Ang I/mL per hour) and losartan (1.3±0.3 ng Ang I/mL per hour) treatment groups during treatment with HCTZ alone. Treatment with either ramipril or losartan caused a further increase in PRA (P=0.008) (Figure 2A). The increase in PRA in response to treatment was greater during treatment with ramipril than during treatment with losartan (P=0.031 for drug effect). Treatment with HCTZ significantly increased aldosterone (P=0.002). The magnitude of this effect was similar in the ramipril (from 215±24 to 278±29 pmol/L) and losartan (from 180±25 to 275±27 pmol/L) treatment groups (P=0.345 for effect of group). Addition of either ramipril or losartan significantly decreased aldosterone (P=0.019). The decrease in aldosterone in response to ramipril and losartan was similar (P=0.520 for effect of drug) (Figure 2B).

View larger version (32K): [in this window] [in a new window]   Figure 2. Effect of treatment with HCTZ alone and in combination with ramipril (ACEI) or losartan (AT1RA) on PRA (A) and serum aldosterone (B) concentrations over time in patients with essential hypertension and insulin resistance. Treatment with HCTZ significantly increased aldosterone (P=0.002) but not PRA (P=0.069). Addition of either ACE inhibition or AT1RA increased PRA (P=0.008), and the effect was greater during ACE inhibition (P=0.031). Treatment with either ACE inhibition or AT1RA decreased aldosterone (P=0.019).

Fibrinolytic Effects
Treatment with HCTZ significantly increased plasma PAI-1 antigen (P=0.007), but not tPA antigen (P=0.431) (Table 3) or activity (P=0.845). The effect on PAI-1 antigen was not significantly different between the groups (P=0.287). Treatment with either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046); however, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). Moreover, the change in PAI-1 antigen over time in response to treatment was significantly less during losartan treatment compared with ramipril treatment (Figure 3). Treatment with either ramipril or losartan significantly decreased plasma tPA antigen (P=0.032). The change in tPA antigen over time was similar in the ramipril and losartan treatment groups (P=0.57 for drug effect) (Figure 3). However, tPA activity decreased during treatment with losartan (from 0.47±0.15 to 0.24±0.08 IU/mL at 6 weeks, P=0.018) but not during treatment with ramipril (from 0.47±0.25 to 0.46±0.23 IU/mL at 6 weeks, P=0.993) (Figure 3).

View larger version (18K): [in this window] [in a new window]   Figure 3. Change in mean arterial pressure (A), PAI-1 (B) and tPA antigen (C) concentrations, and tPA activity (D) over time in response to treatment with ramipril (ACEI) or losartan (AT1RA) in patients with essential hypertension and insulin resistance taking HCTZ. The decrease in PAI-1 antigen over time was significantly greater during ACE inhibition than during AT1RA (P=0.043), whereas the changes in MAP and tPA were similar in the 2 treatment groups. tPA activity decreased significantly over time during AT1RA (P=0.018) but not during ACE inhibition (P=0.993).

Metabolic Effects
Table 4 provides data on the effect of therapy on fasting glucose, fasting insulin, HOMA-IR index, hemoglobin A_1C, cholesterol, and triglycerides. There were no significant effects of treatment with HCTZ, ACE inhibition, or AT₁RA on any of these parameters. There was no effect of therapy on body fat composition (percent body fat: before and after treatment with HCTZ plus ramipril, respectively, 38±3% and 38±2%; before and after treatment with HCTZ plus losartan, respectively, 33±2% and 33±3%).

	Discussion

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Prior studies indicated that ACE inhibition decreases plasma PAI-1 antigen^12,17 but provided conflicting evidence as to the effect of AT₁RA on fibrinolytic balance.^16,21–23 The present study suggests that short-term interruption of the RAAS by either ACE inhibition or AT₁RA decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT₁RA.

In the present study, we measured the effect of ACE inhibition and AT₁RA on PAI-1 antigen in subjects with essential hypertension and clinical evidence of insulin resistance who were treated with HCTZ. Consistent with previously published studies,^13,14 12.5 mg HCTZ caused a significant 34% increase in PAI-1 antigen. The magnitude of this effect is comparable to that observed in healthy volunteers treated with 25 mg HCTZ for 2 weeks¹⁴ and approximately half the effect we have observed in hypertensive subjects treated with 25 mg HCTZ for 2 weeks.¹³ These studies, all performed in young to middle-age subjects, support a detrimental effect of HCTZ on fibrinolytic balance in this age group.

The finding that ramipril, but not losartan, decreased PAI-1 antigen after prolonged treatment is consistent with data from 3 other studies that found no effect of losartan on PAI-1 antigen after 3 to 12 weeks of treatment.^21–23 For example, in normotensive subjects in whom the RAAS had been activated by low salt intake, 3-week treatment with quinapril (40 mg BID) significantly lowered PAI-1 antigen but not tPA antigen, whereas losartan, given at an equipotent hypotensive dose (50 mg BID), had no effect on PAI-1 antigen and significantly depressed tPA antigen.²¹ Thus, the effects of ACE inhibition and AT₁RA on PAI-1 and tPA antigen were qualitatively similar to those seen at 3 weeks in the present study in which the RAAS was activated by diuretic use; in contrast to in the present study, the acute effects of ACE inhibition and AT₁RA on fibrinolytic balance were not measured in the prior study. Similarly, Seljeflot et al²³ and Fogari et al²² have reported no effect of AT₁RA on PAI-1 antigen after 4 weeks of losartan or after 6 and 12 weeks of losartan, valsartan, irbesartan, or candesartan.

The present study may help to explain the discrepancy between these studies and the study of Goodfield et al.²⁴ The investigators reported that acute administration of losartan decreased PAI-1 antigen in patients with congestive heart failure, although they did not control for diurnal variation in PAI-1. Lottermoser et al¹⁴ also reported that short-term administration of losartan attenuated the increase in PAI-1 in response to HCTZ, although the effect was not statistically significant.¹⁴ Thus, the present study concurs with data from a number of groups, indicating that short-term AT₁RA decreases PAI-1 antigen and long-term AT₁RA does not.

Several possible mechanisms could account for the differential time-course of effects of ACE inhibition and AT₁RA on PAI-1 antigen concentrations in the setting of activation of the RAAS. One possible explanation is that plasma PAI-1 is derived from endothelium and that Ang II increases PAI-1 expression in humans through its hexapeptide metabolite, Ang IV, as has been observed in vitro in human endothelial cells.¹⁹ If this were the case, however, one would expect to measure increased PAI-1 antigen concentrations even during short-term AT₁ receptor blockade, when Ang II concentrations,²⁸ and presumably Ang IV concentrations, are increased and the AT₄ receptor is not blocked. Rather, the finding that losartan decreased PAI-1 concentrations after 1 week of therapy suggests that Ang IV–mediated effects on the endothelium do not contribute significantly to circulating PAI-1 antigen concentrations, and that activation of the RAAS in humans increases circulating PAI-1 through an AT₁ receptor–dependent mechanism. The brevity of the effect of losartan on PAI-1 antigen could then result from AT₁ receptor upregulation.

Alternatively, the different length of effect of ACE inhibition and AT₁RA on PAI-1 antigen concentrations could have resulted from differences in the duration of suppression of tissue Ang II. In support of this hypothesis, the increase in PRA, which in part reflects loss of feedback inhibition by Ang II,²⁹ was greater after 3 weeks of ramipril treatment, than after 3 weeks of losartan treatment. On the other hand, aldosterone "escape," which also reflects tissue angiotensin effects, tended to occur earlier during treatment with ramipril than during treatment with losartan.

The different effects of long-term ACE inhibition and AT₁RA on PAI-1 antigen may also relate to the contrasting effects of ACE inhibition and AT₁RA on bradykinin degradation. ACE inhibition, but not AT₁RA, potentiates the effects of systemic bradykinin,³⁰ a stimulus to endothelial NO release.³¹ Recent studies indicate that NO suppresses PAI-1 expression after stimulation by Ang II in aortic smooth muscle cells.³² ACE inhibition, but not AT₁RA, attenuates the effects of NO synthase inhibition on PAI-1 expression and cardiovascular remodeling in a rat model.³³ Further studies are needed to determine whether NO contributes to the effect of acute or chronic ACE inhibition and/or AT₁RA on PAI-1 antigen concentrations in humans.

In addition to increasing NO synthesis, bradykinin stimulates tPA release from the human vasculature through a NO-independent mechanism.³⁴ In the present study, the effects of ACE inhibition and AT₁RA on plasma tPA antigen were similar and paralleled effects on PAI-1 antigen. This likely reflects the fact that tPA exists in several forms in the blood, including free active tPA and tPA bound to PAI-1.³⁵ Because tPA/PAI-1 complexes are cleared more slowly than is active tPA, total tPA antigen tends to rise and fall in parallel with PAI-1 antigen.³⁶ In this regard, the lack of HCTZ on total tPA antigen in the face of increased PAI-1 antigen concentrations in this and 2 prior studies,^13,14 raises the possibility that HCTZ blunts tPA secretion, impairs tPA/PAI-1 complex formation, or enhances the clearance of free tPA. Similarly, the preservation of tPA activity during ACE inhibition may have reflected bradykinin-stimulated secretion.

Finally, differential effects of long-term ACE inhibition and AT₁RA on PAI-1 antigen concentrations may reflect different effects of the 2 drugs on insulin sensitivity in the insulin-resistant subjects studied. ACE inhibitors have been shown to improve insulin sensitivity, whereas AT₁RA appear to have neutral effects on insulin sensitivity.³⁷ However, the lack of effect of either ramipril or losartan on fasting glucose, insulin, HOMA-IR index, hemoglobin A_1C, or lipids makes it unlikely that metabolic factors underlie the different effects of the drugs on fibrinolysis over time. On the other hand, this relatively small study may not have been powered to detect significant metabolic differences between the treatment groups.

Perspectives
ACE inhibitors decrease the rate of progression of diabetic and nondiabetic nephropathies^38,39 and reduce the risk of MI in patients with left ventricular dysfunction,¹ diabetes,⁴⁰ and other risk factors for coronary artery disease.² More recently, AT₁RAs have also been demonstrated to reduce the rate of progression of diabetic nephropathy^41,42 and to decrease the risk of stroke in hypertensive patients with left ventricular dysfunction.⁴³ In neither the Irbesartan Diabetic Nephropathy Trial (IDNT)⁴¹ nor the Reduction of Endpoints in non–insulin-dependent diabetes mellitus (NIDDM) with the Angiotensin II Antagonist Losartan (RENAAL) trial⁴² did treatment with an AT₁RA significantly reduce the risk of cardiovascular death or MI. Similarly, in the Losartan Intervention For Endpoint reduction (LIFE) trial,⁴³ although treatment with losartan significantly reduced the risk of fatal and nonfatal stroke, there was no effect of AT₁RA on the risk of MI. Although differences in study design make it impossible to compare outcomes across trials of ACE inhibitors and AT₁RAs, it is nevertheless important to consider how mechanistic differences between ACE inhibitors and AT₁RAs might influence the effects of these drugs on cardiovascular morbidity and mortality. Drugs that interrupt the RAAS reduce the risk of cardiovascular events through a number of potential mechanisms, including preventing the effects of Ang II on cellular growth and proliferation,⁴⁴ on vascular superoxide radical formation,⁴⁵ and on PAI-1 expression.³ The present study suggests that there are important differences between the effects of ACE inhibitors and AT₁RAs on fibrinolytic balance, differences that may be relevant to our understanding of how these drugs impact on the risk of MI.

	Acknowledgments

 
This research was supported by an unrestricted grant from Monarch Pharmaceuticals; by National Institutes of Health grants HL60906, HL65193, HL67308, RR00095, and GM07569; and by a Geriatric Research, Education, and Clinical Center (GRECC) from the Department of Veterans Affairs Research Administration.

Received May 1, 2002; first decision May 24, 2002; accepted September 23, 2002.

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