Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension

Sato, Aiko; Fukuda, Seiichi

doi:10.1038/jhh.2009.81

Cited by 25 publications

(20 citation statements)

References 43 publications

(59 reference statements)

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“…However, none of these randomized trials focused on patients with metabolic syndrome. Two nonrandomized open label studies 29,30 have examined the add-on effects of mineralocorticoid receptor blockade on blood pressure in patients with metabolic syndrome who were already using other antihypertensive medications. These studies reported significant reductions in blood pressure (P < 0.05), but their findings have not been confirmed by wellcontrolled trials.…”

Section: Blood Pressurementioning

confidence: 99%

Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome

Hwang

Yoo

Luttrell

et al. 2015

Metabolic Syndrome and Related Disorders

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Background: The prevalence of metabolic syndrome is especially high in older adults. Metabolic syndrome is associated with impaired vascular endothelial function, insulin resistance, and increased risk for cardiovascular disease but the underlying mechanisms are not fully elucidated. Plasma aldosterone is independently associated with metabolic syndrome and is linked to endothelial dysfunction and insulin resistance. Thus, we hypothesized that mineralocorticoid receptor (MR) blockade would improve flow-mediated dilation and insulin resistance in older adults with metabolic syndrome. Methods: To test this hypothesis, we conducted a balanced, randomized, double-blind, placebo-controlled, crossover study using selective MR blockade (eplerenone; 100 mg/day) for 1 month with 1 month washout in older adults with metabolic syndrome (62.6 -3.2 yrs; mean -standard error). We evaluated brachial artery flowmediated dilation (ultrasonography), oxidative stress (oxidized low-density lipoproteins and F 2 -isoprostanes) and insulin resistance (homeostatic model assessment). Results: In response to MR blockade, flow-mediated dilation (5.37 -0.85 vs. 5.98 -1.29%; placebo vs. eplerenone; P = 0.4), oxidized low-density lipoproteins (51.6 -11.5 vs. 56.1 -10.9 U/L; P = 0.6), and F 2 -isoprostanes (0.07 -0.02 vs. 0.06 -0.01 pg/mL; P = 0.3) did not improve. Insulin resistance also did not change following MR blockade (1.04 -0.26 vs. 1.38 -0.50; P = 0.6). However, MR blockade resulted in a large reduction (10 mmHg) in systolic blood pressure (140 -6 vs. 130 -6 mmHg; P = 0.02), with no significant change in diastolic blood pressure (81 -3 vs. 75 -2 mmHg; P = 0.2). Conclusions: Our data do not support a contributing role for MRs in endothelial dysfunction and insulin resistance in older adults with metabolic syndrome. However, our findings suggest MR activation is an important contributor to systolic hypertension in this patient group.

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Section: Blood Pressurementioning

confidence: 99%

Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome

Hwang

Yoo

Luttrell

et al. 2015

Metabolic Syndrome and Related Disorders

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“…Importantly, triglyceride levels (a surrogate measure of VLDL levels) are positively correlated with serum aldosterone levels in obese subjects (Goodfriend et al 1995), and eplerenone, an MR antagonist, decreases blood pressure and serum triglyceride levels in hypertensive individuals with or without metabolic syndrome (Sato & Fukuda 2010). In addition to providing cholesterol for steroid hormone biosynthesis as described previously, recent results suggest that lipoproteins can increase aldosterone levels by initiating signaling pathways that regulate steroidogenesis.…”

Section: Obesity Aldosterone and Hypertensionmentioning

confidence: 78%

Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production

Tsai

Rainey

Bollag

2017

Journal of Endocrinology

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Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.

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“…On average, obese patients have statistically significantly higher plasma aldosterone concentrations, which may contribute to the salt-sensitive hypertension frequently observed in these individuals (6,25); however, plasma aldosterone levels are not elevated in every patient. Nevertheless, treatment with an MR blocker decreased both BP and proteinuria in patients with metabolic syndrome, including those with normal aldosterone levels (105). This finding suggests that aberrant MR activation can occur in subjects with normal aldosterone levels.…”

Section: Novel Pathway Of Mr Activationmentioning

confidence: 78%

“…As described above, an MR antagonist is effective in BP reduction and cardiovascular protection in patients with metabolic syndrome, even those with normal aldosterone levels (105). Furthermore, in a rodent model, kidney-localized Rac1/MR activation contributed to obesity-related diabetic kidney disease (142).…”

Section: Mechanism Of Salt-sensitive Hypertension In Obese Subjectsmentioning

confidence: 99%

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways

Nishimoto

Fujita

2015

American Journal of Physiology-Renal Physiology

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Nishimoto M, Fujita T. Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways. Am J Physiol Renal Physiol 308: F377-F387, 2015. First published December 17, 2014 doi:10.1152/ajprenal.00477.2013.-Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the ␤ 2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na ϩ -Cl Ϫ cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1-mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. ␤ 2-Adrenergic stimulation due to increased renal sympathetic activity in obesity-and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na ϩ -Cl Ϫ cotransporters in the DCT and elevated Na ϩ retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt-sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na ϩ handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients.salt-sensitive hypertension; mineralocorticoid receptor; glucocorticoid receptor; Ras-related C3 botulinum toxin substrate 1; sympathetic nervous system HIGH LEVELS of dietary salt intake can induce hypertension, with salt restriction being one of the most effective treatments for this condition (32,72,79). Hypertensive patients, however, exhibit a large spectrum of salt sensitivity (71), with the mechanisms determining salt sensitivity as yet incompletely understood.Several factors influence salt sensitivity, including the activities of the sympathetic nervous system (SNS), the reninangiotensin system (RAS), aldosterone, and insulin. In the Guytonian model, dysfunctional excretion of renal Na ϩ plays a major role in Na ϩ retention and salt-sensitive hypertension (42). Several genes have been found to cause rare Mendelian forms of human hypertension (134), with these findings providing insights into the basic mechanisms of human hypertension and highlighting the key role of altered Na ϩ handling by the kidneys as a final common pathway in the pathogenesis of hypertension. In...

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Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension

Cited by 25 publications

References 43 publications

Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome

Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome

Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways

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