Published online before print July 5, 2005, doi: 10.1161/01.HYP.0000174327.53863.86
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2005;46:313.)
© 2005 American Heart Association, Inc.
Original Articles |
Differing Effects of Mineralocorticoid Receptor–Dependent and –Independent Potassium-Sparing Diuretics on Fibrinolytic Balance
From the Divisions of Clinical Pharmacology (J.M., F.A., N.J.B.), Cardiovascular Medicine (F.A., D.E.V.), and General Internal Medicine (D.W.B.), the Departments of Medicine and Pharmacology and Biostatistics (C.Y.), and from the General Clinical Research Center (C.Y., D.W.B.), Vanderbilt University, 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 |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1±7.8 to 16.9±9.9 ng/mL at 9 AM, P=0.019; from 7.6±5.4 to 11.5±7.3 ng/mL at 11 AM, P=0.027; from 9.3±7.7 to 13.7±8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0±23.4 to 16.7±19.0 ng/mL at 10 AM, P=0.041; from 17.5±21.7 to 12.7±16.8 ng/mL at 11 AM, P=0.043; from 20.3±22.6 to 16.6±19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.
Key Words: renin • aldosterone • angiotensin II • plasminogen
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with an increased risk of ischemic cardiovascular events, independent of blood pressure, whereas interruption of the RAAS by angiotensin-converting enzyme (ACE) inhibition reduces cardiovascular mortality.1–4 One possible mechanism for the vascular toxicity associated with activation of the RAAS derives from the effects of angiotensin II (Ang II) on fibrinolytic balance. Ang II causes a dose-dependent increase in the expression of plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of fibrinolysis in vivo.5 In humans, activation of the RAAS by either sodium depletion or diuretic use is associated with increased morning plasma PAI-1 antigen concentrations, whereas ACE inhibition improves fibrinolytic balance.6–8
Although these effects of activation and interruption of the RAAS on the fibrinolytic system have been attributed to Ang II, aldosterone also regulates PAI-1 expression. Aldosterone interacts with Ang II to increase PAI-1 expression in vascular smooth muscle cells (VSMCs), and aldosterone alone induces PAI-1 expression in endothelial cells and monocytes through a mineralocorticoid receptor (MR)–dependent mechanism.9,10 Although the molecular basis for this interaction has yet to be defined, aldosterone enhances the vasoconstrictor11 and fibrotic effects12 of Ang II by increasing Ang II type 1 receptor binding and signaling.13 In rat models, aldosterone receptor antagonism attenuates renal PAI-1 expression after radiation injury or streptozotocin14,15 and cardiac PAI-1 expression after N
-nitro-L-arginine methyl ester (L-NAME)/Ang II.16 In humans, plasma PAI-1 antigen concentrations correlate with serum aldosterone concentrations in salt-depleted normal controls, hypertensive subjects, and individuals with primary hyperaldosteronism.6,8,9
A study comparing the effects of the diuretic hydrochlorothiazide (HCTZ; 25 mg) per day with spironolactone (100 mg per day) on fibrinolytic balance in hypertensive subjects supports the hypothesis that aldosterone increases PAI-1 synthesis in humans.6 In that study, although HCTZ and spironolactone increased Ang II and aldosterone, only HCTZ increased PAI-1 antigen concentrations. Moreover, MR antagonism abolished the relationship between aldosterone and plasma PAI-1 concentrations in hypertensive subjects.6 However, interpretation of the previous study was confounded by the fact that serum potassium concentrations were higher and systolic blood pressure (SBP) was lower during spironolactone treatment compared with during HCTZ treatment.
Therefore, the present study tests the hypothesis that spironolactone attenuates the effect of activation of the RAAS on PAI-1 concentrations in humans through an effect of MR antagonism rather than through an indirect effect of increased potassium. To do this, we compared the effects of spironolactone and the MR-independent, potassium-sparing diuretic triamterene on fibrinolytic balance in subjects pretreated with HCTZ to activate their RAAS. HCTZ was chosen as the diuretic to reflect the clinical administration of combined HCTZ/potassium-sparing diuretic.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects participated in a randomized, crossover, double-blind protocol. Each subject underwent a complete history, physical examination, and laboratory examination (serum chemistry, complete blood count with differential, urinalysis, and ECG) before investigation. Subjects with significant cardiovascular, renal, endocrine, or pulmonary disease were excluded. Written informed consent was obtained, and the study protocol was approved by the Vanderbilt institutional review board.
Each subject completed 5 study days over a 12-week period. Antihypertensive medications were discontinued 3 weeks before the first study day. Each subject collected his urine for 24 hours before each study day for measurement of sodium and potassium excretion. On the morning of each study day, subjects reported to the Vanderbilt General Clinical Research Center at 7 AM in the fasting state. An indwelling catheter was placed in an antecubital vein for blood drawing. Blood for measurement of PAI-1 and t-PA antigen, plasma renin activity (PRA), Ang II, aldosterone, insulin, proinsulin, potassium, and glucose was drawn after subjects had been supine for 30 minutes. Thereafter, PA1–1 and t-PA were measured hourly, and RAAS parameters were measured every 2 hours for a total of 4 hours. Thirty minutes after the last blood sample, supine blood pressure was measured in triplicate in the right arm.
After the first study day, each subject was treated with 12.5 mg of HCTZ per day for 4 weeks, and the study day was repeated. The dose of HCTZ was chosen on the basis of the usual starting dose. Subjects were then randomized using a permutated block method to 2-week treatment with spironolactone (50 mg per day), or triamterene (50 mg per day), and the study day was repeated. After the third study day, subjects continued taking 12.5 mg per day of HCTZ alone for 4 weeks (washout period), and study day 4 was performed. After the fourth study day, subjects were crossed over to either spironolactone or triamterene for 2 weeks, and the final fifth study day was completed. All medications were prepared by the Vanderbilt University Investigational Drug Service in identical-appearing capsules. Serum potassium and blood pressure were measured at least weekly during active medication. A serum potassium 
5.5 mEq/L resulted in exclusion from the protocol (no subjects). A serum potassium 
3.5 mEq/L resulted in potassium supplementation (12 subjects during HCTZ alone).
Laboratory Analysis
For laboratory analysis, please see the online supplement, available at http://www.hypertensionaha.org.
Statistical Analysis
Data are presented as means±SDs. One subject was discontinued from the protocol because of anemia before the last study day, and missing values for that day were imputed based on series means. The results of data analyses were similar if the data from this subject were excluded. The inclusion of 2 HCTZ periods in the study design allowed us to test for carryover effects using the methods of Kenward and Jones.17 Significantly, in the spironolactone-to-triamterene sequence, we found a carryover effect on PRA (for example, 10 AM PRA 0.6±0.4 versus 2.6±6.9 ng Ang I/mL per hour [P=0.05] during the first and second HCTZ study days in the spironolactone-to-triamterene sequence and 1.4±1.3 versus 1.1±0.9 ng Ang I/mL per hour in the triamterene-to-spironolactone treatment sequence). In addition, in hypertensives randomized to the spironolactone-to-triamterene sequence, there was also a carryover effect on PAI-1 (P values 0.09, 0.03, 0.26, 0.12, and 0.08 for treatment-by-period interaction for PAI-1 antigen concentrations at 8 AM, 9 AM, 10 AM, 11 AM, and 12 PM). Given this evidence for a carryover effect and the prolonged half-life of the active metabolite of spironolactone, we therefore treated the study as a parallel design study, analyzing only the data from the first 3 study days. General linear models were used to compare treatments while controlling for covariates such as subject type (normotensive or hypertensive). A Mann–Whitney test or an unpaired t test was used for post hoc comparisons (provided in tables) as appropriate. A 2-tailed P value <0.05 was considered significant. All analyses were performed using SPSS for Windows (version 11.0; SPSS).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Eighteen normotensive subjects (8 males and 10 females; 4 black Americans and 14 white Americans) and 20 hypertensive subjects (10 males and 10 females; 10 black Americans and 10 white Americans) were studied. Hypertensive subjects were significantly older (50.1±8.4 versus 39.8±8.8 years; P<0.001) and heavier (mean body mass index 27.3±3.7 versus 24.8±3.0 kg/m2; P=0.033) than the normotensive subjects. As expected, SBP (P<0.001) and diastolic blood pressure (DBP; P<0.001) were significantly higher in the hypertensive subjects compared with the normotensive subjects (Table 1). Among normotensive subjects, 8 (3 males and 5 females; 2 blacks and 6 whites) were randomized to spironolactone treatment first and 10 (5 males and 5 females; 2 blacks and 8 whites) to triamterene. Among hypertensive subjects, 9 (4 males and 5 females; 4 blacks and 5 whites) were randomized to spironolactone first and 11 (6 males and 5 females; 6 blacks and 5 whites) to triamterene. There were no differences in gender (53% and 52% female, respectively; P=1.0), ethnicity (41% and 38% black; P=1.0), or body mass index (25.5±3.6 and 26.6±3.6 kg/m2; P=0.33) in those subjects randomized to spironolactone first versus those randomized to triamterene first. Normotensive subjects, but not hypertensive subjects, randomized to spironolactone first were significantly older than those randomized to triamterene (44.7±7.0 versus 35.9±8.4 years; P=0.030).
|
Hemodynamic and Electrolyte Effects of Treatment
HCTZ alone did not significantly affect SBP or DBP (Table 1); however, the addition of either spironolactone or triamterene significantly lowered SBP and DBP compared with baseline. The change in SBP and DBP and the absolute SBP and DBP were similar in the spironolactone and triamterene groups, within either normotensive or hypertensive subjects. There was no effect of spironolactone or triamterene on heart rate and no difference in heart rate between spironolactone and triamterene treatment groups.
Serum potassium was decreased significantly during treatment with HCTZ compared with baseline in normotensive (P<0.001) and hypertensive (P=0.040) subjects (Table 1) despite potassium supplementation in 12 of 38 subjects. Potassium supplementation was discontinued during administration of spironolactone or triamterene. For this reason, potassium concentrations were similar during HCTZ and during HCTZ plus spironolactone or HCTZ plus triamterene. Serum potassium was similar in the spironolactone and triamterene treatment groups. There was no effect of treatment on urine sodium or potassium excretion in normotensive subjects. HCTZ increased urinary potassium excretion in the hypertensive subjects (P=0.049). Within normotensive and hypertensive subjects, urine sodium or potassium excretion was similar in the spironolactone and triamterene treatment groups.
Effect of Treatment on the RAAS and Metabolic Parameters
Table 2 illustrates the effect of treatment on PRA, Ang II, and aldosterone concentrations at specific time points. There was a significant effect of time on Ang II (P=0.001) and aldosterone (P=0.003). HCTZ alone significantly increased PRA at 8 AM (P=0.010 in normotensive subjects; P=0.008 in hypertensive subjects), and the addition of spironolactone or triamterene increased PRA further (P=0.043 versus HCTZ alone in normotensives; P=0.001 in hypertensives). Treatment with spironolactone or triamterene also increased PRA at 10 AM compared with HCTZ alone (Table 2). PRA was equivalent during spironolactone and triamterene treatment. PRA was significantly lower in hypertensive subjects compared with normotensive subjects (P=0.001 at 8 AM; P=0.010 at 10 AM).
|
There was no effect of treatment with HCTZ alone on circulating Ang II concentrations. Addition of either spironolactone or triamterene significantly increased Ang II compared with baseline in the hypertensive subjects (P=0.025 at 0800; P=0.032 for all time points); however, there was no difference between the effect of spironolactone and triamterene on Ang II concentrations. Ang II concentrations were statistically similar in normotensive and hypertensive subjects.
There was no effect of treatment with HCTZ alone on aldosterone concentrations. The addition of either spironolactone or triamterene significantly increased aldosterone concentrations compared with baseline (P<0.001 at each time point) and HCTZ alone (P<0.001 at 8 AM; P=0.001 at 10 AM and 12 PM) in normotensive but not hypertensive subjects, and the effect of the 2 drugs was similar. Aldosterone concentrations were significantly lower during spironolactone or triamterene in hypertensive subjects compared with normotensive subjects (P=0.003, P=0.007, and P=0.06 for effect of hypertension at 8 AM, 10 AM, and 12 PM, respectively).
Table 3 shows the effect of treatment on metabolic variables. Insulin concentrations (P=0.042) and the homeostasis model assessment of insulin resistance (HOMA-IR; P=0.036) were significantly higher in hypertensive subjects than in normotensive subjects. There was no effect of treatment on glucose or proinsulin concentrations. Treatment with either spironolactone or triamterene significantly increased insulin concentrations (P=0.034) and HOMA-IR (P=0.022) in the combined groups, and the effect on insulin tended to be greater with spironolactone (P=0.05 for effect of drug). However, there was no effect of spironolactone or triamterene on insulin or HOMA-IR, analyzed within normotensive or hypertensive subjects.
|
Effect of Treatment on Fibrinolysis
The Figure shows the effect of treatment on average (from 8 AM to 12 PM) morning PAI-1 and t-PA antigen concentrations for each subject. As reported previously,8 there was significant diurnal variation in PAI-1 (P<0.001 for effect of time) and t-PA antigen (P=0.032) concentrations and for the molar ratio of PAI-1 to t-PA (P=0.004). Therefore, although time was treated initially as a repeated measure in the ANOVA, additional analyses were performed at each time point. Table 4 shows the change in PAI-1 and t-PA antigen concentrations from HCTZ alone after the addition of spironolactone or triamterene at each time point.
|
|
Baseline PAI-1 concentrations were similar among the treatment groups (5.8±5.1, 6.9±4.4, 11.8±16.5, and 9.0±4.9 ng/mL in spironolactone- and triamterene-treated normotensive and spironolactone- and triamterene-treated hypertensive groups, respectively; P=0.530). HCTZ alone tended to increase the 8 AM (P=0.073) and 9 AM (P=0.056) PAI-1 antigen concentrations. This effect was significant in the hypertensive subjects treated subsequently with spironolactone at 9 AM (P=0.030). However, there was no difference in the change in PAI-1 in response to HCTZ alone (P=0.171) or in PAI-1 antigen concentrations during HCTZ among the 4 treatment groups (P=0.161). Addition of spironolactone or triamterene exerted opposing effects on PAI-1 antigen (P=0.006 effect of drug for all time points), and there was a significant interactive effect of treatment with hypertension status (P=0.021). Hence, in normotensive subjects, there was no effect of spironolactone on PAI-1 antigen, but triamterene significantly increased PAI-1 antigen (from 10.1±7.8 to 16.9±9.9 ng/mL at 9 AM, P=0.019; from 7.6±5.4 to 11.5±7.3 ng/mL at 11 AM, P=0.027; from 9.3±7.7 to 13.7±8.5 ng/mL for the average of all time points, P=0.054). In contrast, in hypertensive subjects, spironolactone decreased PAI-1 antigen compared with HCTZ alone (from 22.0±23.4 to 16.7±19.0 ng/mL at 10 AM, P=0.041; from 17.5±21.7 to 12.7±16.8 ng/mL at 11 AM, P=0.043; from 20.3±22.6 to 16.6±19.7 ng/mL for the average of all time points, P=0.014), whereas there was no effect of triamterene on PAI-1.
Although there was no difference in PAI-1 antigen concentrations during HCTZ between spironolactone- and triamterene-treated subjects, because HCTZ increased PAI-1 antigen significantly only in the spironolactone-treated hypertensive subjects, we performed regression analysis to determine whether the effect of drug treatment on PAI-1 antigen depended on the initial PAI-1 response to HCTZ. Predictors of the PAI-1 response to therapy were the drug (P=0.014 for spironolactone versus triamterene), hypertension (P=0.002), and previous PAI-1 response to HCTZ (P=0.019). Aldosterone tended to predict PAI-1 response to therapy (P=0.061). There was no significant effect of race, gender, age, body mass index, PRA, Ang II, or potassium.
There was no effect of HCTZ alone on t-PA antigen. Addition of either spironolactone or triamterene significantly increased t-PA antigen compared with baseline (P=0.003), and there was no significant difference between the 2 drugs. Thus, the net effect was that spironolactone significantly decreased the molar ratio of PAI-1 to t-PA antigen compared with HCTZ alone in hypertensive patients (P=0.025 at 8 AM; P=0.007 at 9 AM), whereas triamterene did not.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Elevated levels of PAI-1 have been associated with increased cardiovascular risk.18 Whereas activation of the RAAS by thiazide or loop diuretics or by sodium depletion increases PAI-1 antigen concentrations,8,19,20 treatment with the MR antagonist spironolactone attenuates the effect of activation of the RAAS on circulating PAI-1.6,21 However, previous studies have not addressed the possibility that spironolactone affects fibrinolytic balance indirectly through effects on serum potassium. The present study, comparing the effects of spironolactone to the MR-independent, potassium-sparing diuretic triamterene, indicates that spironolactone attenuates the effect of activation of the RAAS in normotensive subjects and improves fibrinolytic balance in hypertensive subjects independently of effects on potassium.
Two groups have reported that treatment with HCTZ increases PAI-1 concentrations in normotensive or hypertensive individuals.6,19,20 Although in the present study, 12.5 mg per day of HCTZ alone tended to increase early morning circulating PAI-1 antigen, this effect attained significance only in the hypertensive subjects subsequently randomized to spironolactone. Normotensive and hypertensive subjects were studied because circulating PAI-1 concentrations are increased in insulin-resistant and hypertensive individuals compared with normotensive individuals.22,23 The effect of HCTZ on PAI-1 antigen may also be greater in hypertensive individuals compared with normotensive individuals.6,20 Moreover, in hypertensive subjects, the effect of HCTZ appears to be dose dependent.6,19 In this study, PAI-1 concentrations were 40% versus 22% higher during 12.5 mg per day of HCTZ in the hypertensive and normotensive subjects, respectively.
Surprisingly, 12.5 mg per day of HCTZ induced hypokalemia, requiring supplementation in almost one third of study participants. This may reflect the low dietary potassium intake observed in this and studies in similar populations.24 Spironolactone and triamterene exerted similar effects on blood pressure and serum potassium. Spironolactone and triamterene activated the RAAS. The comparable effect of triamterene and spironolactone on the RAAS suggests that activation resulted largely from volume depletion. MR antagonists may also increase renin and aldosterone25 through loss of feedback inhibition, as well as a direct effect on aldosterone synthase activity.26
Despite the fact that spironolactone and triamterene activated the RAAS, the effect of the 2 drugs on fibrinolytic balance differed significantly. Thus, triamterene worsened fibrinolytic balance in normotensive subjects and was neutral in hypertensive subjects, whereas spironolactone was neutral in normotensive subjects but improved fibrinolytic balance in hypertensive subjects. The different effect of these 2 drugs on fibrinolytic balance cannot be attributed to any metabolic effects but, rather, may reflect differences in their mechanisms of action. Whereas triamterene acts by blocking apical sodium channels,27 spironolactone antagonizes the MR. In vitro and in vivo, MR antagonism with spironolactone or its metabolite canrenone decreases PAI-1 expression in VSMCs, endothelial cells, monocytes, the heart, and kidney.9,10,14–16 The potassium independence of the effect of spironolactone on fibrinolytic balance is consistent with studies in animals and in humans, demonstrating potassium-independent cardiovascular effects of MR blockade. For example, MR blockade but not potassium prevents L-NAME/Ang II–induced myocardial injury in rats,28 and spironolactone but not the potassium-sparing diuretic amiloride improves endothelial function in chronic heart failure.29,30
The differential effects of spironolactone and triamterene in normotensive and hypertensive subjects in the present study may reflect the relative activity of the RAAS in these 2 groups. Compared with the normotensive subjects, the hypertensive subjects had lower PRA and a diminished aldosterone response to spironolactone or triamterene, but were relatively insulin resistant. Thus, in normotensive subjects, increased activation of the RAAS may have driven the increase in PAI-1 after triamterene and MR blockade with spironolactone may have only partially overcome this. In contrast, in hypertensive subjects, MR blockade may have been sufficient to overcome the modest activation of the RAAS.
In this context, the data from the present study are compatible with 2 previous studies reporting the effect of spironolactone on fibrinolytic balance. Our group has reported previously that spironolactone prevented the effect of activation of the RAAS on PAI-1 antigen and significantly increased t-PA antigen in a group of male hypertensive subjects.6 This is similar to the effect of spironolactone observed in normotensive subjects in the present study, in which group the PRA was comparable to that measured in the hypertensive subjects of the previous study. However, as observed in hypertensive subjects in the current study Yalcin et al reported that treatment with 50 mg per day of spironolactone significantly decreased PAI-1 and increased t-PA antigen in 14 hypertensive subjects; renin data were not provided.21 Thus, it would appear that spironolactone consistently increases t-PA antigen, whereas the effect on PAI-1 may depend on the extent of activation of the RAAS.
A limitation of this investigation was the detection of a carryover effect in the spironolactone-to-triamterene sequence of the original crossover study, requiring us to treat the study instead as a parallel design study and analyze data only from the first treatment period. Such an unpaired analysis decreases the power to detect treatment effects, and the normotensive groups were not matched with respect to age. Although we cannot exclude a confounding effect of age on the differing fibrinolytic response to spironolactone and triamterene in normotensive subjects, there was no relationship between age and PAI-1 concentrations. Moreover, the design of the study to include a baseline HCTZ period before each active treatment may be viewed as a strength that allowed for the detection of the carryover effect despite a 4-week washout.
The results of this study should be interpreted in the light of randomized clinical trials. Low-dose thiazide diuretics have been shown to reduce mortality in trials such as Systolic Hypertension in the Elderly Program (SHEP),31 Medical Research Council (MRC) trial,32 and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).33 Epidemiological studies indicate that the risk of sudden cardiac death in patients treated with thiazide diuretics correlates inversely with dose and with the use of potassium-sparing diuretics.34 On the other hand, the present study suggests that clinical trials are needed to compare the effects of combined HCTZ/MR blockade versus HCTZ/triamterene on cardiovascular mortality.
Perspectives
Two large clinical trials have now demonstrated a beneficial effect of MR blockade on mortality in patients with congestive heart failure who have already been treated with ACE inhibitor and diuretics.35,36 The specific mechanism(s) underlying the beneficial effect of MR antagonism are not known. MR antagonism may prevent sudden death by increasing serum potassium or altering myocardial uptake of norepinephrine,37 by improving endothelial function,29 or by decreasing cardiovascular remodeling.38 The present study suggests improved fibrinolytic balance may represent another mechanism whereby MR antagonism could protect diuretic-treated patients from fibrosis and thrombotic cardiovascular events.
|
Acknowledgments |
|---|
This work was supported by National Institutes of Health grants HL67308, HL60906, HL65193, DK037868, and MO1RR00095.
Received April 4, 2005; first decision April 21, 2005; accepted May 3, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991; 324: 1098–1104.[Abstract]
- Pfeffer MA, Braunwald EA, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992; 327: 669–677.[Abstract]
- Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992; 340: 1173–1178.[CrossRef][Medline] [Order article via Infotrieve]
- Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145–153.
[Abstract/Free Full Text] - Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest. 1995; 96: 2515–2520.[Medline] [Order article via Infotrieve]
- Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ. Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab. 2002; 87: 448–452.
[Abstract/Free Full Text] - 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]
- 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] - 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] - 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]
- Ullian ME, Walsh LG, Morinelli TA. Potentiation of angiotensin II action by corticosteroids in vascular tissue. Cardiovasc Res. 1996; 32: 266–273.
[Abstract/Free Full Text] - Robert V, Heymes C, Silvestre JS, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension. 1999; 33: 981–986.
[Abstract/Free Full Text] - Mazak I, Fiebeler A, Muller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004; 109: 2792–2800.
[Abstract/Free Full Text] - Brown NJ, Nakamura S, Ma L-J, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo AB. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int. 2000; 58: 1219–1227.[CrossRef][Medline] [Order article via Infotrieve]
- Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, Ishibashi S. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int. 2004; 66: 1493–1502.[CrossRef][Medline] [Order article via Infotrieve]
- 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] - Kenward MG, Jones B. The analysis of data from 2 x 2 cross-over trials with baseline measurements. Stat Med. 1987; 6: 911–926.[Medline] [Order article via Infotrieve]
- 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] - 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] - Lottermoser K, Hertfelder HJ, Vetter H, Dusing R. Fibrinolytic function in diuretic-induced volume depletion. Am J Hypertens. 2000; 13: 359–363.[CrossRef][Medline] [Order article via Infotrieve]
- Yalcin AU, Dincer M, Aslan V, Gulbas Z. Effect of spironolactone on impaired fibrinolysis of hypertensive patients. Kidney Blood Press Res. 2002; 25: 260–264.[CrossRef][Medline] [Order article via Infotrieve]
- Eliasson M, Evrin PE, Lundblad D. Fibrinogen and fibrinolytic variables in relation to anthropometry, lipids and blood pressure. The Northern Sweden MONICA Study. J Clin Epidemiol. 1994; 47: 513–524.[CrossRef][Medline] [Order article via Infotrieve]
- 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]
- Province MA, Arnett DK, Hunt SC, Leiendecker-Foster C, Eckfeldt JH, Oberman A, Ellison RC, Heiss G, Mockrin SC, Williams RR. Association between the alpha-adducin gene and hypertension in the HyperGEN Study. Am J Hypertens. 2000; 13: 710–718.[CrossRef][Medline] [Order article via Infotrieve]
- Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002; 15: 709–716.[CrossRef][Medline] [Order article via Infotrieve]
- Silvestre JS, Heymes C, Oubenaissa A, Robert V, Aupetit-Faisant B, Carayon A, Swynghedauw B, Delcayre C. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation. 1999; 99: 2694–2701.
[Abstract/Free Full Text] - Knauf H, Wais U, Lubcke R, Albiez G. On the mechanism of action of triamterene: effects on transport of Na+, K+, and H+/HCO3- -ions. Eur J Clin Invest. 1976; 6: 43–50.[Medline] [Order article via Infotrieve]
- Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, Williams GH, Adler GK. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertension. 2002; 39: 614–618.
[Abstract/Free Full Text] - Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000; 101: 594–597.
[Abstract/Free Full Text] - Farquharson CA, Struthers AD. Increasing plasma potassium with amiloride shortens the QT interval and reduces ventricular extrasystoles but does not change endothelial function or heart rate variability in chronic heart failure. Heart. 2002; 88: 475–480.
[Abstract/Free Full Text] - Anonymous. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). J Am Med Assoc. 1991; 265: 3255–3264.[Abstract]
- Anonymous. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ. 1992; 304: 405–412.[Medline] [Order article via Infotrieve]
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc. 2002; 288: 2981–2997.
[Abstract/Free Full Text] - Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, Cobb L, Rautaharju PM, Copass MK, Wagner EH. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994; 330: 1852–1857.
[Abstract/Free Full Text] - Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709–717.
[Abstract/Free Full Text] - Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309.
[Abstract/Free Full Text] - Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995; 76: 1259–1265.[CrossRef][Medline] [Order article via Infotrieve]
- Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000; 102: 2700–2706.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  N. J. Brown Aldosterone and Vascular Inflammation Hypertension, February 1, 2008; 51(2): 161 - 167. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Luther, J. V. Gainer, L. J. Murphey, C. Yu, D. E. Vaughan, J. D. Morrow, and N. J. Brown Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor-Dependent Mechanism Hypertension, December 1, 2006; 48(6): 1050 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
|
|
|
|
G. H. Williams Cardiovascular Benefits of Aldosterone Receptor Antagonists: What About Potassium? Hypertension, August 1, 2005; 46(2): 265 - 266. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||