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BACKGROUND Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS This was a post hoc analysis of the “Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension” study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (−2.6 [−5.0, −0.2] and −6.4 mm Hg [−8.8, −4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP., Graphical Abstract Graphical Abstract

We recently reported that aldosterone-induced cellular senescence via an increase in p21, a cyclin-dependent kinase (CDK) inhibitor, in rat kidney and cultured human proximal tubular cells. In the present study, we investigated the contribution of aldosterone to the renal p21 expression and senescence during the development of angiotensin II (AngII)-induced hypertension.Mice received 1% salt in drinking water and vehicle or AngII, and were divided into five groups: 1, vehicle; 2, AngII; 3, AngII+olmesartan; 4, AngII+eplerenone; and 5, AngII+hydralazine.Plasma aldosterone levels were increased by AngII infusion. Eplerenone further elevated the plasma aldosterone level, but olmesartan and hydralazine did not. AngII group showed significant increase in blood pressure compared to vehicle. Olmesartan and hydralazine, but not eplerenone, suppressed the AngII-salt hypertension. The increase in urinary protein excretion by AngII-salt was suppressed only by olmesartan. AngII with high salt induced a greater expression of p21 mRNA in the kidney than vehicle. Olmesartan abolished the increase in p21 expression, whereas neither eplerenone nor hydralazine affected it. AngII with high salt did not change the expression of p16, another CDK inhibitor. The mice lacking p21 showed identical changes on blood pressure and albuminuria in response to AngII with high salt compared to wild type.These results suggest that aldosterone does not predominantly contribute to renal p21 expression and senescence during the development of AngII-salt hypertension, and that the increase in p21 in the kidney is not likely involved in the development of hypertension and albuminuria.

This review and update focuses on the clinical features of hydrochlorothiazide (HCTZ), the thiazide-like agents chlorthalidone (CTDN) and indapamide (INDAP), potassium-sparing ENaC inhibitors and aldosterone receptor antagonists, and loop diuretics. Diuretics are the second most commonly prescribed class of antihypertensive medication, and thiazide-related diuretics have increased at a rate greater than that of antihypertensive medications as a whole. The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension. HCTZ is 4.2-6.2 systolic mm Hg less potent than CTDN, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers by 24-hour measurements and 5.1mm Hg systolic less potent than INDAP by office measurements. For reducing cardiovascular events (CVEs), HCTZ is less effective than enalapril and amlodipine in randomized trials, and, in network analysis of trials, it is less effective than CTDN and HCTZ-amiloride. Combined with thiazide-type diuretics, potassium-sparing agents decrease ventricular ectopy and reduce the risk for sudden cardiac death relative to thiazide-type diuretics used alone. A recent synthesis of 44 trials has shown that the relative potencies in milligrams among spironolactone (SPIR), amiloride, and eplerenone (EPLER) are approximately from 25 to 10 to 100, respectively, which may be important when SPIR is poorly tolerated. SPIR reduces proteinuria beyond that provided by other renin angiotensin aldosterone inhibitors. EPLER also reduces proteinuria and has beneficial effects on endothelial function. While guidelines often do not differentiate among specific diuretics, this review demonstrates that these distinctions are important for managing hypertension.

Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension.This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP).Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P.05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P.05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities.Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.

Background We have demonstrated that angiotensin II receptor blocker (ARB) improved endothelial progenitor cells (EPCs) dysfunction through the antioxidative mechanism. Therefore, we investigate whether the selective mineralocorticoid receptor (MR) antagonist eplerenone improves EPCs function in rat hindlimb ischemia. Methods Unilateral hindlimb ischemia was surgically induced in Wistar rats. After induced ischemia, rats received eplerenone (30 mg/kg/day), valsartan (3 mg/kg/day), or vehicle for 3 weeks. Peripheral blood mononuclear cells were isolated, subjected to flow cytometric analysis to determine the number of circulating EPCs, cultured to assay EPC colony formation, and subjected to a migration chamber assay to evaluate EPCs migration. Results Blood perfusion by laser Doppler image was significantly higher in eplerenone than in vehicle. Capillary density by isolectin B4 stained of ischemic muscle was significantly increased in eplerenone compared with vehicle. Eplerenone significantly increased the number, colony formation, and migration of EPCs. Levels of endothelial nitric oxide synthase (eNOS) and angiogenic factor such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) protein expression by western blot were significantly higher in eplerenone than in vehicle. Eplerenone significantly decreased the NAD(P)H oxidase p22(phox), p47(phox), gp91(phox) and MR expression and expression of aldosterone effector kinase serum and glucocorticoid-induced protein kinase 1 (Sgk1). These effects of eplerenone are similar extent as valsartan. Conclusions This study showed that eplerenone improves the proliferation and function of EPCs in rat hindlimb ischemia, suggesting that eplerenone may provide a novel and effective therapeutic strategy for the repair of cardiovascular diseases.

We previously reported that a high-sodium diet activates the local renin-angiotensin-aldosterone system (RAAS) in cardiovascular tissues of Dahl salt-sensitive hypertensive (DS) rats. Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of blood pressure (BP) and cardiac function. The effect of blockade of aldosterone or angiotensin II (Ang II) on cardiac angiotensinogen and ACE2 in DS rats is unknown.The BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), heart weight, endothelium-dependent relaxation (EDR), and messenger RNA (mRNA) levels of collagen III, angiotensinogen, ACE, and ACE2 in the heart were measured in DS rats and in Dahl salt-resistant (DR) rats fed high or low salt diets. The rats were treated orally with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs combined for 8 weeks.A high salt diet increased BP (140%), heart/body weight (132%), and collagen III mRNA levels (146%) and decreased PRA and PAC concomitant with increased expression of cardiac angiotensinogen mRNA and decreased mRNA levels of ACE2 in DS rats. Eplerenone or candesartan significantly decreased the systolic BP from 240 +/- 5 mm Hg to 164 +/- 4 mm Hg or to 172 +/- 10 mm Hg, respectively (P.05). Eplerenone or candesartan partially improved heart/body weight and cardiac fibrosis, improved EDR and decreased cardiac ACE and angiotensinogen mRNA levels in DS rats. Candesartan increased ACE2 mRNA levels in the heart. Combination therapy normalized BP and further improved cardiac hypertrophy, fibrosis, and EDR.In DS rats, blockade of aldosterone or Ang II protects cardiac hypertrophy and fibrosis by inactivation of the local RAAS in the heart.

We previously reported that the mineralocorticoid receptor antagonists spironolactone and eplerenone markedly reduce proteinuria and vascular injury in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP). Presently, we examined whether amiloride, an epithelial sodium channel blocker, would also protect against pathology in these rats.In acute studies, saline-drinking SHRSP (n = 5) were instrumented with radiotelemetry blood pressure (BP) probes and housed in metabolic cages. Mean arterial pressure and electrolyte excretion were quantified over the 24-h period after oral administration of vehicle or amiloride at 1, 3, 10, and 30 mg/kg. In a survival study, 8.5-week-old SHRSP were either untreated (control, n = 7) or given amiloride (1 mg/kg/day, n = 8) in their 1% NaCl drinking solution. Systolic BP, proteinuria, body weight, and renal and brain histopathology were assessed.Acute amiloride treatment did not alter urine output, urinary electrolyte excretion, and sodium-to-potassium ratio or body weight. The mean arterial pressure was unaffected except for a 16-mm Hg reduction at 30 mg/kg (P.01). Six of eight SHRSP chronically treated with amiloride survived through 20 weeks of age, whereas all control SHRSP died by 16.4 weeks (P.0001). Amiloride delayed proteinuria (119 +/- 24 v 15 +/- 2 mg/day, P.002) with no significant effect on systolic BP (228 +/- 6 v 217 +/- 4 mm Hg) at 12 weeks of age.These findings suggest that interference with sodium channel function, perhaps at sites other than the kidney epithelium, may play a role in protecting against the evolution of cerebral and renal vascular injury in saline-drinking SHRSP.

Background : We previously reported that the mineralocorticoid receptor antagonists spironolactone and eplerenone markedly reduce proteinuria and vascular injury in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP). Presently, we examined whether amiloride, an epithelial sodium channel blocker, would also protect against pathology in these rats. Methods: In acute studies, saline-drinking SHRSP (n = 5) were instrumented with radiotelemetry blood pressure (BP) probes and housed in metabolic cages. Mean arterial pressure and electrolyte excretion were quantified over the 24-h period after oral administration of vehicle or amiloride at 1, 3, 10, and 30 mg/kg. In a survival study, 8.5-week-old SHRSP were either untreated (control, n = 7) or given amiloride ( 1 mg/kg/day, n = 8) in their 1% NaCI drinking solution. Systolic BP, proteinuria, body weight, and renal and brain histopathology were assessed. Results: Acute amiloride treatment did not alter urine output, urinary electrolyte excretion, and sodium-to-potassium ratio or body weight. The mean arterial pressure was unaffected except for a 16-mm Hg reduction at 30 mg/kg (P