Review
Recent studies with eplerenone, a novel selective aldosterone receptor antagonist

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Abstract

Activation of the renin–angiotensin–aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and congestive heart failure, in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin-converting enzyme inhibitors and the AT1 receptor antagonists, unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the past few years strongly support the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone receptor antagonist eplerenone has been shown to produce significant cardioprotective effects in experimental models of cardiovascular disease. Early clinical testing suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure.

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 3radical dotradical dot. 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:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

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