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Hypertension. 2006;47:441-448
Published online before print January 23, 2006, doi: 10.1161/01.HYP.0000202478.79587.1a
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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

Nancy J. Brown; James A.S. Muldowney, III; Douglas E. Vaughan

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


*    Abstract
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 *Abstract
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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.


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


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Plasminogen 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-ß, tumor necrosis factor-{alpha}, 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 platelet-derived 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-NG-nitro-arginine-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 precursor L-arginine decreased circulating PAI-1 in 2 men with hypertension and hypercholesterolemia.12 More recently, Sakamoto et al reported that nicorandil, a combined KATP channel opener and NO donor that significantly reduced cardiovascular end points in patients with stable angina,13 decreases PAI-1 activity.14 ACE inhibition decreases circulating PAI-1 and enhances fibrinolytic balance, particularly during activation of the RAAS.15–21 Although ACE inhibition likely improves fibrinolytic balance by attenuating Ang II-induced PAI-1 expression,22 ACE inhibition could also modulate PAI-1 expression by increasing kinin-mediated NO production and release.23

This study tests the hypothesis that NO contributes to the effect of ACE inhibitors on fibrinolytic balance. Specifically, we tested the hypothesis that coadministration of the NO precursor L-arginine would enhance the effect of ACE inhibition on circulating PAI-1 concentrations, whereas NOS inhibition would abrogate the effects of ACE inhibition on fibrinolytic balance.


*    Methods
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 *Methods
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The study protocol (Figure 1) was approved by the Vanderbilt institutional review board. All subjects gave written informed consent. As reported previously, after screening, subjects were given placebo tablets for 2 weeks.24 On the mornings of the 12th and 14th days of placebo, subjects reported to the Vanderbilt General Clinical Research Center (GCRC) for infusion of L-NAME (Clinalfa AG) or vehicle (normal saline) in randomized order during normal sodium intake. At the end of the second infusion day, subjects were randomized to double-blind treatment with L-arginine+placebo, ramipril+placebo, or L-arginine+ramipril for 4 weeks. L-arginine (Professional Compounding Centers of America) was started at 750 mg TID and titrated to 3 g TID over 1 week. Ramipril (Monarch Pharmaceuticals) was given at 2.5 mg per day and titrated to 10 mg per day over 1 week. Medications and identical placebos were prepared by the Vanderbilt Investigational Pharmacy. On the 26th and 28th days of treatment, subjects again underwent infusion of L-NAME or vehicle. After the second infusion, subjects repeated 2 additional cycles of 2-week washout, 4-week treatment, and infusion studies until they had completed all active treatment arms.


Figure 1
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  		Figure 1. Study protocol. IV indicates intravenous catheter; L-arg, L-arginine; ram, ramipril.

On infusion days, subjects reported to the GCRC fasting and were studied in the supine position. At 8:00 AM, a catheter was placed in a vein of each arm for drawing blood and administering drugs. One half-hour later, oral study medication was given and 2 mg/kg L-NAME or vehicle was given intravenously in 250 mL over 30 minutes (66 µg/kg per minute) or until systolic blood pressure (SBP) increased 20 mm Hg from the 8:30 AM baseline. Blood pressure and heart rate were measured every 5 minutes for 4 hours after the start of the infusion using an automated oscillometric cuff (Critikon) and telemetry. L-NAME was stopped early because of an exaggerated hypertensive response in 2 of the 17 subjects (after 15 and after 20 minutes). After the first L-NAME infusion, the same dose was used for each L-NAME study day in the same subject. Blood was drawn for measurement of PAI-1 and tissue-type plasminogen activator (t-PA) antigen before the start of infusion and hourly thereafter for 4 hours. Blood was drawn for measurement of ACE activity before infusion and for plasma renin activity (PRA), Ang II, and aldosterone before and 1 and 4 hours after the start of infusion.

Laboratory Analysis
For laboratory analysis, please see the online supplement, available at http://www.hypertensionaha.org.

Statistical Analysis
Data are presented as means±SD in text and the Table and means±SEM in the figures. A sample size of 17 was calculated to have a power of 0.79 to detect a within-group difference in PAI-1 antigen between treatment arms of 3.2 ng/mL with {alpha}=0.05 and an SD of the difference of 4.5 ng/mL. The effect of treatment on hemodynamic, endocrine, and fibrinolytic variables was assessed using a general linear model repeated-measures ANOVA in which within-subject variables were treatment and time after normality of the data and equality of variances were confirmed. D-dimer and plasmin-{alpha}2–antiplasmin concentrations were log transformed before analysis. For fibrinolytic parameters, quartile of body mass index and renin status were included as between-subject variables because they affect PAI-1 concentrations.4,18 There was no effect of gender on fibrinolysis, and therefore this was not included in analyses. Unless otherwise noted, P values from the ANOVA are presented in the text and the Table. P values for paired comparisons are presented in the figures. A 2-tailed P value ≤0.05 was considered significant. Analyses were performed using SPSS for Windows (version 11.0; SPSS).


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  		Effect of Treatment on Baseline Hemodynamics and the RAAS


*    Results
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 *Results
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Effect of ACE Inhibition and L-Arginine on Basal RAAS, NO Metabolites, and Hemodynamics
Seventeen moderately active subjects (11 males and 6 females; 15 whites and 2 blacks) completed the study. Mean age was 36.1±10.7 years. Mean body mass index was 26.8±1.9 kg/m2. Five women were premenopausal, and 1 was taking hormone replacement therapy. Treatment with ramipril significantly reduced serum ACE activity, SBP, and aldosterone and increased PRA (Table). L-Arginine did not affect blood pressure or the RAAS or alter the effects of ramipril. L-Arginine supplementation significantly increased circulating L-arginine and L-citrulline concentrations whether given alone or in combination with ramipril. Neither ramipril nor L-arginine affected baseline NO metabolite concentrations.

Effect of ACE Inhibition and L-Arginine on Basal Fibrinolytic Balance
Figure 2 shows the effect of L-arginine and ramipril alone and in combination on basal morning (8:00 AM) PAI-1 antigen, PAI-1 activity, D-dimers, and plasmin-{alpha}2–antiplasmin complexes. In contrast to previous studies in individuals in whom the RAAS has been activated, there was no effect of ramipril alone on morning PAI-1 antigen, t-PA antigen, or the molar ratio of PAI-1 to t-PA. L-Arginine alone did not significantly affect morning PAI-1 antigen. However, in combination with ramipril, L-arginine reduced PAI-1 antigen compared with either placebo (P=0.006) or ramipril (P=0.009) alone. There was no effect of L-arginine alone or in combination on t-PA antigen (data not shown). Consequently, combined treatment with ramipril and L-arginine significantly reduced the molar ratio of PAI-1 to t-PA (2.3±1.6) compared with either placebo (2.9±2.1; P=0.015) or ramipril (3.7±3.3; P=0.005) alone but not compared with L-arginine alone (2.8±2.3). PAI-1 activity was also suppressed 25% by combination therapy (Figure 2B) and correlated with the molar ratio of PAI-1 to t-PA antigen (R2=0.652; P<0.001). Basal t-PA activity was unchanged by any treatment (data not shown). To determine whether decreased PAI-1 antigen and activity resulted in increased fibrinolysis, we measured D-dimers and plasmin-{alpha}2–antiplasmin complexes; L-arginine and ramipril synergistically increased circulating D-dimers (Figure 2C) and plasmin-{alpha}2–antiplasmin (Figure 2D).


Figure 2
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  		Figure 2. Effect of treatment with placebo, L-arginine, ramipril, or combination L-arginine and ramipril on basal morning (8:00 AM). A, PAI-1 antigen. B, PAI-1 activity. C, D-dimers. D, Plasmin-{alpha}2–antiplasmin. *P<0.01 vs placebo; {dagger}P<0.01 vs ramipril alone; {ddagger}P<0.05 vs placebo; §P<0.05 vs L-arginine alone; ||P<0.05 vs ramipril alone; ¶P<0.01 vs L-arginine alone.

Effect of Acute L-NAME Infusion on the RAAS, NO Metabolites, and Hemodynamics
During the placebo arm, L-NAME significantly increased blood pressure (P<0.001), and this effect lasted for ≥210 minutes after discontinuation of the infusion, consistent with the conversion of L-NAME to a long-acting active metabolite.25 However, there was no carryover effect on blood pressure between treatment days. L-NAME also increased blood pressure during the ramipril treatment arm (P=0.008) and the L-arginine treatment arm (P<0.001). However, pretreatment with ramipril (P=0.014 for change in SBP in response to L-NAME during ramipril versus during placebo) or L-arginine (P=0.046) significantly blunted the pressor response after L-NAME. Hence, the mean increase in SBP after L-NAME was 10.1±8.7 mm Hg during the placebo arm and 6.2±7.8 and 7.3±8.7 mm Hg during the ramipril and L-arginine treatment arms, respectively. During combined treatment with L-arginine+ramipril, L-NAME induced a transient increase in SBP but the change in SBP over the 4 hours after L-NAME was no longer significant compared with vehicle (4.6±9.1 mm Hg; P=0.06).

As we have reported previously in a subset from this study,24 L-NAME increased circulating aldosterone concentrations compared with vehicle during placebo (P=0.013 for the current study), L-arginine (P=0.031), and ra-mipril (P=0.049) but not during combined treatment with L-arginine+ramipril (P=0.236). There was no effect of L-NAME on PRA, Ang II concentrations, or NO metabolites (data not shown).

Effect of Acute L-NAME Infusion on Fibrinolytic Balance
Figure 3 illustrates the effect of L-NAME and vehicle infusion on PAI-1 antigen concentrations from 8:00 AM to 12:00 PM. PAI-1 antigen concentrations decreased with time (P=0.023) during vehicle infusion, consistent with the previously described diurnal variation in PAI-1.16 There was no effect of L-NAME infusion on PAI-1 antigen concentrations in subjects during either the placebo (Figure 3A) or L-arginine (Figure 3B) treatment arm. However, during ramipril treatment (Figure 3C), L-NAME significantly increased plasma PAI-1 antigen concentrations compared with vehicle (P= 0.020). This effect became evident 2 hours after the initiation of L-NAME, with a 44% increase in PAI-1 antigen from 9.4±8.6 to 13.5±11.0 ng/mL (P=0.020). Simultaneous treatment with the NOS precursor L-arginine abolished this effect (Figure 3D). L-NAME increased t-PA antigen compared with vehicle during placebo treatment (P=0.017; data not shown); however, there was no effect of L-NAME on t-PA antigen during L-arginine, ramipril, or combination. Because the majority of t-PA antigen circulates complexed to PAI-126 and the effect of L-NAME on t-PA antigen may reflect effects of NOS inhibition on PAI-1 expression, PAI-1 release or t-PA expression or release, we measured the effect of L-NAME on active t-PA. L-NAME significantly increased t-PA activity during either placebo treatment (Figure 4A; P=0.004) or ramipril (Figure 4C; P=0.017) alone; in either case, pretreatment with L-arginine abolished this effect (Figure 4B and 4D). In contrast to the effect of L-NAME on PAI-1 antigen, the effect of L-NAME on t-PA activity was already present 1 hour after the initiation of infusion.


Figure 3
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  		Figure 3. Effect of L-NAME or vehicle on PAI-1 antigen during treatment with placebo (A), L-arginine (B), ramipril (C), or L-arginine and ramipril (D). *P<0.05 vs vehicle; {dagger}P<0.01 vs vehicle.


Figure 4
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  		Figure 4. Effect of L-NAME or vehicle on t-PA activity during treatment with placebo (A), L-arginine (B), ramipril (C), or L-arginine and ramipril (D). *P<0.05 vs vehicle; {dagger}P<0.01 vs vehicle.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Previous studies in vitro and in animal models suggest that NO regulates PAI-1 expression.9,10 Administration of an exogenous NO donor has been reported to decrease PAI-1 activity in patients with coronary artery disease.14 The present study indicates that during interruption of the RAAS by ACE inhibition, endogenous NO modulates PAI-1.

Unexpectedly and in contrast to data from several previous studies,15–21 ACE inhibition alone did not decrease PAI-1 antigen in the normotensive salt-replete subjects studied. Most previous studies of the effect of ACE inhibition on fibrinolytic balance have been conducted in subjects in whom the circulating RAAS was activated by dietary salt restriction,18 by concurrent diuretic use,20 or after myocardial infarction.15–17 However, in the current study, we studied normal subjects during free sodium intake such that both PRA and aldosterone concentrations were depressed compared with our previous studies.18,20 Under these conditions, ramipril did not decrease circulating Ang II concentrations, and this might have contributed to the lack of effect of ramipril on PAI-1 concentrations. Against this, ramipril significantly decreased ACE activity and aldosterone and increased PRA, indicating that adequate ACE inhibition was achieved and that there was loss of feedback inhibition of Ang II on renin synthesis.27 Thus, we hypothesize that in the sodium-replete state, factors other than Ang II and aldosterone, such as insulin, glucose, triglycerides, or NO, primarily regulate endogenous PAI-1 expression.1

ACE inhibition increases the bioavailability of endothelial NO in vivo in humans as measured, for example, by effects on endothelium-dependent vasodilation.28–30 In this study, treatment with an ACE inhibitor unmasked a role for NO in the regulation of PAI-1 expression in humans. Thus, during ACE inhibition, the NO precursor L-arginine significantly decreased active PAI-1 and the molar ratio of PAI-1 to t-PA antigen, whereas acute administration of the NOS inhibitor L-NAME attenuated the diurnal decrease in PAI-1, and this effect was reversed by pretreatment with L-arginine. No effect of L-arginine or L-NAME on PAI-1 concentrations was ob-served in the absence of ACE inhibition, suggesting that interruption of the RAAS enhances the effect of NO to modulate PAI-1 expression.

An alternative explanation for the effect of L-NAME on PAI-1 antigen concentrations during ramipril is that ACE inhibition enhances an effect of endogenous NO not on the expression of PAI-1 but rather on the release of PAI-1 from platelets. Platelets contain PAI-1 in their {alpha}-granules.31 ACE inhibitors are known to decrease platelet activation,32 and NO donors reduce PAI-1 release from platelets.7,8 Although we cannot exclude this possibility, the time course of the effect of L-NAME on circulating PAI-1 concentrations would mediate against an immediate effect on PAI-1 release and is consis-tent with the time course of effects of Ang II33 on PAI-1 expression. Similarly, it is possible that L-NAME increased PAI-1 antigen concentrations not through a direct effect of NOS inhibition but rather through an indirect effect of increased aldosterone. Aldosterone stimulates PAI-1 expression in vascular cells and monocytes.34–36 However, if the effect of L-NAME on PAI-1 antigen were mediated via aldosterone, L-NAME would be expected to increase PAI-1 antigen during all of the experimental conditions (placebo, L-arginine alone, and ramipril alone), during which L-NAME also increased circulating aldosterone concentrations relative to vehicle.

Neither ACE inhibition nor L-arginine significantly affected basal t-PA antigen or activity; however, acute inhibition of NOS with L-NAME significantly increased active t-PA. The rapid onset of this effect is consistent with an effect on t-PA release. t-PA is stored in endothelial cells in either small dense granules37 or Weible-Palade bodies38 and released via G-protein-coupled receptor-mediated, calcium-dependent pathways.39,40 ACE inhibition enhances endothelial t-PA release through a bradykinin B2 receptor-dependent pathway.41 Tranquille and Emeis reported that both the NO donor sodium nitroprusside and atrial natriuretic factor inhibit bradykinin-stimulated t-PA release; although this would seem to suggest a cGMP-dependent mechanism, the cGMP analogue 8-bromo-cGMP does not reproduce the inhibitory effect.42 More recently, Matushita et al reported that NO inhibits exocytosis of Weible-Palade bodies by nitrosylating cysteine residues of N-ethylmaleimide-sensitive factor (NSF), thereby inhibiting NSF disassembly of soluble NSF attachment protein receptor.43 Interestingly, circulating t-PA activity, but not tissue t-PA expression, is increased in endothelial NOS-deficient mice,44 again consistent with a moderating effect of NO on t-PA release. In the human forearm, although low doses of the NOS inhibitor L-NG-mono-methyl-arginine (L-NMMA) do not affect bradykinin-stimulated t-PA release,45 Smith et al reported that high-dose L-NMMA enhances bradykinin-stimulated t-PA release.46 Together with the data from the present study, these data suggest that NO inhibits t-PA release in humans.

A few study limitations require comment. First, because of safety considerations and the prolonged effect of L-NAME on blood pressure, we chose to study normotensive subjects. Additional studies will be needed to confirm these findings in individuals with endothelial dysfunction. Second, neither chronic administration of L-arginine nor acute administra-tion of L-NAME altered circulating concentrations of NO me-tabolites. Although this could suggest that L-arginine and L-NAME did not affect endogenous NO bioavailability, these findings are compatible with data from several other studies indicating that circulating NO metabolite concentrations do not adequately reflect the effect of L-arginine or L-NAME on endothelial NOS function.47,48 Moreover, the observations that L-NAME significantly increased blood pressure as well as PAI-1 antigen and t-PA activity, whereas L-arginine pre-treatment counteracted the effect of L-NAME administration on blood pressure, PAI-1 antigen, and t-PA activity, provide functional evidence that the effects of L-NAME were mediated via NOS inhibition.

In summary, the findings of this study suggest that during ACE inhibition, endogenous NO decreases PAI-1 expression but also attenuates endothelial t-PA release in normotensive salt-replete subjects in whom the RAAS is suppressed. Hence, combined administration of an ACE inhibitor and the NO precursor L-arginine produces a significant decrease in plasma PAI-1 antigen and activity and the molar ratio of PAI-1 to t-PA without a significant change in t-PA activity, resulting in an increase in fibrinolytic activity as measured by D-dimers and plasmin-{alpha}2–antiplasmin complexes.

Perspectives
Recent clinical trials suggest that NO donors decrease PAI-114 activity and improve mortality in congestive heart failure patients treated concurrently with ACE inhibitors or angiotensin receptor blockers.49 The finding that endogenous NO regulates PAI-1 activity during ACE inhibition in normal controls raises the possibility that an NO donor could also enhance the effect of ACE inhibition on fibrinolytic balance in individuals with endothelial dysfunction. Moreover, because NO decreases PAI-1 expression in vitro through a cGMP-dependent mechanism9 but may attenuate t-PA release through a cGMP-independent mechanism,42 additional studies are needed to define the effects of pharmacological strategies to increase cGMP on fibrinolytic balance during ACE inhibition.


*    Acknowledgments
 
This work was funded by National Institutes of Health grants HL060906, HL067308, HL065193, RR000095, and HL007411. J.A.S.M. is supported in part by the Stanley J. Sarnoff Endowment for Cardiovascular Research.

Received October 20, 2005; first decision November 10, 2005; accepted December 22, 2005.


*    References
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 *References
 

  1. Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, Mihaly J, Prager GW. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci. 2002; 17: 56–61.[Abstract/Free Full Text]
  2. Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992; 89: 6998–7002.[Abstract/Free Full Text]
  3. Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, Vitacolonna E, Capani F, Consoli A. Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol. 2001; 21: 1378–1382.[Abstract/Free Full Text]
  4. Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost. 1997; 78: 656–660.[Medline] [Order article via Infotrieve]
  5. Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation. 1998; 98: 2241–2247.[Abstract/Free Full Text]
  6. Vaughan DE. Plasminogen activator inhibitor-1 and the calculus of mortality after myocardial infarction. Circulation. 2003; 108: 376–377.[Free Full Text]
  7. Drummer C, Ludke S, Spannagl M, Schramm W, Gerzer R. The nitric oxide donor SIN-1 is a potent inhibitor of plasminogen activator inhibitor release from stimulated platelets. Thromb Res. 1991; 63: 553–556.[CrossRef][Medline] [Order article via Infotrieve]
  8. Korbut R, Marcinkiewicz E, Cieslik K, Gryglewski RJ. The effect of nitric oxide donors on the release of plasminogen activator inhibitor (PAI) from rabbit platelets in vitro. J Physiol Pharmacol. 1995; 46: 37–44.[Medline] [Order article via Infotrieve]
  9. Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol. 1998; 18: 1771–1779.[Abstract/Free Full Text]
  10. Katoh M, Egashira K, Mitsui T, Chishima S, Takeshita A, Narita H. Angiotensin-converting enzyme inhibitor prevents plasminogen activator inhibitor-1 expression in a rat model with cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis. J Mol Cell Cardiol. 2000; 32: 73–83.[CrossRef][Medline] [Order article via Infotrieve]
  11. Kaikita K, Fogo AB, Ma L-J, Schoenhard JA, Brown NJ, Vaughan DE. Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to chronic nitric oxide synthase inhibition. Circulation. 2001; 104: 839–844.[Abstract/Free Full Text]
  12. Korbut R, Bieron K, Gryglewski RJ. Effect of L-arginine on plasminogen-activator inhibitor in hypertensive patients with hypercholesterolemia. N Engl J Med. 1993; 328: 287–288.[Free Full Text]
  13. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002; 359: 1269–1275.[CrossRef][Medline] [Order article via Infotrieve]
  14. Sakamoto T, Kaikita K, Miyamoto S, Kojima S, Sugiyama S, Yoshimura M, Ogawa H. Effects of nicorandil on endogenous fibrinolytic capacity in patients with coronary artery disease. Circ J. 2004; 68: 232–235.[CrossRef][Medline] [Order article via Infotrieve]
  15. Wright RA, Flapan AD, Alberti KG, Ludlam CA, Fox KAA. Effects of captopril therapy on endogenous fibrinolysis in men with recent uncomplicated myocardial infarction. J Am Coll Cardiol. 1994; 24: 67–73.[Abstract]
  16. Vaughan DE, Rouleau J-L, Ridker PM, Arnold JMO, Menapace FJ, Pfeffer MA, on behalf of the HEART Study Investigators. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation. 1997; 96: 442–447.[Abstract/Free Full Text]
  17. Oshima S, Ogawa H, Mizuno Y, Yamashita S, Noda K, Saito T, Sumida H, Suefuji H, Kaikita K, Soejima H, Yasue H. The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma plasminogen activator inhibitor activity in patients with acute myocardial infarction. Am Heart J. 1997; 134: 961–966.[CrossRef][Medline] [Order article via Infotrieve]
  18. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin angiotensin system on plasma PAI-1 in humans. Hypertension. 1998; 32: 965–971.[Abstract/Free Full Text]
  19. Fogari R, Zoppi A, Preti P, Fogari E, Malamani G, Mugellini A. Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women. Am J Hypertens. 2001; 14: 921–926.[CrossRef][Medline] [Order article via Infotrieve]
  20. Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. Hypertension. 2002; 40: 859–865.[Abstract/Free Full Text]
  21. Pahor M, Franse LV, Deitcher SR, Cushman WC, Johnson KC, Shorr RI, Kottke-Marchant K, Tracy RP, Somes GW, Applegate WB. Fosinopril versus amlodipine comparative treatments study: a randomized trial to assess effects on plasminogen activator inhibitor-1. Circulation. 2002; 105: 457–461.[Abstract/Free Full Text]
  22. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. J Clin Invest. 1995; 95: 995–1001.[Medline] [Order article via Infotrieve]
  23. Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA, Noble NA. Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int. 1997; 51: 664–671.[Medline] [Order article via Infotrieve]
  24. Muldowney JA III, Davis SN, Vaughan DE, Brown NJ. NO synthase inhibition increases aldosterone in humans. Hypertension. 2004; 44: 739–745.[Abstract/Free Full Text]
  25. Pfeiffer S, Leopold E, Schmidt K, Brunner F, Mayer B. Inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME): requirement for bioactivation to the free acid, NG-nitro-L-arginine. Br J Pharmacol. 1996; 118: 1433–1440.[Medline] [Order article via Infotrieve]
  26. Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator Inhibitor type 1 (PAI-1) complex relation-ship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation. 1997; 96: 761–768.[Abstract/Free Full Text]
  27. Kurtz A, Wagner C. Regulation of renin secretion by angiotensin II-AT1 receptors. J Am Soc Nephrol. 1999; 10 (suppl 11): S162–S168.[Medline] [Order article via Infotrieve]
  28. Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S, Momohara M, Takeshita A. Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension. 1992; 20: 175–180.[Abstract/Free Full Text]
  29. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) Study. Circulation. 1996; 94: 258–265.[Abstract/Free Full Text]
  30. Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000; 35: 60–66.[Medline] [Order article via Infotrieve]
  31. Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest. 1984; 74: 1465–1472.[Medline] [Order article via Infotrieve]
  32. Schafer A, Fraccarollo D, Hildemann S, Christ M, Eigenthaler M, Kobsar A, Walter U, Bauersachs J. Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition. Thromb Haemost. 2003; 89: 1024–1030.[Medline] [Order article via Infotrieve]
  33. Rydzewski B, Zelezna B, Tang W, Sumners C, Raizada MK. Angiotensin II stimulation of plasminogen activator inhibitor-1 gene expression in astroglial cells from the brain. Endocrinology. 1992; 130: 1255–1262.[Abstract]
  34. Calo LA, Zaghetto F, Pagnin E, Davis PA, De Mozzi P, Sartorato P, Martire G, Fiore C, Armanini D. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab. 2004; 89: 1973–1976.[Abstract]
  35. Brown NJ, Kim KS, Chen YQ, Blevins LS, Nadeau JH, Meranze SG, Vaughan DE. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab. 2000; 85: 336–344.[Abstract/Free Full Text]
  36. Oestreicher EM, Martinez-Vasquez D, Stone JR, Jonasson L, Roubsanthisuk W, Mukasa K, Adler GK. Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury. Circulation. 2003; 108: 2517–2523.[Abstract/Free Full Text]
  37. Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol. 1997; 139: 245–256.[Abstract/Free Full Text]
  38. Rosnoblet C, Vischer UM, Gerard RD, Irminger JC, Halban PA, Kruithof EK. Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 1796–1803.[Abstract/Free Full Text]
  39. van den Eijnden-Schrauwen Y, Atsma DE, Lupu F, de Vries RE, Kooistra T, Emeis JJ. Involvement of calcium and G proteins in the acute release of tissue-type plasminogen activator and von Willebrand factor from cultured human endothelial cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2177–2187.[Abstract/Free Full Text]
  40. Muldowney JA III, Vaughan DE. Tissue-type plasminogen activator release: new frontiers in endothelial function. J Am Coll Cardiol. 2002; 40: 967–969.[Free Full Text]
  41. Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ. Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation. 2003; 107: 579–585.[Abstract/Free Full Text]
  42. Tranquille N, Emeis JJ. The role of cyclic nucleotides in the release of tissue-type plasminogen activator and von Willebrand factor. Thromb Haemost. 1993; 69: 259–261.[Medline] [Order article via Infotrieve]
  43. Matsushita K, Morrell CN, Cambien B, Yang SX, Yamakuchi M, Bao C, Hara MR, Quick RA, Cao W, O’Rourke B, Lowenstein JM, Pevsner J, Wagner DD, Lowenstein CJ. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell. 2003; 115: 139–150.[CrossRef][Medline] [Order article via Infotrieve]
  44. Iafrati MD, Vitseva O, Tanriverdi K, Blair P, Rex S, Chakrabarti S, Varghese S, Freedman JE. Compensatory Mechanisms Influence Hemostasis in the Setting of eNOS-Deficiency. Am J Physiol Heart Circ Physiol. 2005; 288: H1627–H1632.[Abstract/Free Full Text]
  45. Brown NJ, Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B2 receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation. 2000; 102: 2190–2196.[Abstract/Free Full Text]
  46. Smith DT, Hoetzer GL, Greiner JJ, Stauffer BL, DeSouza CA. Endothelial release of tissue-type plasminogen activator in the human forearm: role of nitric oxide. J Cardiovasc Pharmacol. 2003; 42: 311– 314.[CrossRef][Medline] [Order article via Infotrieve]
  47. Avontuur JA, Stam TC, Jongen-Lavrencic M, van Amsterdam JG, Eggermont AM, Bruining HA. Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNF alpha and nitrite/nitrate in human septic shock. Intensive Care Med. 1998; 24: 673–679.[CrossRef][Medline] [Order article via Infotrieve]
  48. Pereira EC, Bertolami MC, Faludi AA, Salem M, Bersch D, Abdalla DS. Effects of simvastatin and L-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects. Free Radic Res. 2003; 37: 529–536.[CrossRef][Medline] [Order article via Infotrieve]
  49. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351: 2049–2057.[Abstract/Free Full Text]



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