ReviewRecent studies with eplerenone, a novel selective aldosterone receptor antagonist
Introduction
Over the past few decades, the introduction and widespread use of new therapeutic agents for the treatment of hypertension, dyslipidemia, and heart disease has reduced significantly the morbidity and mortality associated with cardiovascular disorders; however, the incidence of end-stage renal disease and congestive heart failure (CHF) continues to rise despite improved control of blood pressure and lipids. For many years, it has been acknowledged that activation of the renin–angiotensin–aldosterone system (RAAS) is associated with unsatisfactory outcomes in patients with CHF and hypertension. Despite the availability of potent upstream blocking agents for this system, aldosterone levels remain elevated in these patients. New data described in this review suggest that aldosterone has significant deleterious effects on the cardiovascular system. Moreover, data from several animal studies using the new highly selective antagonist of aldosterone receptors, eplerenone, support the hypothesis that additional end-organ protection in hypertension and heart failure can be achieved by the selective blockade of aldosterone receptors.
Section snippets
Renin–angiotensin–aldosterone system
The RAAS is the fundamental mechanism in the body responsible for blood pressure and volume homeostasis. As such, a number of the commonly prescribed medications for the control of hypertension and heart failure are inhibitors of this system, a schematic of which is illustrated in Fig. 1. The angiotensin-converting enzyme (ACE) inhibitors (ACEi) block the conversion of the inactive angiotensin I (AngI) peptide to the active pressor molecule angiotensin II (AngII). The newer angiotensin receptor
Aldosterone and cardiovascular pathology
The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant cardiorenal effect of this hormone; however, there is now compelling evidence that aldosterone mediates significant deleterious cardiovascular effects via the action of this hormone on mineralo- corticoid receptors (MRs) outside the kidney, namely in the brain, heart and vasculature 3. Furthermore, the enzymes responsible for extra-adrenal
Cardioprotective effects of eplerenone
Eplerenone (formerly epoxymexrenone) is a 9-α, 11-α epoxy derivative of spironolactone (Fig. 4) that is currently undergoing late-stage clinical testing for hypertension and heart failure post-myocardial infarction (MI). Although eplerenone is 20-fold less potent at MRs compared with spironolactone, this molecule is substantially more selective than spironolactone against androgen and progesterone receptors 21; however, eplerenone demonstrates efficacy comparable to spironolactone in vivo in
Early clinical results with eplerenone
Early clinical results with eplerenone in essential hypertensive patients are very encouraging. In a recently reported eight-week double-blind placebo-controlled trial in patients with mild to moderate hypertension, eplerenone (50 mg, 100 mg and 400 mg given once daily) lowered systolic and diastolic blood pressure effectively 36. In these early clinical studies, eplerenone was well tolerated and the incidence of adverse events was similar to placebo, with no reports of gynecomastia.
Patients
Conclusions
New data suggest that aldosterone levels rise in patients with hypertension and heart failure, even when these patients receive maximal doses of both ACEi and AT1 receptor antagonists. This ‘aldosterone escape’ phenomenon leaves the patients vulnerable to the deleterious effects of high aldosterone levels.
There is now compelling evidence that aldosterone mediates significant deleterious effects on the cardiovascular system via its action at aldosterone receptors in the heart, brain and blood
Acknowledgements
I thank Ricardo Rocha and Stuart Ross for critical reading and review of this manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
References (38)
- et al.
Tissue-specific corticosteroidogenesis in the rat
Mol Cell Endocrinol
(2000) - et al.
Aldosterone modulates plasminogen activator-1 and glomerulosclerosis in vivo
Kidney Int
(2000) - et al.
Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy
Am J Cardiol
(2000) - et al.
Antialdosterones: incidence and prevention of sexual side effects
J Ster Biochem
(1989) - et al.
Eplerenone (SC-66110), a highly selective aldosterone antagonist
Am J Hypertens
(1998) - et al.
Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study: The RESOLVD Pilot Study Investigators
Circulation
(1999) - et al.
Regulation of aldosterone secretion
Annu Rev Physiol
(1988) - et al.
Identification and role of aldosterone receptors in the cardiovascular system
Ann Endocrinol (Paris)
(2000) - et al.
Cardiac aldosterone production in genetically hypertensive rats
Hypertension
(2000) - et al.
Expression of 11β-hydroxylase and aldosterone synthase genes in the rat brain
J Mol Endocrinol
(2000)
Remodeling of the right and left ventricles in experimental hypertension
Circ Res
Determinants of cardiac fibrosis in experimental hypertension
Am J Physiol
Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension
Hypertension
Aldosterone: a mediator of myocardial necrosis and renal arteriopathy
Endocrinology
Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats
Arterioscler Thromb Vasc Biol
Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients
Eur Heart J
Spironolactone increase nitric oxide bioactivitiy, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure
Circulation
Na+ influx and Na+-K+ pump activation during short-term exposure of cardiac myocytes to aldosterone
Am J Physiol
Aldosterone upregulates Ca2+ current in adult rat cardiomyocytes
Circ Res
Cited by (91)
Central serous chorioretinopathy: Towards an evidence-based treatment guideline
2019, Progress in Retinal and Eye ResearchCitation Excerpt :Similar to spironolactone, eplerenone is primarily used to treat heart failure (Pitt et al., 2003). Eplerenone was originally designed to avoid the hormone-associated side effects of spironolactone, serving as a more selective MR antagonist due to the addition of a 9,11-epoxide group (Cook et al., 2003; Delyani, 2000; McMahon, 2001). Although eplerenone likely has more tolerable side effects compared to spironolactone, eplerenone does not appear to be clinically superior to ‒ and possibly not equivalent to ‒ spironolactone in treating CSC (Chin et al., 2015; Pichi et al., 2017).
OCT-A in chronic central serous chorioretinopathy treated with oral eplerenone and half-fluence photodynamic therapy: A comparative study
2023, European Journal of OphthalmologyRole of Renin-Angiotensin-Aldosterone System and Cortisol in Endometriosis: A Preliminary Report
2023, International Journal of Molecular SciencesEndocrine Hypertensive Emergencies
2022, Endocrine Surgery Comprehensive Board Exam Guide