eplerenone and Hyperaldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In this review we discuss about current knowledge on pathophysiology, natural history, diagnosis and treatment of PA in pregnancy. Because of the physiologic changes in the renin-angiotensin-aldosterone system (RAAS) and the contraindication to both confirmatory test and subtype differentiation, diagnosis of PA during pregnancy is challenging and relies mostly on detection of low/suppressed renin and high aldosterone levels. The course of pregnancy in patients with PA is highly variable, ranging from progesterone-induced amelioration of blood pressure (BP) control to severe and resistant hypertension with potential maternal and fetal complications. Mineralcorticoid receptor antagonists (MRA) are the recommended and most effective drugs for treatment of PA. As the anti-androgenic effect of spironolactone can potentially interfere with sexual development, their prescription is not recommended during pregnancy. On the other side, eplerenone, has proven to be safe and effective in 6 pregnant women and may be added to conventional first line drug regimen in presence of resistant hypertension or persistent hypokalemia. Ideally, patients with unilateral forms of PA should undergo adrenalectomy prior to conception, however, when PA is diagnosed during pregnancy and medical therapy fails to adequately control hypertension or its complications, adrenalectomy can be considered during the second trimester in case of unilateral adrenal mass at MRI-scan.

Topics: Eplerenone; Female; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Pregnancy; Spironolactone

Primary aldosteronism with a prevalence of 8 % of hypertension and 20 % of pharmacologically resistant hypertension is the most common secondary cause of hypertension. Yet, the diagnosis is missed in the vast majority of patients. Current clinical practice guidelines recommend screening for primary aldosteronism in patients with sustained elevation of blood pressure (BP) ≥150/100 mmHg if possible prior to initiation of antihypertensive therapy, and in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, obstructive sleep apnea, a family history of early onset of hypertension or cerebrovascular accident

Topics: Adrenalectomy; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Laparoscopy; Mass Screening; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Prevalence; Spironolactone

Primary aldosteronism (PA) is the most common cause of secondary hypertension. In this review, we discuss the diagnosis and management of PA during pregnancy based on the literature. As aldosterone and renin are physiologically increased during pregnancy and confirmation tests are not recommended, the diagnosis of PA during pregnancy relies on a repeatedly suppressed plasma renin level. Mineralocorticoid receptor antagonists (MRAs) are the most effective drugs to treat hypertension and hypokalemia in patients with PA. However, spironolactone (FDA pregnancy category C) might lead to undervirilization of male infants due to the anti-androgenic effects. Although data in the literature are very limited, treatment with spironolactone is not recommended. Eplerenone (FDA pregnancy category B) is a selective MRA without anti-androgenic potential. If MRA treatment is required in pregnancy, eplerenone appears to be a safe and effective alternative, although symptomatic treatment with approved antihypertensive drugs and supplementation with potassium is the first choice. In case of aldosterone-producing adenoma, laparoscopic adrenalectomy is a therapeutic option in the second trimester of pregnancy.

Topics: Animals; Disease Management; Eplerenone; Female; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Pregnancy; Pregnancy Complications; Spironolactone

The mineralocorticoid receptor antagonists have been shown to have favourable safety and cost-effectiveness profiles across a broad range of clinical indications, including heart failure, primary aldosteronism and resistant hypertension. The clinical biology of the first aldosterone blocker, i.e. spironolactone, and its effects in several organ systems has been well elucidated from multiple studies. The range of adverse effects experienced with spironolactone has led to its modification and the consequent synthesis of eplerenone. Scientific evidence accumulated so far supports the role of eplerenone as first-choice drug in heart failure, with lower prevalence rates of sex-related adverse effects associated with eplerenone as compared to spironolactone. In Europe, eplerenone is currently marketed only in some countries and only with the indication of heart failure, whereas its clinical efficacy and safety in mild to moderate hypertension is said to be uncertain. A review of available scientific evidence, however, discloses that 11 randomized clinical trials assessing eplerenone in >3500 hypertensives have been reported so far. The results of these studies clearly show that eplerenone is an effective antihypertensive agent when used alone or in combination with other medications. In doses ranging from 25 to 100mg daily, eplerenone monotherapy results in a dose-dependent reduction in clinic blood pressure. As compared to placebo, eplerenone reduces significantly blood pressure from baseline. In general, 100mg daily eplerenone has a blood pressure lowering that is 50 to 75% that of spironolactone. Eplerenone results in a greater reduction in blood pressure as compared with losartan, and comparison between eplerenone and amlodipine shows that both treatments decrease systolic blood pressure to a similar extent but eplerenone is better tolerated. In conclusion, there is now evidence that eplerenone can play an important role in the treatment of mild to moderate arterial hypertension and therefore scientific experts and regulatory authorities should support its wider use in clinical practice worldwide.

Topics: Eplerenone; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Spironolactone

Primary aldosteronism (PA) is the most common cause of secondary hypertension. The main aims of this paper were to review outcome after surgical versus medical treatment of PA and partial versus total adrenalectomy in patients with PA.. Relevant medical literature from PubMed, the Cochrane Library and Embase OvidSP from 1985 to June 2014 was reviewed.. Of 2036 records, 43 articles were included in the final analysis. Twenty-one addressed surgical versus medical treatment of PA, four considered partial versus total adrenalectomy for unilateral PA, and 18 series reported on surgical outcomes. Owing to the heterogeneity of protocols and reported outcomes, only a qualitative analysis was performed. In six studies, surgical and medical treatment had comparable outcomes concerning blood pressure, whereas six showed better outcome after surgery. No differences were seen in cardiovascular complications, but surgery was associated with the use of fewer antihypertensive medications after surgery, improved quality of life, and (possibly) lower all-cause mortality compared with medical treatment. Randomized studies indicate a role for partial adrenalectomy in PA, but the high rate of multiple adenomas or adenoma combined with hyperplasia in localized disease is disconcerting. Surgery for unilateral dominant PA normalized BP in a mean of 42 (range 20-72) per cent and the biochemical profile in 96-100 per cent of patients. The mean complication rate in 1056 patients was 4·7 per cent.. Recommendations for treatment of PA are hampered by the lack of randomized trials, but support surgical resection of unilateral disease. Partial adrenalectomy may be an option in selected patients.

Topics: Adrenalectomy; Epidemiologic Methods; Eplerenone; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Hypertension is one of the most common cardiovascular diseases during pregnancy. Primary hyperaldosteronism (PHA) is the most frequent endocrinological, secondary cause of hypertension, rarely diagnosed in pregnant women. In the available literature about 50 cases of PHA in pregnant women have been described. PHA is often a cause of resistant hypertension. PHA can cause life-threatening complications both for the pregnant woman and the fetus. Diagnosis of PHA in pregnancy is difficult due to the antagonistic effect of progesterone on aldosterone, physiological increase of aldosterone release during gestation and frequent normokalaemic clinical course. Typical pharmacological treatment of PHA is limited due to the anti‑androgenic effect of spironolactone, lack of data concerning the safety of eplerenone and limited access to amiloride in Poland. Surgical treatment is a therapeutic option only in early pregnancy. This paper presents the current state of knowledge on diagnostic methods and treatment of PHA in pregnant women and a systematic review of cases described in the literature.

Topics: Acid Sensing Ion Channel Blockers; Aldosterone; Amiloride; Antihypertensive Agents; Eplerenone; Female; Humans; Hyperaldosteronism; Hypertension; Poland; Pregnancy; Pregnancy Complications; Progesterone; Spironolactone

Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.

Topics: Aldosterone; Cytochrome P-450 CYP11B2; Dihydropyridines; Drug Interactions; Epithelial Sodium Channel Blockers; Eplerenone; Glucocorticoids; Heart Failure; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

The identification of primary aldosteronism as a common cause of resistant hypertension is a significant advance in our ability to care for patients with hypertension. Primary aldosteronism is common, and when unrecognized is associated with an increased incidence of adverse cardiovascular outcomes. Identification of primary aldosteronism is based on use of the plasma aldosterone level, plasma renin activity, and the aldosterone:renin ratio. Differentiation between unilateral and bilateral autonomous adrenal aldosterone production then guides further therapy, with use of mineralocorticoid-receptor blockers for patients with bilateral autonomous adrenal aldosterone production and laparoscopic adrenalectomy for patients with unilateral autonomous aldosterone production. In this review, we discuss in detail the pathogenesis of primary aldosteronism-induced hypertension and potassium disorders, the evaluation of the patient with suspected primary aldosteronism, and the management of primary aldosteronism, both through medications and surgery.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Adenoma; Aldosterone; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Mineralocorticoid Receptor Antagonists; Renin; Spironolactone

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.

Topics: Adrenal Cortex Neoplasms; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adrenocortical Adenoma; Aldosterone; Antihypertensive Agents; Diagnosis, Differential; Eplerenone; Hyperaldosteronism; Hypertension; Hypokalemia; Magnetic Resonance Imaging; Mass Screening; Renin; Spironolactone; Tomography, X-Ray Computed

Primary aldosteronism (PA) is an important cause of secondary hypertension, is being increasingly diagnosed and may account for more than 10% of hypertensive patients, both in primary care and in referral centers. Aldosterone excess is associated with adverse cardiovascular, renal and metabolic effects that are in part hypertension-independent. Laparoscopic adrenalectomy remains the mainstay of treatment for unilateral forms of PA, whereas medical treatment is recommended for bilateral forms of PA. However, a favourable surgical outcome depends on several factors and many patients are not suitable for this treatment. On the other hand, surgery in patients considered to have bilateral PA may contribute to better blood pressure control. In this review, established and novel strategies for the management of different types of PA are discussed.

Topics: Adrenalectomy; Eplerenone; Humans; Hyperaldosteronism; Spironolactone

Primary aldosteronism (PA) has been recognized as a common cause of secondary hypertension and accounts for approximately 5-15% of the hypertensive population in Japan. Screening for PA should therefore be carried out in all hypertensive patients as we have shown the estimated prevalence of PA is 13.6% in pre-hypertensive subjects and 9.1% in stage 1 hypertensive patients. The screening test most advocated is the aldosterone-to-renin ratio (ARR), and when the ARR is >20 the following confirmatory tests should be carried out; the captopril challenge test, frusemide-upright test, or saline infusion test. Adrenal CT is not accurate for distinguishing between an aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Adrenal venous sampling (AVS) is therefore essential for selecting the appropriate therapy in patients a high probability of PA who require surgical treatment. Rapid cortisol assays during AVS to monitor cortisol levels can reduce the failure associated with AVS. We have developed a new rapid cortisol assay using immunochromatography, in which cortisol concentration can be measured within 6 min. Using this technique, the success rate of AVS improved to 93%. IHA underlies about one-half of cases with PA; treatment with eplerenone (100 mg twice a daily), a specific mineralocorticoid receptor antagonist, results in substantial improvement in hypertension, with fewer side effects compared to spironolactone.

Topics: Eplerenone; Humans; Hyperaldosteronism; Japan; Spironolactone

Topics: Albuminuria; Diabetes Mellitus, Type 2; Eplerenone; Female; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Hyperaldosteronism is associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. When present, endothelial dysfunction is an independent predictor of adverse cardiovascular events. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone reduce morbidity and mortality, and it has been suggested that this occurs, in part, as a result of improved vascular function. The routine use of MR antagonists in patients with cardiovascular disease, however, is limited by the development of gynecomastia with spironolactone use and hyperkalemia with the use of both agents. Therefore, the development of newer agents with more favorable side-effect profiles is needed.

Topics: Aldosterone; Animals; Endocrine System Diseases; Endothelium, Vascular; Eplerenone; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Spironolactone

The following review presents recent diagnostic and therapeutic developments in the field of endocrinology. With the development of strontium ranelate and teriparatide (human recombinant parathyroid hormone) two new drugs are now available for the treatment of postmenopausal osteoporosis. In addition, the therapeutic use of the calcimimetic agent cinacalcet in the treatment of primary and secondary hyperparathyroidism is discussed. The recent introduction of a novel, long-acting testosterone formulation (testosterone undecanoate) which only requires one intramuscular injection every 3 months, together with the already available hydroalcoholic testosterone gels, appear to be promising alternatives to the previous standard substitution therapy for male hypogonadism. Recently, the mineralocorticoid hormone aldosterone has gained much interest due to its central pathophysiological role in secondary hypertension and its potential deleterious role as a cardiovascular risk factor in nonepithelial target tissues. In this context, the therapeutic potential of a new selective mineralocorticoid receptor antagonist, eplerenone, will be ventilated. In addition, (18)F-DOPA positron emission tomography ((18)F-DOPA-PET), a new functional imaging modality for the diagnostic localization of chromaffin tumors, will be presented and the role of the somatostatin receptor radionuclide therapy with (90)Y-[DOTA](0)-Tyr(3)-octreotide ((90)Y-DOTATOC) for the treatment of advanced neuroendocrine tumors discussed. Furthermore, the ongoing controversy about the diagnosis and treatment of subclinical hypothyroidism will be summarized.

Topics: Adrenal Gland Neoplasms; Adult; Bone Density Conservation Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Clinical Trials as Topic; Endocrinology; Eplerenone; Female; Humans; Hyperaldosteronism; Hyperparathyroidism; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Hypogonadism; Hypothyroidism; Male; Naphthalenes; Neuroendocrine Tumors; Organometallic Compounds; Osteoporosis, Postmenopausal; Pheochromocytoma; Positron-Emission Tomography; Pregnancy; Radiography, Abdominal; Spironolactone; Teriparatide; Testosterone; Testosterone Congeners; Thiophenes; Time Factors; Tomography, X-Ray Computed

The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls.

Topics: Adrenal Hyperplasia, Congenital; Adrenalectomy; Adrenocortical Adenoma; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diagnosis, Differential; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Risk Factors; Spironolactone

Aldosterone antagonists have been available for many decades for the treatment of hypertension, but their use has been mostly limited to patients with classic primary aldosteronism or to combination products with hydrochlorothiazide to minimize risk for hypokalemia. Recently, indications for aldosterone antagonists have been expanded to include congestive heart failure and first-line treatment of mild-to-moderate hypertension. In addition, we have reported that spironolactone has significant antihypertensive benefit when added to existing regimens in patients with resistant hypertension. This benefit was present in patients with and without hyperaldosteronism and was additive to chronic renin-angiotensin blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Eplerenone, a selective aldosterone antagonist, avoids the androgen and progesterone receptor-related adverse events that sometimes occur with spironolactone, such as breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. In clinical trials, eplerenone has been shown to have antihypertensive benefit in treating mild-to-moderate hypertension similar to other widely used classes of agents. With recent demonstrations of benefit in multiple segments of the hypertensive population, aldosterone antagonists represent emerging opportunity for controlling high blood pressure.

Topics: Eplerenone; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Hyperaldosteronism in its various forms is a recognized secondary cause of hypertension, yet the frequency of these disorders and the appropriate evaluation of suspected patients remain controversial. This review will summarize recent literature concerning the frequency of hyperaldosteronism in the hypertensive population, insight from uncommon forms of hyperaldosteronism, and new developments in the diagnosis and treatment of this condition.. Several series report that around 10% of hypertensive patients have some form of hyperaldosteronism, but aldosterone-producing adenomas are rare. Diagnostic criteria for idiopathic hyperaldosteronism remain controversial, as is the wisdom of widespread screening. Patients with even mild hyperaldosteronism, however, which could be a continuum with low-renin hypertension, may respond exceptionally well to mineralocorticoid antagonism. Eplerenone, a new mineralocorticoid receptor antagonist without antiandrogen side effects, has been an effective antihypertensive in clinical trials and appears to be particularly suitable for low-renin hypertensives. Accumulating evidence suggests that aldosterone excess is cardiotoxic and nephrotoxic, suggesting that mineralocorticoid blockade has specific benefits beyond blood pressure reduction. For patients with severe, confirmed hyperaldosteronism, selective adrenal vein sampling is the only reliable method for determining the source of the aldosterone.. Hyperaldosteronism, when defined with liberal criteria, could account for a substantial portion of hypertension. Few of these patients will harbor adrenal adenomas, but those with severe hypertension and hypokalemia often require adrenal vein sampling to direct surgery. With more precise diagnostic strategies, better treatments, and evolving evidence of pathological consequences of aldosterone excess, subtle disorders of aldosterone excess demand precise definition and specific treatment.

Topics: Eplerenone; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Hypertension; Incidence; Male; Renin-Angiotensin System; Risk Assessment; Severity of Illness Index; Spironolactone; Treatment Outcome

Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT). Patients were 1:1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or placebo for 8 weeks. Second, we measured the ARR in 4 PA patients from the Graz Endocrine Causes of Hypertension Study (GECOH) before and after MR blocker treatment. Ninety-seven participants completed the EPATH trial, and the mean treatment effect (95% confidence interval) for log(e)ARR was 0.08 (-0.32 to 0.48) ng/dl/μU/ml (p=0.694). The treatment effect was 0.71 (0.47 to 0.96; p<0.001) ng/dl for log(e)PAC and 0.64 (0.19 to 1.10; p=0.006) μU/ml for log(e)DRC, respectively. In the 4 PA patients, the ARR decreased from 11.24±3.58 at baseline to 2.70±1.03 (p=0.013) ng/dl/μU/ml after MR blocker treatment. In this study with limited sample size, MR blocker treatment did not significantly alter the ARR in pHPT patients but significantly reduced the ARR in PA patients. Diagnostic utility of ARR and its components for PA diagnostics under MR blocker treatment warrants further study.

Topics: Aged; Aldosterone; Double-Blind Method; Eplerenone; Female; Humans; Hyperaldosteronism; Hyperparathyroidism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin; Spironolactone; Time Factors

The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25-100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated.

Topics: Adult; Aged; Blood Pressure; Eplerenone; Female; Humans; Hyperaldosteronism; Kidney Function Tests; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone

Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce.. This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; n=86); spironolactone (n=65); and eplerenone (n=18)).. GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications.. Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

Topics: Adrenalectomy; Adult; Aged; Aged, 80 and over; Albuminuria; Blood Pressure; Creatinine; Eplerenone; Female; Glomerular Filtration Rate; Humans; Hyperaldosteronism; Kidney; Kidney Function Tests; Male; Middle Aged; Prospective Studies; Spironolactone

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); P<0.001]. 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.

Topics: Adult; Antihypertensive Agents; Double-Blind Method; Eplerenone; Female; Humans; Hyperaldosteronism; Male; Middle Aged; Placebos; Quality of Life; Spironolactone

The aim of this prospective, randomised, open-label, blinded-end point study was to compare the efficacy and safety of eplerenone versus spironolactone in patients with bilateral idiopathic hyperaldosteronism (IHA). After a 2-week washout period, 34 patients with IHA were assigned to receive either spironolactone 25 mg b.i.d. (n = 17) or eplerenone 25 mg b.i.d. (n = 17) for 24 weeks. If the patients' blood pressure (BP) was not < 140/90 mmHg, the doses were gradually increased up to 400 mg for spironolactone and 200 mg for eplerenone. If the patients' BP remained uncontrolled, a daily dose of hydrochlorothiazide 12.5 mg was added at week 16. The primary outcome was the percentage of patients with BP < 140/90 mmHg at 16 weeks (i.e., with aldosterone antagonist monotherapy). The patients' BP was normalised in 13 out of 17 (76.5%) and 14 out of 17 (82.4%) patients in the spironolactone and eplerenone groups, respectively (p = 1.00). Systolic BP decreased more rapidly with eplerenone. Serum potassium levels were normalised (> 3.5 mmol/l) in all patients at 4 weeks. Mild hyperkalaemia was observed in two patients receiving 400 mg of spironolactone and in three patients receiving 150 mg of eplerenone. Two patients presented with bilateral painful gynaecomastia at the end of week 16 while receiving 400 mg of spironolactone. Switching spironolactone to 150 mg of eplerenone daily resulted in resolution of gynaecomastia and also maintained BP control. At the end of the study, 19 patients were on eplerenone and 15 were on spironolactone. However, this did not affect the primary end point, because the switch from spironolactone to eplerenone (in two patients) occurred at the end of week 16. It was concluded that eplerenone was as effective as spironolactone in reducing BP in patients with IHA. The risk of mild hyperkalaemia was similar with both drugs.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Eplerenone; Female; Gynecomastia; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Hypokalemia; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Prospective Studies; Spironolactone; Time Factors; Treatment Outcome

Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist.. The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks.. There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered.

Topics: Adult; Agoraphobia; Eplerenone; Female; Humans; Hyperaldosteronism; Hypertension; Panic Disorder

Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy.. A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment.. Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Antihypertensive Agents; Bisoprolol; Eplerenone; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged

The aim of our study was to evaluate the adherence to mineralocorticoid receptor (MR) antagonists and other antihypertensive therapy and blood pressure control in conservatively treated patients with primary aldosteronism (PA).. Conservatively treated subjects with previously confirmed PA (n-50, 64.5 ± 9 years of age, 24% women) were investigated. Good blood pressure control was detected (mean 24 h systolic/diastolic BP 130 ± 12/77 ± 9 mmHg). The average number of antihypertensive drugs was 3.9 ± 1.5. All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 ± 20 mg) and in the remaining 56% of subjects eplerenone was administered (average daily dose 80 ± 30 mg) due to spironolactone side effects. Assessment of antihypertensive drug concentrations revealed full adherence in 80% of all subjects, partial nonadherence was noted in the remaining 20% of subjects. MR antagonist levels were detected in almost all subjects (49 out of 50).. Good blood pressure control and adherence to therapy were detected in conservatively treated patients with PA. Eplerenone had to be used quite often as male subjects did not tolerate dose escalation due to spironolactone side effects.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Eplerenone; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone

Primary aldosteronism (PA) is associated with a high risk of cardiovascular complications. Large-scale clinical studies have demonstrated that mineralocorticoid receptor antagonists (MRA) exhibit organ-protective effects and improve the prognosis of patients with heart failure and myocardial infarction, and daily clinical practice suggests that MRA seem to improve vascular endothelial dysfunction. In this pilot study, we treated 10 PA patients with eplerenone for 3 months. We used Endo-PAT to evaluate the effects of MRA on vascular endothelial function and analyzed the data for correlative factors. The primary outcome measure, the reactive hyperemia index (RHI), was 1.71 before therapy and increased significantly to 2.21. Univariate analysis showed a significant correlation between the rate of change in RHI and that in plasma renin activity (PRA). Since plasma aldosterone concentration increases during MRA therapy, PRA may be the best marker for selecting the most appropriate dose of MRA. PRA can potentially be used for adjusting the dose of MRA, in addition to adjusting blood pressure and serum potassium level.

Topics: Eplerenone; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Pilot Projects

BACKGROUND When mineralocorticoid receptor antagonist therapy is initiated for primary aldosteronism, the response of plasma renin activity indicates the level of cardiovascular risk. The purpose of this article was to compare the effect of mineralocorticoid receptor blockers on plasma renin activity levels in a patient with primary aldosteronism. CASE REPORT The patient was a 45-year-old male with severe hypertension. Because his aldosterone/renin ratio was high and a saline infusion test was positive, primary aldosteronism was diagnosed. Computed tomography revealed a low-density mass measuring 10 mm in the left adrenal gland. Segmental adrenal vein sampling demonstrated bilateral primary aldosteronism, so pharmacotherapy was started. Before treatment, his plasma renin activity was 0.5 ng/mL/hour. Eplerenone was commenced and the dose was increased to 100 mg/day. However, his plasma renin activity was still 0.8 ng/mL/hour and the maximum dose of eplerenone did not elevate plasma renin activity above 1 ng/mL/hour. Since plasma renin activity remained below 1 ng/mL/hour with mineralocorticoid receptor antagonist therapy, this patient was considered to have a higher cardiovascular risk than patients with essential hypertension. Accordingly, eplerenone was switched to esaxerenone, a new generation mineralocorticoid receptor blocker that became available in May 2019. After switching to esaxerenone (5 mg/day), the patient's plasma renin activity increased to 1.8 ng/mL/hour and subsequently remained at 1 ng/mL/hour or higher. CONCLUSIONS This is the first case report to present interesting changes of plasma renin activity in a primary aldosteronism patient after switching from eplerenone to esaxerenone. Elevation of plasma renin activity by esaxerenone in our primary aldosteronism patient reflected a mineralocorticoid receptor antagonistic effect that may have alleviated excessive mineralocorticoid receptor activation and volume expansion.

Topics: Eplerenone; Humans; Hyperaldosteronism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pyrroles; Renin; Renin-Angiotensin System; Sulfones

It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA).. The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA.. Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA.. Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters.. Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Adenoma; Adult; Aldosterone; Blood Pressure; Endothelium, Vascular; Eplerenone; Female; Humans; Hyperaldosteronism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Nitroglycerin; Vasodilation

Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA).. Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA.. After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 ± 0.25 to 0.69 ± 0.25 (P < 0.01) and NID from 12.8 ± 5.8 to 14.9 ± 6.9% (P = 0.02) and it decreased baPWV from 1540 ± 263 to 1505 ± 281 (P = 0.04) and ROCK activity from 1.20 ± 0.54 to 0.89 ± 0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 ± 3.4 to 4.6 ± 3.6%, P = 0.99) or brachial IMT (decrease from 0.28 ± 0.07 to 0.28 ± 0.04 mm, P = 0.14).. Eplerenone improves microvascular endothelial function, vascular smooth muscle function, arterial stiffness and ROCK activity in patients with IHA.. URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

Topics: Adult; Aldosterone; Ankle Brachial Index; Antihypertensive Agents; Blood Pressure; Brachial Artery; Endothelium, Vascular; Eplerenone; Female; Humans; Hyperaldosteronism; Hyperemia; Hypertension; Male; Microvessels; Middle Aged; Nitroglycerin; Pilot Projects; Pulse Wave Analysis; Renin; rho-Associated Kinases; Ultrasonography; Vascular Stiffness; Vasodilation; Vasodilator Agents

Objective Eplerenone (EPL) is a mineralo-corticoid receptor antagonist that is highly selective and has few side effects. This study was conducted to examine whether or not EPL treatment was able to reverse glomerular hyperfiltration, as an indicator of aldosterone renal action, in primary aldosteronism (PA) patients. Methods Changes in the estimated glomerular filtration rate (ΔGFR) were examined in 102 PA patients with EPL treatment. Furthermore, the sequential ΔGFR in 40 patients initially treated with EPL followed by adrenalectomy was examined in order to evaluate the extent of the remaining glomerular hyperfiltration in the patients treated with EPL. Results EPL decreased the GFR at 1 month after treatment. The GFR at baseline was the sole significant predictor for the ΔGFR. Patients initially treated by EPL followed by adrenalectomy showed three different ΔGFR patterns during the treatment, despite having comparable doses of EPL and comparable control of blood pressure and serum potassium levels. The urinary aldosterone excretion was significantly different among these three groups, and the group with no decrease in the GFR after EPL treatment showed greater urinary aldosterone excretion. Glomerular hyperfiltration was completely restored only in 17.5% of our unilateral PA patients after EPL treatment. Conclusion The present study revealed that blockade of aldosterone action by EPL could, at least partially, reverse glomerular hyperfiltration in PA. Whether or not these differential effects on the GFR affect the long-term outcome needs to be investigated, especially in patients with unilateral PA who do not want adrenalectomy and choose the EPL treatment option.

Topics: Adrenalectomy; Adult; Blood Pressure; Drug Administration Schedule; Eplerenone; Female; Glomerular Filtration Rate; Humans; Hyperaldosteronism; Kidney Glomerulus; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Preoperative Care; Retrospective Studies; Spironolactone

Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA.

Topics: Adrenalectomy; Adult; Aged; Aldosterone; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Drug Monitoring; Eplerenone; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Japan; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Reproducibility of Results; Risk; Spironolactone

The kidney is the primary organ ensuring K(+) homeostasis. K(+) is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K(+) channel (Kir1.1) and by the Ca(2+)-activated K(+) channel (KCa1.1). Here, we report a novel knockout mouse of the β2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K(+) excretion. KCNMB2(-/-) mice displayed hyperaldosteronism, normal plasma K(+) concentration, and produced dilute urine with decreased K(+) concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2(-/-) mice. Renal K(+) excretion rates were similar in the two genotypes; however, KCNMB2(-/-) mice required elevated plasma aldosterone to achieve K(+) balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K(+) excretion in KCNMB2(-/-) mice. Knockout mice for the α-subunit of the KCa1.1 channel (KCNMA1(-/-) mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K(+) secretion. KCNMB2(-/-) mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1(-/-) mice but were normotensive and displayed intact flow-induced K(+) secretion. Despite elevated plasma aldosterone, KNCMB2(-/-) mice did not display salt-sensitive hypertension and were able to decrease plasma aldosterone on a high-Na(+) diet, although plasma aldosterone remained elevated in KCNMB2(-/-) mice. In summary, KCNMB2(-/-) mice have a reduced ability to excrete K(+) into the urine but achieve K(+) balance through an aldosterone-mediated, β2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1(-/-) mice.

Topics: Aldosterone; Animals; Blood Pressure; Epithelial Sodium Channels; Eplerenone; Female; Hyperaldosteronism; Kidney; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Male; Mice, Inbred C57BL; Mice, Knockout; Polyuria; Potassium; Sodium, Dietary; Solute Carrier Family 12, Member 3; Spironolactone

Spironolactone, which is a potent mineralocorticoid receptor antagonist, represents the first line medical treatment of primary aldosteronism (PA). As spironolactone is also an antagonist of the androgen and progesterone receptor, it may present side effects, especially in male patients. In case of intolerance to spironolactone, amiloride may be used to control hypokaliemia and we suggest that eplerenone, which is a more selective but less powerful antagonist of the mineralocorticoid receptor, be used in case of intolerance to spironolactone and insufficient control of hypertension by amiloride. Specific calcic inhibitors and thiazide diuretics may be used as second or third line therapy. Medical treatment of bilateral forms of PA seem to be as efficient as surgical treatment of lateralized PA for the control of hypertension and the prevention of cardiovascular and renal morbidities. This allows to propose medical treatment of PA to patients with lateralized forms of PA who refuse surgery or to patients with PA who do not want to be explored by adrenal venous sampling to determine whether they have a bilateral or lateralized form.

Topics: Eplerenone; Female; France; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Topics: Aldosterone; Eplerenone; Gynecomastia; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Meta-Analysis as Topic; Mineralocorticoid Receptor Antagonists; Spironolactone

Primary aldosteronism (PA), the most common form of secondary hypertension, causes relevant morbidity. The value of salivary measurements of aldosterone in clinical routine in PA so far has not been assessed. First, we analyzed salivary and plasma aldosterone concentrations of 42 patients with PA and 37 hypertensive controls (HC) during a sodium infusion test prospectively. Second, morning salivary and plasma aldosterone concentrations as well as diurnal saliva aldosterone profiles were analyzed in 115 patients treated for PA (46 adrenalectomy, 56 spironolactone, 13 eplerenone). Salivary aldosterone was substantially elevated in PA patients compared to HC at baseline (106±119 vs. 40±21 ng/l, p=0.01), and after 4-h sodium infusion test (60±36 vs. 23±14, p=0.01). Positive correlation between salivary and plasma aldosterone levels was evident, with exception of concentrations in or below the lower normal range. Applying a salivary aldosterone cutoff of 51.2 ng/l, found by ROC curve analysis, rendered a sensitivity of 81% and a specificity of 73% for PA. The diurnal rhythm of aldosterone was preserved in untreated PA patients, but concentrations were higher in the context of PA, and normalized after surgery (118±57 vs. 31±18 ng/l, p<0.01). Taken together, salivary aldosterone measurements correlate with plasma levels, allowing simple and cost effective assessments of aldosterone secretion in an outpatient setting. Nevertheless, as this method alone cannot replace other plasma parameters, and as aldosterone profiling would not alter diagnostic or treatment strategies, salivary aldosterone measurements in routine practice are of limited clinical value.

Topics: Adrenalectomy; Aged; Aldosterone; Case-Control Studies; Circadian Rhythm; Eplerenone; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Prognosis; Prospective Studies; Retrospective Studies; Saliva; Spironolactone

Spironolactone is often used to treat hypertension caused by hyperaldosteronism, and as a result, can form concentrically laminated electron dense spironolactone body inclusions within the adrenal gland. Spironolactone bodies have not been investigated in a contemporary cohort or in patients treated with the more recently approved aldosterone antagonist, eplerenone.. Spironolactone bodies were retrospectively investigated in patients treated for hyperaldosteronism (n=15) from 2012-2013 that underwent a subsequent adrenalectomy.. Inclusions were identified in 33% of patients treated with aldosterone antagonists, far less than previously reported. Remarkably, 50% of patients treated with spironolactone had inclusions while no patients using eplerenone alone had inclusions. Two patients treated with spironolactone had bodies present longer than the duration described in prior studies. Inclusions unexpectedly persisted in 1 patient despite increased duration of discontinued pharmacological treatment. A spectrum of histologic and ultrastructural findings were encountered within an adrenal cortical adenoma from a patient treated with both spironolactone and eplerenone. Ultrastructural examination revealed laminated electron dense bodies with the appearance of classic spironolactone inclusions as well as electron dense bodies without laminations and laminated bodies without electron dense cores.. Our incidence rate of spironolactone bodies was much lower than previously reported, with no inclusions seen in patients treated solely with the newer aldosterone antagonist, eplerenone. Pathologists should be aware of these infrequently encountered inclusions, particularly as the clinical history of hyperaldosteronism and pharmacologic treatment may not be provided.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4597918761268031.

Topics: Adrenal Glands; Adrenalectomy; Adult; Aged; Eplerenone; Female; Humans; Hyperaldosteronism; Hypertension; Incidence; Inclusion Bodies; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Retrospective Studies; Spironolactone

Primary aldosteronism (PA) is one of the commonest forms of curable hypertension, and use of the plasma aldosterone-to-renin ratio as a screening test has led to a more efficient identification of this condition. Both animal and human studies have indicated that PA is associated with a variety of cardiovascular and renal complications that reflect the capability of elevated aldosterone to induce tissue damage exceeding that induced by hypertension itself. Involvement of the kidney in PA is highly relevant because structural renal damage is associated with less favorable outcome, both in terms of blood pressure response to treatment and possibility to develop progressive renal failure. However, early involvement of the kidney in PA is characterized by functional changes that are largely reversible with treatment. Unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adenoma or idiopathic adrenal hyperplasia. Both treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that both surgery and medical treatment are of considerable value.

Topics: Eplerenone; Female; Humans; Hyperaldosteronism; Kidney; Male; Spironolactone

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Adenoma; Adult; Eplerenone; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Pregnancy; Pregnancy Complications; Spironolactone; Treatment Outcome

Primary aldosteronism (PA) patients display an increased incidence of insulin resistance. Herein we demonstrate the decreased gene expression of lipid metabolism genes PCK1, PLIN, ADIPOQ and PPARG in the visceral adipose tissue (VAT) of PA patients compared to age-, sex- and BMI-matched controls. In VAT, the expression of PCK1, PLIN, ADIPOQ and PPARG was inversely correlated with aldosterone levels; furthermore, PLIN and ADIPOQ gene expression was correlated with potassium levels. Therefore, raised aldosterone and low potassium may contribute to the reduced expression of these genes in PA patients. Finally, incubation of primary cultures of human adipocytes with aldosterone resulted in a decrease in the expression of PCK1, PLIN and ADIPOQ and this effect was blocked by eplerenone. Therefore, the characteristic aldosterone excess of PA patients may mediate the down-regulation of PCK1, PLIN and ADIPOQ in VAT that in turn may contribute to the insulin resistance observed in PA patients.

Topics: Adipocytes; Adiponectin; Adult; Aged; Aldosterone; Carrier Proteins; Cells, Cultured; Down-Regulation; Eplerenone; Female; Gene Expression; Humans; Hyperaldosteronism; Insulin Resistance; Intra-Abdominal Fat; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Perilipin-1; Phosphoenolpyruvate Carboxykinase (GTP); Phosphoproteins; Potassium; PPAR gamma; Spironolactone

The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-β1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4).

Topics: Aldosterone; Animals; Animals, Newborn; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Pressure; Blotting, Western; Bone Morphogenetic Protein 4; Cells, Cultured; Cytochrome P-450 CYP11B2; Eplerenone; Female; Fibrosis; Galectin 3; Gene Expression; Hyperaldosteronism; Hypertension; Male; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Myocardium; Natriuretic Peptide, Brain; Organ Size; Renin; Reverse Transcriptase Polymerase Chain Reaction; Spironolactone

Hyperaldosteronism is associated with vascular injury and increased cardiovascular events. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in endothelial repair and vascular homeostasis. We hypothesized that hyperaldosteronism impairs EPC function and vascularization capacity in mice and humans.. We characterized the effects of aldosterone and mineralocorticoid receptor (MR) blockade on EPC number and function as well as vascularization capacity and endothelial function. Treatment of human EPC with aldosterone induced translocation of the MR and impaired multiple cellular functions of EPC, such as differentiation, migration, and proliferation in vitro. Impaired EPC function was rescued by pharmacological blockade or genetic ablation of the MR. Aldosterone protein kinase A (PKA) dependently increased reactive oxygen species formation in EPC. Aldosterone infusion in mice impaired EPC function, EPC homing to vascular structures and vascularization capacity in a MR-dependent but blood pressure-independent manner. Endothelial progenitor cells from patients with primary hyperaldosteronism compared with controls of similar age displayed reduced migratory potential. Impaired EPC function was associated with endothelial dysfunction. MR blockade in patients with hyperaldosteronism improved EPC function and arterial stiffness.. Endothelial progenitor cells express a MR that mediates functional impairment by PKA-dependent increase of reactive oxygen species. Normalization of EPC function may represent a novel mechanism contributing to the beneficial effects of MR blockade in cardiovascular disease prevention and treatment.

Topics: Aldosterone; Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Endothelial Cells; Endothelium, Vascular; Eplerenone; Female; Humans; Hyperaldosteronism; Male; Mice; Middle Aged; Mineralocorticoid Receptor Antagonists; Reactive Oxygen Species; Receptors, Mineralocorticoid; Spironolactone; Stem Cells; Vasodilation

Resistant hypertension has evolved as an important global health care problem. Primary aldosteronism is one of several potentially reversible causes of resistant hypertension. Primary aldosteronism can be effectively treated, when recognized, with a mineralocorticoid receptor antagonist, such as spironolactone and eplerenone. Each of these compounds can reduce blood pressure as monotherapy or when given with a range of other antihypertensive drug classes. These compounds have distinctive pharmacokinetic and pharmacodynamic patterns that require some forethought in their use before they are prescribed. However, as the use of mineralocorticoid-blocking agents has gradually increased, the hazards inherent to use of such drugs has become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove fatal if sufficient degrees of hyperkalemia develop. However, for most patients the risk of developing hyperkalemia in and of itself should not discourage the prudent clinician from bringing these compounds into play. Hyperkalemia should always be considered as a likelihood in any patient receiving one or the other of these medications. As such, steps should be taken to lessen the likelihood of it occurring if therapy is being contemplated with agents in this class.

Topics: Aldosterone; Eplerenone; Female; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Spironolactone

Mice lacking the beta1-subunit (gene, Kcnmb1; protein, BK-beta1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-beta1 is an ancillary subunit. However, the beta1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1(-/-) has a renal origin. We found that Kcnmb1(-/-) are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1(-/-) with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1(-/-) under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1(-/-) is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.

Topics: Analysis of Variance; Animals; Eplerenone; Hyperaldosteronism; Hyperkalemia; Hypertension; Kidney Tubules, Collecting; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Mice; Mice, Knockout; Potassium; Spironolactone

It is now widely recognized that primary aldosteronism (PA) is much more common than previously thought, accounting for up to 5-10% of hypertensives, and that aldosterone excess has adverse cardiovascular consequences that go above and beyond hypertension development. These findings have precipitated a marked resurgence of research activity, most of which has supported the concept that PA plays an important role in cardiovascular disease states and should be systematically sought and specifically treated, and the development of an Endocrine Society clinical guideline for the case detection, diagnosis, and management of this common, specifically treatable, and potentially curable condition. Areas of recent, topical research include: 1) the demonstration of excess morbidity in patients with PA compared with other forms of hypertension, confirming the clinical relevance of non-blood pressure-dependent adverse effects of aldosterone excess; 2) the further demonstration that this excess morbidity and mortality are ameliorated with specific (but not nonspecific antihypertensive) therapy directed against aldosterone excess, confirming the importance of detection and diagnosis of PA to enable optimal specific management; 3) the development of new treatment strategies; 4) an ongoing appraisal and refinement of diagnostic approaches including screening, subtype differentiation, and new assay development; and 5) further insights into the importance and nature of genetic factors related to the development of PA.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Aldosterone; Amiloride; Antihypertensive Agents; Chromosomes, Human, Pair 7; Cytochrome P-450 CYP11B2; Diagnosis, Differential; Drug Administration Schedule; Eplerenone; Genetic Linkage; Glucocorticoids; Humans; Hyperaldosteronism; Hypertension; Lod Score; Mineralocorticoid Receptor Antagonists; Spironolactone

Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism.. The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration.. Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations.. Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes.. We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.

Topics: Algorithms; Catheterization; Combined Modality Therapy; Cosyntropin; Diagnostic Techniques, Endocrine; Eplerenone; Hormone Replacement Therapy; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Reproducibility of Results; Spironolactone

Since the introduction of the aldosterone-to-renin ratio (ARR ) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive subjects. A meta-analysis from the literature shows a PA prevalence of almost 8% among hypertensive patients, with a twofold higher prevalence in referred patients as compared with primary care patients (9.0 vs 4.3%). However, the usefulness of the ARR remains subject of debate, because of doubts on its validity, and the many factors affecting the ARR , including posture, time of day of blood sampling, and use of antihypertensive medication. Furthermore, there is no clear cut-off value and it is unknown what population should be screened. Recently, The Dutch ARR AT Study was initiated. This is a multicentre, prospective trial aiming to evaluate the test characteristics of the ARR within a Dutch population of therapy-resistant hypertensive patients. The effect of antihypertensive medication on the ARR will be studied. Furthermore, from this study the prevalence of PA in this population will follow. Last, the blood pressure response to the selective aldosterone-receptor-antagonist eplerenone will be evaluated. The Dutch ARR AT Study will run until the end of 2009 and will contribute to the formulation of uniform guidelines for the screening for PA in the Netherlands.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Drug Resistance; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Mass Screening; Mineralocorticoid Receptor Antagonists; Netherlands; Prevalence; Renin-Angiotensin System; Risk Factors; Spironolactone

Topics: Administration, Oral; Aldosterone; Clinical Trials as Topic; Eplerenone; Gynecomastia; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin; Sex Factors; Spironolactone

The prevalence of primary hyperaldosteronism (PHA) in the hypertensive population has increased in recent years. Glucocorticoid-remediable aldosteronism (GRA) is a rare monogenic form of PHA. Here we report a German family with GRA. Since the phenotype of GRA varies widely, we asked whether recommended algorithms for PHA diagnosis distinguish GRA from other forms of PHA.. Plasma aldosterone (pg/ml) and renin (pg/ml) levels were determined in three hypertensive family members with GRA before and after sodium loading with 2 l of saline (0.9%), during posture and after 1 week of 2 mg dexamethasone daily. 24 h blood pressure and urinary excretion of aldosterone, cortisol precursors and metabolites were measured before and after dexamethasone. Southern blot hybridization and long-range PCR were performed to identify the chimeric gene.. All three affected patients had normal potassium levels but markedly increased aldosterone/renin ratios of 472, 213 and >322 (normal range<50) indicating PHA. Sodium loading failed to lower plasma aldosterone below the threshold of 50 pg/ml in all patients. During posture, aldosterone increased in one but decreased in both other GRA patients. Elevated 18-hydroxycortisol, free aldosterone and its main metabolite aldosterone-18-glucuronid and tetrahydroaldosterone returned to normal range after 1 week dexamethasone in all patients, but blood pressure was reduced only in one patient. The chimeric gene was identified in affected family members by Southern blot and PCR.. The aldosterone/renin ratio is a valid screening and sodium loading a valid confirmation test in GRA. Determination of elevated urinary excretion of specific aldosterone metabolites and identification of the chimeric gene are mandatory since a lacking blood pressure response to dexamethasone can be misleading.

Topics: Adolescent; Aldosterone; Algorithms; Blood Pressure; Dexamethasone; Eplerenone; Female; Germany; Glucocorticoids; Humans; Hydrocortisone; Hyperaldosteronism; Male; Middle Aged; Molecular Sequence Data; Pedigree; Sodium; Spironolactone; Steroid 11-beta-Hydroxylase

Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na+-K+ pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na+-K+ pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na+-K+ pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na+-K+ pump current (I(p)), arising from the 3:2 Na+:K+ exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I(p); treatment with losartan reversed aldosterone-induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I(p) at near physiological levels of intracellular Na+ concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Eplerenone; Heart Ventricles; Hyperaldosteronism; Losartan; Magnesium; Male; Membrane Potentials; Mineralocorticoid Receptor Antagonists; Patch-Clamp Techniques; Potassium; Rabbits; Sodium; Sodium-Potassium-Exchanging ATPase; Spironolactone; Ventricular Function

Previous studies have demonstrated the development of cardiac fibrosis in aldosterone (Aldo)-salt hypertensive rats. Our aim was to determine the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on in vivo mechanical properties of the carotid artery using echo-tracking system.. Aldo was administered (1 microg/h) in uninephrectomized Sprague-Dawley rats (SD) receiving a high-salt diet from 8 to 12 weeks of age. Uninephrectomized control SD rats received a normal salt diet without Aldo. Three groups of Aldo-salt rats were treated with 1, 10, or 30 mg/kg(-1) x d(-1) of Epl by gavage. Elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The structure of the arterial wall was analyzed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo produced increased systolic arterial pressure, pulse pressure, Einc, MCSA, and EIIIA Fn with no change in wall stress or elastin and collagen densities compared with controls without Aldo. No differences in collagen mRNA levels were detected between groups. Epl blunted the increase in pulse pressure in Aldo rats and normalized Einc-wall stress curves, MCSA, and EIIIA Fn. These effects were dose dependent and not accompanied by a reduction in wall stress.. Aldo is able to increase arterial stiffness associated with Fn accumulation, independently of wall stress. The preventive effects of Epl suggest a direct role for mineralocorticoid receptors in mechanical and structural alterations of large vessels in rat hyperaldosteronism.

Topics: Aldosterone; Animals; Blood Pressure; Blotting, Northern; Carotid Arteries; Collagen; Collagen Type I; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Elasticity; Elastin; Eplerenone; Fibronectins; Hyperaldosteronism; Immunohistochemistry; Injections, Subcutaneous; Male; Mineralocorticoid Receptor Antagonists; Nephrectomy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium, Dietary; Spironolactone; Ultrasonography; Vascular Patency