Pleiotropic actions of aldosterone and the effects of eplerenone, a selective mineralocorticoid receptor antagonist.

Aldosterone plays an important role in the pathogenesis of cardiovascular and renal disease that is independent of angiotensin II. Mineralocorticoid receptors are expressed in nonepithelial tissues such as the heart and blood vessels. Although mineralocorticoid receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific mineralocorticoid receptor antagonist, spironolactone, have limited its usefulness in the treatment of cardiovascular diseases. This review examines the expanding role of aldosterone, including its broad spectrum of non-classical effects, and the recent clinical and experimental trials with the selective mineralocorticoid receptor antagonist, eplerenone.     

Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post‐infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co‐morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence‐based approach with personalized medicine.     

Adrenocorticotrophin-induced hypertension: effects of mineralocorticoid and glucocorticoid receptor antagonism

OBJECTIVE: To examine whether the increase of blood pressure in adrenocorticotrophin-treated rats is mediated through mineralocorticoid or glucocorticoid receptors or corticosterone 6 beta-hydroxylation inhibition. DESIGN: Rats were randomly allocated to 14 treatment groups for 10 days. The treatments included sham injection (n = 35), adrenocorticotrophin (5, 100, 500 micrograms/kg per day, subcutaneously, n = 5, 15 and 15, respectively), spironolactone (100 mg/kg per day, subcutaneously, n = 15), standard-dose or high-dose RU 486 (70 mg/kg every 3 days or 70 mg/kg per day, subcutaneously, n = 5 and 10, respectively), spironolactone + adrenocorticotrophin (100 micrograms/kg per day, n = 5, or 500 micrograms/kg per day, n = 10), standard-dose RU 486 + adrenocorticotrophin (500 micrograms/kg per day, n = 5), high-dose RU 486 + adrenocorticotrophin (100 micrograms/kg per day, n = 10), troleandomycin (40 mg/kg per day, subcutaneously, n = 5) and troleandomycin + adrenocorticotrophin (5 micrograms/kg per day, n = 5). Systolic blood pressure and metabolic parameters were measured every second day. RESULTS: Adrenocorticotrophin treatment increased systolic blood pressure dose-dependently (5 micrograms/kg per day: +14 +/- 2 mmHg; 100 micrograms/kg per day: +20 +/- 2 mmHg; 500 micrograms/kg per day: +28 +/- 2 mmHg, all P < 0.001). Adrenocorticotrophin at 100 and 500 micrograms/kg per day increased plasma sodium and decreased plasma potassium concentrations. Spironolactone did not block adrenocorticotrophin-induced systolic blood pressure changes but did block changes in plasma sodium and potassium levels. Standard-dose RU 486 did not modify the adrenocorticotrophin-induced (500 micrograms/kg per day) systolic blood pressure rise but blocked the effect of adrenocorticotrophin on body weight. High-dose RU 486 partially blocked the adrenocorticotrophin-induced (100 micrograms/kg per day) systolic blood pressure increase (adrenocorticotrophin at 100 micrograms/kg per day: 143 +/- 3 mmHg; high-dose RU 486 + adrenocorticotrophin at 100 micrograms/kg per day: 128 +/- 5 mmHg, P < 0.001) and body-weight loss. Troleandomycin did not alter the development of adrenocorticotrophin-induced hypertension. CONCLUSIONS: Spironolactone and standard-dose RU 486 did not modify adrenocorticotrophin-induced hypertension despite demonstrable antimineralocorticoid and antiglucocorticoid actions. High-dose RU 486 partially blocked adrenocorticotrophin-induced (100 micrograms/kg per day) hypertension, suggesting either a permissive effect of glucocorticoid on blood pressure or other antihypertensive actions of RU 486. Inhibition of glucocorticoid 6 beta-hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6 beta-hydroxylation in adrenocorticotrophin-induced hypertension are negligible.     

Fibrates for treatment of the metabolic syndrome

The National Cholesterol Education Program Adult Treatment Panel III has provided a clinical definition for the metabolic syndrome that is practical for use in an office setting. Identification and treatment of the metabolic syndrome is of enormous public health importance because it is associated with a marked elevation in coronary heart disease risk and affects nearly 25% of adults in the United States. First-line therapy is lifestyle modification, which includes body weight reduction, increased physical activity, and moderation of the dietary glycemic load. Drug treatments focusing on the major components of the syndrome (atherogenic dyslipidemia, hypertension, and a prothrombotic state) have demonstrated efficacy for reducing coronary heart disease events. Fibrates seem to be particularly effective in patients for whom a disturbance of the triglyceride-high-density lipoprotein axis is the primary lipid disorder. Fibrates also appear to influence a number of emerging risk factors, including hemostatic and inflammatory markers and indicators of improved vascular wall biology, which may contribute to their cardioprotective effects.     

A number of marketed dihydropyridine calcium channel blockers have mineralocorticoid receptor antagonist activity

Calcium channel blockers are widely used antihypertensives. Mineralocorticoid receptor antagonists are also used to treat hypertension and heart failure. We report here that a number of widely used dihydropyridine class calcium channel blockers are able to inhibit aldosterone-induced activation of mineralocorticoid receptor. These dihydropyridines varied in the extent of their effect on mineralocorticoid receptor, with nimodipine and felodipine the most potent and amlodipine the least. In contrast, both diltiazem and verapamil, nondihydropyridine calcium channel blockers, had no effect on mineralocorticoid receptor. These dihydropyridines compete with aldosterone for binding and block aldosterone-induced coactivator recruitment to mineralocorticoid receptor. The mineralocorticoid receptor S810L mutant, which is activated by steroidal mineralocorticoid receptor antagonist such as eplerenone, is inhibited by these drugs. Furthermore, nimodipine decreased aldosterone-induced expression of the mineralocorticoid receptor target gene epithelial sodium channel gamma subunit in adrenalectomized rats, demonstrating that dihydropyridine calcium channel blockers can function as mineralocorticoid receptor antagonists in vivo. Molecular modeling indicates that dihydropyridines dock into the ligand binding domain of mineralocorticoid receptor in a consensus pose that partially overlaps with steroidal mineralocorticoid receptor antagonists. Together, our data suggest that, in addition to their calcium channel blocking activity, a number of dihydropyridine calcium channel blockers also have mineralocorticoid receptor antagonist activity at high doses, a finding which may thus prove useful for the design of novel antihypertensive drugs in the future.     

Current treatment options for the metabolic syndrome

Optional statement The metabolic syndrome is defined as a condition characterized by a set of clinical criteria: insulin resistance, visceral obesity, atherogenic dyslipidemia, and hypertension. The major risk factors leading to the epidemic of this syndrome in the United States are visceral obesity, physical inactivity, and an atherogenic diet. The available current evidence suggests that the first step in management of patients with metabolic syndrome should be focused on lifestyle modifications (eg, weight loss and physical activity). The treatment should be based on two major components: behavioral change to reduce caloric intake and an increase in physical activity. A realistic goal for weight reduction should be 7% to 10% over 6 to 12 months. The general dietary recommendations include low intake of saturated fats, trans fats and cholesterol, and diets with low glycemic index. Soy protein could be more beneficial than animal protein in weight reduction and correction of dyslipidemia. Physical activity is associated with successful weight reduction and these therapeutic lifestyle changes can reduce by half the progression to new-onset diabetes in patients with metabolic syndrome. Physical activity recommendations should include practical, regular, and moderated regimens of exercise, with a daily minimum of 30 to 60 minutes. An equal balance between aerobic exercise and strength training is advised. Medication therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. There is no single best therapy and the treatment should consist of treatment of individual component(s). Atherogenic dyslipidemia should be controlled with statins if there is concomitant increase in low-density lipoprotein cholesterol and if indicated with combination therapy, including fibrates, nicotinic acid, bile acid-binding resins, or ezetimibe. Drugs such as thiazolidinediones and renin-angiotensin system blockers are a few of the available agents in this category. Some evidence suggests that angiotensin-converting enzyme inhibitors and β blockers are more beneficial for treatment of hypertension in patients with metabolic syndrome. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor agonists, will broaden the horizons of the current treatment options in metabolic syndrome.     

Seaweeds as potential therapeutic interventions for the metabolic syndrome

Seaweeds are a characteristic part of the traditional diet in countries such as Japan and Korea; these countries also have a lower prevalence of metabolic syndrome than countries such as the USA and Australia. This suggests that seaweeds may contain compounds that reduce the characteristic signs of obesity, diabetes, hypertension, fatty liver and inflammation in the metabolic syndrome. Potentially bioactive compounds from seaweeds include polysaccharides, peptides, pigments, minerals and omega-3 fatty acids. This review emphasises current research on these compounds in isolated cells, animal models and patients. Key problems for future research include chemical characterisation of the bioactive principles, defining pharmacological responses in all aspects of the metabolic syndrome, determining if a therapeutic dose has been administered, and defining oral bioavailability of the active ingredients.     

The metabolic syndrome in a Congolese population and its implications for metabolic syndrome definitions

AimMetabolic syndrome defined by International cut-off values are limited to detect people at high cardiometabolic risk in Central Africans in comparison with metabolic syndrome defined by ethnic-specific definition. We examined the relationship between metabolic syndromes, diabetes control, abdominal obesity, HDL-cholesterol groups and atherosclerotic complications.Materials and methodsA representative sample of type-2 diabetic central Africans from Kinshasa were studied. Outcome measures included control of diabetes, atherosclerosis, abdominal obesity, insulin resistance, total cholesterol, triglycerides, HDL-cholesterol, metabolic syndromes and atherosclerosis.ResultsOf 1266 type-2 diabetic patients (48.8%), (61.8%), (27.1%) and (81%) had uncontrolled diabetes, atherosclerotics, metabolic syndrome (IDF/Europe), and metabolic syndrome (IDF/local) respectively. There was a significant U-shaped relationship between atherosclerotics complications, insulin resistance, delta postprandial glycaemia and HDL-cholesterol stratification. There was also a significant U-shaped relationship between cardiometabolic risk (P < 0.01) and atherosclerotic complications.ConclusionType-2 diabetic Central Africans exhibit very high rates of uncontrolled diabetes, atherosclerotic complications and metabolic syndrome. Both, abdominal obesity, insulin resistance, low and very high HDL-cholesterol levels are cardiometabolic risk factors.     

Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications

Metabolic syndrome (MS) patients exhibit sleep/wake disturbances and other circadian abnormalities, and these may be associated with more rapid weight increase and development of diabetes and atherosclerotic disease. On this basis, the successful management of MS may require an ideal drug that besides antagonizing the trigger factors of MS could also correct the disturbed sleep-wake rhythm. Melatonin is an effective chronobiotic agent able to change the phase and amplitude of circadian rhythms. Melatonin has also significant cytoprotective properties preventing a number of MS sequelae in animal models of diabetes and obesity. A small number of controlled trials indicate that melatonin is useful to treat the metabolic and cardiovascular comorbidities of MS. Whether the recently introduced melatonergic agents (ramelteon, agomelatine, tasimelteon) have the potential for treating sleep disorders in MS patients and, more generally, for arresting the progression of disease, merits further investigation.     

Dyslipidemia in the metabolic syndrome: clinical implications and management

Dyslipidemia is an important component of the metabolic syndrome. Dyslipidemia in the metabolic syndrome is characterized by hypertriglyceridemia, low serum levels of high density lipoprotein cholesterol (HDL-C) and an increase in the serum fraction of small dense low density lipoprotein cholesterol (LDL-C) particles. Serum LDL-C elevation is frequently present, but is not a criterion of the metabolic syndrome. A Medline search was conducted using the terms metabolic syndrome, dyslipidemia, hypertriglyceridemia and HDL cholesterol. The metabolic syndrome is a common and important risk factor for cardiovascular disease and progression to type 2 diabetes mellitus. Dyslipidemia is present in most patients with the metabolic syndrome and is treatable with therapeutic lifestyle changes and pharmacotherapy. Aggressive management of atherogenic dyslipidemia is justified by the very high cardiovascular risk associated with this disorder. Atherogenic dyslipidemia is frequently present in patients with the metabolic syndrome and requires aggressive treatment due to the very high risk for cardiovascular disease and progression to type 2 diabetes mellitus.     

Evidence for cortisol as the mineralocorticoid in the syndrome of apparent mineralocorticoid excess.

The hypothesis that cortisol is the functioning mineralocorticoid in the syndrome of apparent mineralocorticoid excess was tested by suppressing its secretion with dexamethasone. The subjects were two siblings with the type 2 form of this syndrome in which the defect in the peripheral metabolism of cortisol lies predominantly in ring A reduction but not in 11 beta-hydroxy dehydrogenation of cortisol to cortisone. Low dosage dexamethasone improved the hypokalemia within several days and hypertension was corrected after 3 weeks of treatment. Mineralocorticoid manifestations remained in remission during 10 yr of therapy with the synthetic glucocorticoid during which normal growth and development were restored. The effectiveness of dexamethasone supports the hypothesis that cortisol is the functioning mineralocorticoid in the AME syndrome.     

Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics

The blockade of mineralocorticoid receptors (MR) has been shown to be an invaluable therapy in heart failure and hypertension. To date, only two steroidal antimineralocorticoids, spironolactone (and its active metabolite canrenone) and eplerenone, have been approved, whereas novel non-steroidal compounds are in preclinical and early development. The careful investigation of the efficacy and tolerance of spironolactone in essential hypertension initially supported the idea that a more selective second generation of MR antagonists is desired for chronic treatment of cardiovascular diseases. More than 40 years went by between the approval of the first MR antagonist spironolactone and the market introduction of its sole successor, eplerenone.The molecular pharmacology of MR antagonists may be addressed at different levels. Available preclinical and clinical data of the two approved steroidal antimineralocorticoids allow a good comparison of potency and selectivity of MR antagonists and their pharmacokinetic properties. The search for novel generations of MR antagonists with the ultimate goal of a more tissue selective mode of action may require novel compounds that are differentiated with respect to the binding mode to the MR. Other factors that may contribute to tissue selectivity as e.g. the physicochemical properties of a drug and how they influence the resulting pharmacology in the context of tissue selective co-factor expression are even less well understood.In the following we will review these aspects and demonstrate that the molecular pharmacology of current MR antagonists is on the one hand far from well understood and, on the other hand, still offers room for improvements.