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To determine whether time-averaged cumulative blood pressure (cumBP) is associated with the risk of cardiovascular outcomes among patients with heart failure with preserved ejection fraction.Three thousand, three hundred and thirty participants from Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were included in this analysis with a median follow-up of 3 years. CumBP, expressed as mmHg-years, was the sum of mean BP for each pair of successive examinations multiplied by the time. Time-averaged cumBP was calculated by dividing cumBP by total exposure time, also expressed as mmHg. Clinical outcomes of our study including primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization. Multivariable Cox hazard regression models and a restricted cubic spline model were used to assess the association and linearity between time-averaged cumBP and adverse outcomes.There is a U-shaped relationship between time-averaged cumBP and primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization among participants with HFpEF, with the nadir risk around 120-129 mmHg of SBP and 70-79 mmHg of DBP after adjusting for confounding variables. Treatment with spironolactone did not affect the association significantly. The finding remained robust across sensitivity analyses.Higher or lower time-averaged cumBP was significantly associated with a higher risk of adverse events. Control of time-averaged cumulative BP within a reasonable range was an important component of hypertension management in HFpEF.

Refractory hypertension (RfHT) and obstructive sleep apnea (OSA) share common pathophysiological mechanisms and probably are intrinsically associated, but their prevalence, clinical profile, and polysomnography (PSG) pattern remain misunderstood.To describe OSA prevalence and PSG pattern of patients with RfHT in a large cohort of resistant hypertension (RHT).This is a cross-sectional study involving 418 RHT patients (30.9% male; mean age of 62.5 ± 9.9 years) who were submitted to full-night PSG. RfHT was defined as uncontrolled ambulatory blood pressure monitoring using five or more antihypertensive drugs, including spironolactone. Bivariate analysis compared RHT and RfHT and multivariate analysis was performed to assess the independent correlates of OSA.A total of 90 patients (21.5%) were diagnosed with RfHT (26.7% male; mean age of 58.5 ± 8.3 years). In comparison with resistant ones, RfHT patients were younger, with higher smoking and previous cardiovascular diseases prevalence, especially stroke. There was no difference regarding anthropometric measures. OSA prevalence (80.0 vs. 82.9%) and moderate/severe OSA (51.1 vs. 57.0%) were similar in both groups as well as apnea-hypopnea index. In its turn, refractory hypertensive patients presented better sleep efficiency (78 vs. 71%), with higher total sleep time (315 vs. 281 min) and lower sleep latency (11 vs. 17 min). There was no difference regarding rapid eye movement sleep, oxygen saturation, microarousals index, and periodic limb movement.In this large RHT cohort, resistant and refractory hypertensive patients have similar OSA prevalence, although refractory ones, which by definition use spironolactone, are younger and apparently have a better sleep pattern.

The randomized, multicentre study compared the efficacy of renal denervation (RDN) versus spironolactone addition in patients with true resistant hypertension. We present the 24-month data.A total of 106 patients with true resistant hypertension were enrolled in this study: 52 patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline SBP of 159 ± 17 and 155 ± 17 mmHg and average number of drugs 5.1 and 5.4, respectively. Two-year data are available in 86 patients. Spironolactone addition, as crossover after 1 year, was performed in 23 patients after RDN, and spironolactone addition followed by RDN was performed in five patients.Similar and comparable reduction of 24-h SBP after RDN or spironolactone addition after randomization was observed, 9.1 mmHg (P = 0.001) and 10.9 mmHg (P = 0.001), respectively. Similar decrease of office blood pressure (BP) was observed, 17.7 mmHg (P 0.001) versus 14.1 mmHg (P 0.001), whereas the number of antihypertensive drugs did not differ significantly between groups. Crossover analysis showed nonsignificantly better efficacy of spironolactone addition in 24-h SBP and office SBP reduction than RDN (3.7 mmHg, P = 0.27 and 4.6 mmHg, P = 0.28 in favour of spironolactone addition, respectively). Meanwhile, the number of antihypertensive drugs was significantly increased after spironolactone addition (+0.7, P = 0.001).In the settings of true resistant hypertension, spironolactone addition (if tolerated) seems to be of better efficacy than RDN in BP reduction over a period of 24 months. However, by contrast to the 12-month results, BP changes were not significantly greater.

Objective Aldosterone excess has been equally associated with resistant hypertension (RHT) and obstructive sleep apnoea (OSA). We conducted a randomized controlled study to assess the effect of continuous positive airway pressure (CPAP) treatment on 24-h urinary aldosterone excretion in patients with RHT and moderate/severe OSA. Methods A total of 117 patients were randomized (57 CPAP and 60 control groups). Aldosterone excretion was determined by 24 h urine (24h-UAldo) collected at randomization and after 6 months of follow-up. Twenty-four hour UAldo differences were assessed by general linear model with the allocation group (CPAP or control) as a fixed factor adjusted for their respective baseline values. Both intention-to-treat and per-protocol (45 patients with optimal adherence to CPAP) analyses were performed. Results Baseline 24h-UAldo was higher in severe OSA than in moderate OSA patients. After CPAP treatment, there was a borderline significant reduction in 24h-UAldo [mean difference: -2.5 μg/24 h; 95% confidence interval (95% CI): -5.3 to +0.3 μg/24 h; P = 0.07] in intention-to-treat analysis, whereas in the per-protocol analysis, the CPAP group had a greater reduction in 24h-UAldo than the control group (mean difference: -3.3 μg/24 h; 95% CI: -6.1 to -0.4 μg/24 h; P = 0.027). This effect occurred solely in patients with uncontrolled ambulatory BPs, and was more pronounced in those with the nondipping pattern, not using spironolactone, less obese, and with lowest sleep SaO2 levels. Conclusion Only optimal CPAP treatment reduced aldosterone excretion in patients with uncontrolled RHT, while on intention-to-treat the effect was borderline. Although nondefinitive, our results suggest that CPAP treatment might improve cardiovascular outcomes by reducing aldosterone excess in resistant hypertensive individuals with OSA. Clinical trial registration ClinicalTrials.gov Identifier: NCT01508754.

Aim This was a nationwide study by National Health Insurance Research Database to investigate the risk of urinary tract cancers (UTCs) for renin-angiotensin-aldosterone system inhibitors including spironolactone. Methods A total of 32 167 UTC patients with hypertension were enrolled in the National Health Insurance program between 2005 and 2011. Results Among different subclasses of renin-angiotensin-aldosterone system inhibitors, the adjusted odds ratio (OR) for UTC risk was 1.00 [95% confidence interval (CI) = 0.96-1.04] in angiotensin-converting enzyme inhibitors, 1.22 (95% CI = 1.18-1.26) in patients who received angiotensin II receptor blockers, 0.91 (95% CI = 0.87-0.96) in spironolactone. Spironolactone is associated with a significantly lower risk of prostate cancer (adjusted OR = 0.88, 95% CI = 0.82-0.94) in the male patients. A similar trend was observed in the female patients for the risk of bladder cancer (adjusted OR = 0.81, 95% CI = 0.72-0.92). Conclusion Our findings show that a lower risk of UTCs significantly associated with spironolactone in patients.

Accumulating evidence points toward mutual interaction between parathyroid hormone (PTH) and aldosterone as potential mechanism for increasing cardiovascular risk in primary hyperparathyroidism (pHPT).The Eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism (EPATH) trial is a single-center, randomized, double-blind, parallel-group, placebo-controlled trial. The primary aim is to evaluate the effects of the mineralocorticoid receptor antagonist eplerenone on plasma intact PTH (iPTH) concentration in patients with pHPT. Secondary end points comprised surrogate parameters of cardiovascular health [24-h ambulatory SBP and DBP and echocardiographic parameters related to systolic/diastolic function as well as to cardiac dimensions].We enrolled 110 study participants with pHPT, 25-hydroxyvitamin D at least 20 ng/ml and estimated glomerular filtration rate more than 50 ml/min per 1.73 m. Patients were 1 : 1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or matching placebo for a treatment period of 8 weeks.The study was completed by 97 participants [mean (SD) age: 67.5 ± 9.5 years; 78.4% women). The mean treatment effect (95% confidence interval) for iPTH was 1.0 (0.9-1.1; P = 0.777) pg/ml. Mean 24-h ambulatory SBP and DBP decreased significantly [mean change (95% confidence interval) -6.3 (-9.4 to -3.3) and -3.7 (-5.7 to -1.7) mmHg, respectively; P 0.001]. No differences were seen in any further secondary outcomes or frequency of adverse events.In pHPT, treatment with eplerenone compared with placebo had no effect on circulating iPTH levels. Eplerenone treatment was well tolerated and safe and followed by significant decrease of ambulatory blood pressure.

Potassium-sparing diuretics (PSDs) are valuable antihypertensives with additional benefits unrelated to control of systolic blood pressure (SBP). However, their key parameters affecting SBP and serum potassium are poorly defined, fostering underutilization.Consequently, we conducted systematic reviews and meta-analyses, yielding 3668 articles and ultimately 84 randomized comparisons.For office SBP, overall placebo-adjusted changes were triamterene -1.9 (low dose only), amiloride -9.9, spironolactone -13.2, and eplerenone -9.2. Differences in antihypertensive effect were due to potency rather than efficacy. Doubling amiloride, eplerenone, and spironolactone doses reduced SBP (95% confidence limits) on average by -2.3 (-3.1, -1.5). Relative antihypertensive potencies were spironolactoneamilorideeplerenone. Spironolactone had significantly greater antihypertensive potency than amiloride, -4.0 (-7.4, -0.6), and eplerenone, -5.5 (-7.4, -3.6). Dose equivalencies were eplerenone-spironolactone 4.5-to-1 (e.g., eplerenone 125∼spironolactone 25), amiloride-spironolactone 3.3-to-1, and eplerenone-amiloride 1.4-to-1. Increases in serum potassium from amiloride and spironolactone at commonly used doses averaged 0.14-0.29 mEq/l; the dose doubling effect was 0.16 (0.10, 0.22). Spironolactone caused greater hyperkalemia than amiloride across their dose ranges: 0.14, P = 0.043. Seven features make important bias unlikely: a comprehensive literature search, adjustment for covariates, all models explaining 95-100% of the between-study variability, similar dose doubling effects among PSDs, two different methods giving the same potency sequence, similar results from double blind comparisons, and similar results for eplerenone versus spironolactone from analysing direct comparison data (i.e., no meta-regression) for office and 24-h SBP.This synthesis accomplishes for PSDs what has already been achieved for thiazide-type diuretics and other antihypertensives and can guide the application of these underutilized medicines.

Objective:The aim of our study was to assess the influence of spironolactone added to a standard therapy of amlodipine/lisinopril on parameters of 24-hour blood pressure (BP) monitoring in patients with uncontrolled hypertension.Design and method:60 patients (28 men and 32 women, aged 50.8 ± 8.9) we

Mineralocorticoid receptor antagonists are increasingly used in patients with treatment-resistant hypertension (TRH). There is experimental evidence for blood pressure (BP) independent effects of mineralocorticoid receptor blockade on cardiovascular target organ damage. We hypothesized that low-dose eplerenone (50 mg) will reduce left ventricular mass (LVM) beyond its BP-lowering effects.We performed a randomized, double-blind, placebo-controlled, parallel group study in 51 patients with TRH. Patients were allocated to receive either eplerenone 50 mg or placebo for 6 months, while other antihypertensive agents could be added in both groups to achieve a BP target of less than 140/90 mmHg. LVM was assessed by MRI before and after treatment.Baseline office BP was similar in the eplerenone and the placebo group (166 ± 21/91 ± 15 versus 159 ± 19/94 ± 8 mmHg, n.s.). BP was similarly reduced in the eplerenone versus the placebo group (-35 ± 20/-15 ± 11 versus -30 ± 19/-13 ± 7 mmHg, n.s.). However, LVM was reduced only in the eplerenone group (from 155 ± 33 to 136 ± 33 g, P 0.001), but not in the placebo group (152 ± 32 versus 148 ± 38 g, P = 0.45).Despite similar BP-lowering, only patients with TRH who were allocated to eplerenone experienced a reduction of LVM. Thus, our data suggest that in patients with TRH, mineralocorticoid receptor antagonists should be used preferentially in order to achieve an effective reduction of LVM along with the improvement of BP control.

We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension.After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12.Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP.In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

Objective:Resistant hypertension (RHTN) is defined as uncontrolled blood pressure (BP) (clinic BP > = 130/80 mmHg, 24-hr ambulatory BP [ABPM] >= 125/75 mmHg) on 3 or more medications including a diuretic. As previously described by us a novel 24hr circadian BP pattern with a large morning dip and ev

Objective:to evaluate effects on blood pressure (BP) control in two treatment options spironolactone (SPIR) versus torsemide (TOR) as an add-on therapy in resistant hypertensive (RAH) patients.Design and method:We studied 78 patients with true RAH confirmed by the office and ambulatory BP monitoring

Mineralocorticoid receptor antagonists (MRAs) are commonly used to reduce blood pressure, left-ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. Effects of MRAs on hypertensive organ damage seem to occur beyond what is expected from the mere reduction of blood pressure. This suggests that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. However, broad use of classic MRAs such as spironolactone has been limited by significant incidence of gynecomastia and other sex-related adverse effects. To overcome these problems, new aldosterone blockers have been developed with different strategies that include use of nonsteroidal MRAs and inhibition of aldosterone synthesis. Both strategies have been designed to avoid the steroid receptor cross-reactivity of classic MRAs that accounts for most adverse effects. Moreover, inhibition of aldosterone synthesis could have an additional benefit due to blockade of the mineralocorticoid receptor-independent pathways that might account for some of the untoward effects of aldosterone. The new aldosterone blockers are currently having extensive preclinical evaluation, and one of these compounds has passed phase 2 trials showing promising results in patients with primary hypertension and primary aldosteronism. This narrative review summarizes the knowledge on the use of classic MRAs in hypertension and covers the evidence currently available on new aldosterone blockers.

Supplemental Digital Content is available in the text, Objective: Both renal denervation (RDN) and spironolactone have been proposed for the treatment of resistant hypertension. However, they have not been compared in a randomized clinical trial. We aimed to compare the efficacy of spironolactone versus RDN in patients with resistant hypertension. Methods: A total of 24 patients with office SBP at least 150 mmHg and 24-h SBP at least 140 mmHg despite receiving at least three full-dose antihypertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to receive RDN or spironolactone (50 mg) as add-on therapy. Primary endpoint was change in 24-h SBP at 6 months. Comparisons between treatment groups were performed using generalized linear models adjusted by age, sex, and baseline values. Results: Spironolactone was more effective than RDN in reducing 24-h SBP and 24-h DBP: mean baseline-adjusted differences between the two groups were −17.9 mmHg (95%CI −30.9 to −4.9); P = 0.010 and −6.6 mmHg (95%CI −12.9 to −0.3); P = 0.041, for 24-h SBP and 24-h DBP, respectively. As regards changes in office blood pressure, mean baseline-adjusted differences between the two groups were −12.1 mmHg (95%CI −29.1 to 5.1); P = 0.158 and of −5.3 mmHg (95%CI −16.3 to 5.8); P = 0.332, for office SBP and office DBP, respectively. Otherwise, the decrease of estimated glomerular filtration rate was greater in the spironolactone group; mean baseline-adjusted difference between the two groups was −10.7 ml/min per 1.73 m2 (95%CI −20.1 to −1.4); P = 0.027. Conclusion: We conclude that spironolactone is more effective than RDN to reduce 24-h SBP and 24-h DBP in patients with resistant hypertension. Therefore, spironolactone should be the fourth antihypertensive drug to prescribe if deemed well tolerated’ in all patients with resistant hypertension before considering RDN.

OBJECTIVE: Both renal denervation (RDN) and spironolactone have been proposed for the treatment of resistant hypertension. However, they have not been compared in a randomized clinical trial. We aimed to compare the efficacy of spironolactone versus RDN in patients with resistant hypertension. METHODS: A total of 24 patients with office SBP at least 150 mmHg and 24-h SBP at least 140 mmHg despite receiving at least three full-dose antihypertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to receive RDN or spironolactone (50 mg) as add-on therapy. Primary endpoint was change in 24-h SBP at 6 months. Comparisons between treatment groups were performed using generalized linear models adjusted by age, sex, and baseline values. RESULTS: Spironolactone was more effective than RDN in reducing 24-h SBP and 24-h DBP: mean baseline-adjusted differences between the two groups were -17.9 mmHg (95%CI -30.9 to -4.9); P = 0.010 and -6.6 mmHg (95%CI -12.9 to -0.3); P = 0.041, for 24-h SBP and 24-h DBP, respectively. As regards changes in office blood pressure, mean baseline-adjusted differences between the two groups were -12.1 mmHg (95%CI -29.1 to 5.1); P = 0.158 and of -5.3 mmHg (95%CI -16.3 to 5.8); P = 0.332, for office SBP and office DBP, respectively. Otherwise, the decrease of estimated glomerular filtration rate was greater in the spironolactone group; mean baseline-adjusted difference between the two groups was -10.7 ml/min per 1.73 m (95%CI -20.1 to -1.4); P = 0.027. CONCLUSION: We conclude that spironolactone is more effective than RDN to reduce 24-h SBP and 24-h DBP in patients with resistant hypertension. Therefore, spironolactone should be the fourth antihypertensive drug to prescribe if deemed well tolerated' in all patients with resistant hypertension before considering RDN. The work was supported by the Spanish Health Authority: EC11–426.

Resistant hypertension (RHTN), blood pressure (BP) at least 140/90 mmHg despite using at least three different medications, including a diuretic, is associated with high dietary sodium and hyperaldosteronism. Mineralocorticoid receptor antagonists are recommended for treatment of RHTN, however, BP response to these agents varies widely. In the current analysis, we assessed predictors of BP response to spironolactone in patients with RHTN.We retrospectively evaluated the BP response to adding spironolactone 12.5-25 mg to existing medications. A favorable BP response was defined as a reduction in SBP of at least 10 mmHg. Tested variables included baseline characteristics and biochemical parameters.A total of 79 patients with RHTN were included in the analysis. Evaluated patients were more likely women (53.2%) and African-American (55.8%); were generally obese (76%) and were prescribed an average of four antihypertensive medications. Baseline SBP was 153.6 ± 22.3 mmHg; addition of spironolactone resulted in a mean reduction of 15.5 ± 20.7 mmHg. Patients with high urinary sodium excretion (≥200 mEq/24 h) had a significantly greater BP reduction compared with patients with normal excretion (200 mEq/24 h) (P = 0.008). Multivariable analysis identified 24 h urinary sodium excretion as a significant predictor of BP response (P = 0.021) after controlling for potential confounders, including primary aldosteronism.The antihypertensive effect of spironolactone is positively related to urinary sodium excretion regardless of aldosterone status. These findings suggest that mineralocorticoid receptor antagonists may be of preferential benefit in counteracting the BP effects of high dietary sodium.

OBJECTIVES: To obtain information about the effect of prolonged aldosterone excess on kidney function. METHODS: We determined kidney function changes defined by cystatin C-based estimations of glomerular filtration rate (CysC-GFR). Pretreatment proteinuria and intrarenal Doppler velocimetric indices in primary aldosteronism were examined and followed after adrenalectomy or spironolactone treatment. RESULTS: This prospective, multicenter study included 130 primary aldosteronism patients (56 men; age, 49.9 ± 13.4 years: 100 with adenoma and 30 with idiopathic hyperaldosteronism) and 73 essential hypertension patients (36 men; age, 51.4 ± 14.8 years) as controls. Patients with primary aldosteronism had higher CysC-GFR (P < 0.05) and heavier proteinuria (0.042) than those with essential hypertension. With primary aldosteronism, a higher aldosterone-renin ratio (odds ratio, OR = 7.85, P = 0.008) was independently related to pretreatment CysC-GFR. The factors related to pretreatment proteinuria included CysC-GFR (OR, -0.006, P = 0.001), plasma aldosterone concentration (OR, 0.004, P = 0.002), and duration of hypertension (OR, 0.016, P = 0.032). Duration of hypertension was also independently correlated with the pretreatment resistive index among primary aldosteronism patients (OR, 0.004, P = 0.035). CysC-GFR (all, P < 0.05), proteinuria (P < 0.001), and resistive index (P < 0.001) decreased 1 year after adrenalectomy but not with spironolactone treatment. CONCLUSION: Our data suggest that prolonged hyperaldosteronism will cause relative kidney hyperfiltration and reversible intrarenal vascular structural changes, which disguise the consequent renal injury, including declining GFR and proteinuria. Adrenalectomy and spironolactone treatment exert different clinical impacts toward kidney damage even with a similar blood pressure-lowering effect.

Eplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism.The study was multicentre, randomized, double-blind, active-controlled, and parallel group design. Following a single-blind, placebo run-in period, patients were randomized 1: 1 to a 16-week double-blind, treatment period of spironolactone (75-225 mg once daily) or eplerenone (100-300 mg once daily) using a titration-to-effect design. To be randomized, patients had to meet biochemical criteria for primary aldosteronism and have a seated DBP at least 90 mmHg and less than 120 mmHg and SBP less than 200 mmHg. The primary efficacy endpoint was the antihypertensive effect of eplerenone versus spironolactone to establish noninferiority of eplerenone in the mean change from baseline in seated DBP.Changes from baseline in DBP were less on eplerenone (-5.6 ± 1.3 SE mmHg) than spironolactone (-12.5 ± 1.3 SE mmHg) [difference, -6.9 mmHg (-10.6, -3.3); P0.001]. Although there were no significant differences between eplerenone and spironolactone in the overall incidence of adverse events, more patients randomized to spironolactone developed male gynaecomastia (21.2 versus 4.5%; P=0.033) and female mastodynia (21.1 versus 0.0%; P=0.026).The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism.

The formation of cerebral aneurysms is associated with endothelial damage and macrophage migration. Hypothesizing that the opening of tight junctions due to the disappearance of the tight junction proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia allows macrophage migration, leading to cerebral aneurysm formation, we investigated the role of tight junction proteins.The vascular wall of female rats subjected to hypertension, oophorectomy (OVX), and hemodynamic stress to induce cerebral aneurysms was evaluated morphologically, immunohistochemically, and by quantitative RT-PCR. We also assessed the regulation of tight junction proteins in human brain endothelial cells (HBECs).In the very early stage before aneurysm formation, the expression of occludin and ZO-1 was reduced in injured endothelial cell junctions exhibiting gaps. In the course of aneurysmal progression their reduction progressed and was correlated with macrophage migration. In hypertension along with OVX rats we observed an increase in angiotensin II and the degradation molecules matrix metalloproteinase-9 (MMP-9), nicotinamide-adenine dinucleotide phosphate oxidases and monocyte chemoattractant protein-1. The mineralocorticoid receptor blocker eplerenone increased occludin and ZO-1 expression; this was associated with a reduction in angiotensin II and the degradation molecules and resulted in the inhibition of macrophage exudation and aneurysm formation. In HBECs, occludin and ZO-1 downregulation by angiotensin II and estrogen deficiency was reversed by eplerenone, the MMP inhibitor SB3CT, and apocynin. Our results suggest that macrophage migration is associated with the reduction in tight junction proteins induced by the degradation molecules.In rats, the destruction of tight junctions may facilitate macrophage migration and cerebral-aneurysm formation.

In a pressure overload model, sympathetic activity is augmented in response to salt intake. Mineralocorticoid receptors and epithelial Na channels (ENaCs) are thought to contribute to Na-processing, but the underlying mechanism is unknown. Here, we investigated the contribution of the brain mineralocorticoid receptor- ENaC pathway to salt-induced sympathetic activation in a pressure overload model.Aortic banding was performed to produce a mouse pressure overload model. Four weeks after aortic banding (AB-4), left-ventricular (LV) wall thickness was increased without a change in percentage fractional shortening (%FS). Sympathetic activity increased in response to a 5-day high-salt diet in AB-4, but not in Sham-4. Brain mineralocorticoid receptor, alphaENaC, and angiotensin II type 1 receptor (AT1R) expression levels were greater in AB-4 than in Sham-4. The increase in sympathetic activity and in the expression of these proteins was blocked by intracerebroventricular (ICV) infusion of eplerenone, a mineralocorticoid receptor blocker. In another protocol, AB-4 mice were fed a high-salt diet (AB-H) for 4 additional weeks. At 4 weeks, %FS was decreased and sympathetic activity was increased in AB-H compared with Sham. Expression of mineralocorticoid receptors and AT1R in the brain was higher in AB-H than in Sham. ICV infusion of eplerenone in AB-H attenuated salt-induced sympathoexcitation and the decreased %FS. ICV infusion of eplerenone also decreased brain AT1R expression.These findings indicate that activation of brain alphaENaC and AT1R through mineralocorticoid receptors contributes to the acquisition of Na sensitivity to induce sympathoexcitation. Therefore, high salt intake accelerates sympathetic activation and LV systolic dysfunction in a pressure overload model.

OBJECTIVES We hypothesized that the aldosterone: renin ratio (ARR) predicts the antihypertensive response to mineralocorticoid receptor antagonist, spironolactone (SPIRO), when compared with bendroflumethiazide (BFZ). METHODS We conducted a randomized, crossover, trial on hypertensive patients with either high ARR (HARR defined as >750 and plasma aldosterone >250 pmol/l) or low ARR (LARR defined as

The (pro)renin receptor exists in the kidney, blood vessels and the heart. (Pro)renin binds to the receptor and induces tissue injuries directly, completely independent of angiotensin II (Ang II). The renal renin-angiotensin-aldosterone system is activated in salt-sensitive hypertensive rats with in-vitro studies showing aldosterone increases angiotensin-converting enzyme (ACE) activity, renin production and angiotensin II type 1 receptor (AT1R) activity. However, the effect of blockade of mineralocorticoid receptor on the renal (pro)renin receptor, angiotensinogen, ACE and AT1R in Dahl salt-sensitive rats is unknown.The following parameters were measured in Dahl salt-sensitive rats and in Dahl salt-resistant rats fed high-salt or low-salt diets and treated for 8 weeks with or without eplerenone (100 mg/kg per day, orally): blood pressure, plasma renin activity, plasma aldosterone concentration, kidney weight and Ang II contents, urinary protein excretion, glomerular injury (assessed by semiquantitative morphometric analysis) and levels of expression in the kidney of (pro)renin receptor protein and messenger RNA (mRNA) for angiotensinogen, ACE and AT1R.Dahl salt-sensitive rats fed a high-salt diet had increased kidney/body weight (175%) and urinary protein excretion (886%) and decreased plasma renin activity and plasma aldosterone concentration. The rats developed progressive sclerotic and proliferative glomerular changes, concomitant with increased expression of renal (pro)renin receptor protein and mRNA levels of angiotensinogen, ACE and AT1R and kidney Ang II content. Treatment with eplerenone in Dahl salt-sensitive rats was associated with significant improvements in kidney to body weight ratio, urinary protein excretion and renal injury scores and decreased renal (pro)renin receptor protein expression and angiotensinogen and AT1R mRNA levels and kidney Ang II content.A high salt diet increased the renal renin-angiotensin system, whereas blockade of mineralocorticoid receptors attenuated renal injuries by decreasing the activity of tissue renin-angiotensin system in Dahl salt-sensitive rats.

We have conducted an open observational study of the use of spironolactone 25-50 mg in the management of patients with resistant hypertension. This drug was recommended in 133 patients who were already receiving an angiotensin-blocking drug in addition to other therapies.Of these, three defaulted from follow-up and 11 could not tolerate spironolactone. We therefore have outcome data on 119 patients. The addition of spironolactone (median dose 25 mg) was associated with a mean (SD) fall in systolic blood pressure of 21.7 mmHg (24.0; P0.001) and diastolic blood pressure of 8.5 mmHg (14.9; P0.001). In two patients spironolactone had to be discontinued on account of a rise of serum potassium to above 6.0 mmol/l, whereas overall the mean increase in serum potassium was 0.3 mmol/l.With careful monitoring of plasma electrolytes, spironolactone at a low dose is an effective add-in drug in patients with hypertension resistant to a regime that includes an angiotensin-blocking agent.

OBJECTIVE The aim of the present study was to investigate possible inter-relationships between connective tissue growth factor (CTGF) and aldosterone in vascular and renal damage associated with hypertension. METHOD Spontaneously hypertensive rats (SHR) were treated with two doses (100 and 30 mg/kg per day) of the mineralocorticoid receptor antagonist eplerenone, or with antihypertensive therapy (HHR) (20 mg/kg per day hydralazine + 7 mg/kg per day hydrochlorothiazide + 0.15 mg/kg per day reserpine). RESULTS CTGF mRNA expression and protein levels in the aorta of SHR were upregulated (P < 0.05) compared with Wistar-Kyoto rats. Both doses of eplerenone similarly and significantly diminished CTGF upregulation, correlated with amelioration of aortic remodelling and endothelium-dependent relaxations. Only high-dose eplerenone and HHR significantly reduced arterial blood pressure. HHR treatment also diminished CTGF overexpression, suggesting a blood-pressure-mediated effect in CTGF regulation. This reduction, however, was lower (P < 0.05) than that produced by eplerenone (100 mg/kg per day). The direct effect of aldosterone on vascular smooth muscle cells was also studied. Incubation of cultured vascular smooth muscle cells with aldosterone increased CTGF production in a dose-related manner, but was reduced (P < 0.05) by the mineralocorticoid receptor antagonist spironolactone. Renal CTGF mRNA and protein levels were higher in SHR than in Wistar-Kyoto rats (P < 0.05), and were similarly diminished by all treatments (P < 0.05). CONCLUSIONS These data show that aldosterone and haemodynamic stress from elevated blood pressure levels regulate vascular and renal CTGF in SHR. The results suggest that aldosterone, through CTGF stimulation, could participate in vascular and renal structural alterations associated with hypertension, describing a novel mechanism of aldosterone in hypertensive target organ damage.

OBJECTIVE Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG. METHODS Experiment 1: Explants of thoracic aortae and aortic vascular smooth muscle cells from Wistar rats were cultured for 24 h in the presence of vehicle or MBG (100 nmol/l) with or without canrenone (10 μmol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56 ± 2 years) with resistant hypertension on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity, plasma MBG, and erythrocyte Na/K-ATPase before and 6 months after addition of placebo (n = 8) or spironolactone (50 mg/day; n = 8) to the therapy. RESULTS In rat aortic explants and in vascular smooth muscle cells, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC50 = 480 ± 67 vs. 23 ± 3 nmol/l in vehicle-treated rings; P

To study the effects of addition of spironolactone to angiotensin-converting enzyme (ACE) inhibition or angiotensin II (AngII) receptor antagonism on proteinuria, blood pressure (BP) and renal function in overt type 2 diabetic nephropathy.A placebo-controlled, double-blind, parallel-group trial in patients from two outpatient clinics with a follow-up of 1 year.Type 2 diabetic patients with macroalbuminuria, despite long-term use of an ACE inhibitor or AngII receptor blocker were allocated to spironolactone, 25-50 mg once daily (n = 29) or placebo (n = 30). Urinary albumin to creatinine ratio, BP and biochemical parameters were measured at regular intervals.Five patients of the spironolactone and one of the placebo group developed hyperkalemia and had to be excluded. Compared to other patients their baseline serum creatinine [161 (123-248) versus 88 (72-170) micromol/l] and potassium concentrations (4.7 +/- 0.3 versus 4.2 +/- 0.2 mmol/l) were elevated (P0.001). Albuminuria decreased by 40.6% [95% confidence interval (CI) 23.4-57.8%] and BP by 7 mmHg (2-12 mmHg)/3 mmHg (1-6 mmHg) with spironolactone, but did not change with placebo. Estimated glomerular filtration rate (eGFR) during the 1-year follow-up declined on average by 12.9 ml/min per 1.73 m (9.5-16.5 ml/min per 1.73 m) in the spironolactone and by 4.9 ml/min per 1.73 m (0.8-8.9 ml/min per 1.73 m) in the placebo group (P = 0.004). This decline was progressive in the placebo but leveled off in the spironolactone group. In the spironolactone group changes in albuminuria and GFR were correlated (r = 0.48, P = 0.007).Addition of spironolactone to an ACE inhibitor or AngII receptor blocker is associated with a marked and sustained antiproteinuric effect, which in part relates to the more pronounced reduction in GFR.

Objective Potassium-sparing diuretics have different effects on angiogenesis that may mediate some abilities to treat cardiovascular diseases. The aim of the current study was to compare the effects of spironolactone and an active metabolite, canrenone, or a derivative, eplerenone, and amiloride, a diuretic without affecting mineralocorticoid activity, on the proliferation of human umbilical vein endothelial cells (HUVEC) and on angiogenesis in fibrin gel chambers implanted in rats. Materials and methods We measured the effects of spironolactone, canrenone, eplerenone, and amiloride on the proliferation of HUVEC in the presence or absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also examined the effects of these compounds on migration and capillary tube formation by HUVEC. Finally, the effects of the compounds on neovessel formation in vivo were investigated by implanting Wistar rats for 14 days with perforated Plexiglas chambers containing rat fibrin. Results Spironolactone and amiloride inhibited the proliferation of HUVEC, but canrenone and eplerenone had no effect. The inhibitory effect of spironolactone was not prevented by VEGF or bFGF. Aldosterone had no effect on spironolactone-induced inhibition of HUVEC proliferation. Spironolactone induced a dose-dependent reduction of both cell chemotaxis and capillary tube formation. In fibrin gel chambers, spironolactone and amiloride significantly reduced the numbers of both peripheral and central neovessels. Canrenone and eplerenone, in contrast, had no antiangiogenic effect. Conclusion Spironolactone and amiloride significantly inhibited angiogenesis in vitro and in the fibrin gel chamber in vivo. Spironolactone antiangiogenic effects are unrelated to antimineralocorticoid activity.

Randomized clinical trials in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) have demonstrated the life-saving and symptomatic benefits of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and, in more selected patients, spironolactone. Despite these major advancements, the prevalence of heart failure continues to increase mainly as a consequence of aging populations. The development of angiotensin II type 1 receptor blockers (ARBs) provides a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system. ARBs offer the potential to produce further clinical improvements for patients with heart failure above and beyond ACE inhibitors, as well as an alternative for those intolerant to an ACE inhibitor.The Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed as three parallel, randomized, double-blind, placebo-controlled clinical trials comparing candesartan with placebo in three different but complementary populations of patients with symptomatic heart failure.In patients with intolerance to an ACE inhibitor and an LVEF of 40% or less (the CHARM-Alternative trial), candesartan reduced cardiovascular mortality and hospitalizations for heart failure by 23% (P0.001). In patients with an LVEF of 40% or less treated with an ACE inhibitor (the CHARM-Added trial), candesartan reduced cardiovascular death and hospitalization for chronic heart failure by 15% (P = 0.011). In patients with a LVEF greater than 40% (the CHARM-Preserved trial), hospitalizations for heart failure and new-onset diabetes were significantly reduced.The CHARM programme, together with evidence from mechanistic studies and from other large trials with ARBs, constitutes a firm basis for including an ARB in the therapeutic arsenal in the treatment for chronic heart failure.

Background: Aldosterone has been shown to substantially contribute to the accumulation of different types of collagen fibres and growth factors in the arterial wall, thus increasing wall thickness. A previous study showed reduction of increased common carotid intima–media thickness (IMT) in patients with primary aldosteronism 1 year after adrenalectomy. Our study in patients with primary aldosteronism was aimed at comparing the long-term effect of adrenalectomy vs. spironolactone therapy on common carotid IMT regression. Method: Forty-two patients with confirmed primary aldosteronism (21 with aldosterone-producing adenoma treated by unilateral laparoscopic adrenalectomy, 21 treated with spironolactone) were investigated by carotid ultrasound at baseline and 1 and 6 years after the specific treatment. Results: There was a decrease in common carotid IMT from 0.956 ± 0.140 to 0.900 ± 0.127 mm (−5.9%; P

Recent evidence points to the effectiveness of spironolactone vs placebo in the treatment of resistant hypertension (RH). However, placebo is rarely a realistic treatment choice in uncontrolled hypertension. Using meta-analysis, we assessed the effectiveness of alternative 4 line anti-hypertensive agents in comparison to 4 line spironolactone/eplenerone in RH. Pubmed, EMBASE and the Cochrane library were systematically searched for randomised and non-randomised studies that compared any 4 line anti-hypertensive agent to spironolactone/eplenerone in RH. Data extraction and quality appraisal were carried out in duplicate. The outcome was change in systolic BP, measured in the office, at home or by ambulatory blood pressure monitoring (AMBP). A random effects model was used to pool the data. Statistical heterogeneity was assessed using the I test. Sensitivity analyses were carried out according to study design and method of BP measurement. From 2,506 records, we identified 1 RCT and 5 observational studies according to our inclusion criteria with 877 included patients (Table 1). The mean age was 57.3yrs, 29.5% female, 41.4% diabetic, mean eGFR of 83.7 ml/min and mean BMI of 29.8 kg/m. The baseline systolic BP was 143.1 mmHg. Other 4 line agents included bisoprolol, doxazosin and furosemide. When all the data was pooled, spironolactone reduced systolic BP by -10.19mmHg (95% CI 6.76 - 13.62) (Figure 1) more than the active comparator. When limited to studies that measured 24hr AMBP, spironolactone reduced BP by 9.99mmHg (95% CI 7.14 - 12.84) relative to the comparator. Analysing observational studies only, spironolactone reduced systolic BP by 11.24mmHg (95% CI 8.04 - 14.43). On the basis of this meta-analysis, spironolactone reduces systolic BP more effectively than other potential 4 line treatment options in RH. The comparative effectiveness of 4 line agents with regard to clinical outcomes such as myocardial infarction and stroke now needs to be determined.

Objective Both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). Methods AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Results Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH 2 . Conclusions AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone.

Background Patients with Cushing's syndrome exhibit a bimodal distribution of maximal rates of the erythrocyte amiloride-sensitive Na+/H+ exchange (NHE). Enhanced erythrocyte NHE has recently been found in patients with primary aldosteronism. Objective To test the hypothesis that occult hypermineralocorticoidism in a subset of patients with Cushing's syndrome is responsible for the greater than normal NHE. Methods NHE was measured as maximal initial rate (Vmax) of amiloride-inhibited efflux of H+ into an alkaline Na+-containing medium, for 47 patients with hypercortisolism (20 with pituitary adenomas, 18 with adrenal adenomas, and nine with ectopic production of adrenocorticotropin). Clinical appearance, blood pressure levels, plasma aldosterone and deoxycorticosterone levels, serum electrolytes, and urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios were assessed for all patients. Twenty patients (10 with greater than normal NHE and 10 with low-to-normal NHE) were randomly selected from 47 patients with hypercortisolism, and treated with 200 mg/day spironolactone for 7 days. NHE in these patients was assessed before starting the treatment and 2 days after its cessation. Results Greater than normal NHE (Vmax) was associated with peripheral edema, high diastolic blood pressure, hypokalemia, and high urine (tetrahydrocortisol plus 5-alpha-tetrahydrocortisol) : tetrahydrocortisone ratios. The enhanced NHE was rapidly normalized by treatment with spironolactone. Conclusion Erythrocyte NHE in patients with hypercortisolism and functional hypermineralocorticoidism is greater than normal due to incomplete peripheral conversion of cortisol (which binds to mineralocorticoid receptors) into metabolically inactive cortisone.

Fluid displacement from the lower extremities to the upper body during sleep is strongly associated with obstructive sleep apnoea in hypertensive patients. The present pathophysiological study tests the hypothesis that intensified diuretic therapy will reduce the apnoea-hypopnoea index and blood pressure of uncontrolled hypertensive patients with obstructive sleep apnoea in proportion to the reduction in overnight change in leg fluid volume.Uncontrolled treated hypertensive patients underwent overnight polysomnography and measurement of overnight changes in leg fluid volume and neck circumference. Those with an apnoea-hypopnoea index at least 20 events per hour (n=16) received metolazone 2.5 mg and spironolactone 25 mg daily for 7 days after which the daily dose was doubled for 7 additional days. Baseline testing was again repeated.Intensified diuretic therapy reduced the apnoea-hypopnoea index from 57.7 ± 33.0 to 48.5 ± 28.2 events per hour (P=0.005), overnight change in leg fluid volume from -418.1 ± 177.5 to -307.5 ± 161.9 ml (P0.001) and overnight change in neck circumference from 1.2 ± 0.6 to 0.7 ± 0.4 cm (P0.001). There was an inverse correlation between the reduction in overnight change in leg fluid volume and decrease in apnoea-hypopnoea index (r=-0.734, P=0.001). The reduction in overnight change in leg fluid volume was also significantly correlated with the change in morning blood pressure (r=0.708, P=0.002 for SBP; r=0.512, P=0.043 for DBP).The findings provide further evidence that fluid redistribution from the legs to the neck during sleep contributes to the severity of obstructive sleep apnoea in hypertension and may be an important link between these two conditions.