The Use of Aldosterone Receptor Blockers in the Treatment of Hypertension

Myron H. Weinberger, MD

Disclosures
In This Article

Abstract and Introduction

The emerging role of aldosterone in hypertension and cardiovascular diseases has prompted a renewal of interest in therapeutic approaches designed to interfere with the action of this mineralocorticoid hormone. While spironolactone has long been used for this purpose, side effects, largely attributable to the interaction of this agent with non-mineralocor-ticoid steroid receptors, has reduced the enthusiasm for its use. Eplerenone, a specific aldosterone receptor blocker with a lower incidence of the sex hormone-related side effects than spironolactone, has been used in several recent clinical trials in hypertension and congestive heart failure. This review will highlight the major findings from these studies.

The renin-angiotensin-aldosterone system has long been recognized as playing a major role in cardiovascular disease by its involvement in the pathophysiology and maintenance of essential hypertension, some forms of secondary hypertension, and the pathophysiology of congestive heart failure (CHF) and other forms of cardiovascular disease. During the past three decades, the emphasis has been placed on renin and angiotensin II in terms of the physiology and treatment of these disorders, with little focus on the role of aldosterone. From a therapeutic standpoint, the mineralocorticoid receptor antagonist spironolactone has been available for over 40 years, but its use has been limited because of side effects, many of which are related to the ability of spironolactone to interact with sex hormone receptors as well as the mineralocorticoid receptor. The development of eplerenone, a selective aldosterone receptor blocker with greater specificity for the mineralocorticoid receptor, less than 1% affinity for the progesterone receptor, and less than 0.1% affinity for the androgen receptor,[1] and thus potentially producing a lower incidence of sex hormone-related side effects than with spironolactone, has renewed interest in this therapeutic approach, i.e., blocking the effects of aldosterone.

In addition to the long-recognized effects of aldosterone to stimulate sodium and water reabsorption by the distal nephron in exchange for potassium and hydrogen ions, and thus to play a major role in the development and maintenance of hypertension by expansion of extracellular fluid volume and diminution of body potassium stores, aldosterone has also been shown to induce left ventricular hypertrophy (LVH); induce fibrosis of myocardial, vascular, and renal tissues; and promote magnesium loss.[2,3] The plasma aldosterone concentration has been found to be directly related to mortality in severe CHF.[3,4]

The use of angiotensin-converting enzyme (ACE) inhibitors and, more recently, angiotensin receptor blockers (ARBs) in the treatment of hypertension and CHF assume that aldosterone as well as angiotensin II levels will be reduced or their effects blocked. However, recent studies, such as the Randomized Evaluation Of Strategies for Left Ventricular Dysfunction (RESOLVD) trial[5,6] utilizing ACE inhibitors or angiotensin receptor blocking (ARB) drugs[7] have demonstrated a lack of persistent suppression of aldosterone with these agents. Aldosterone levels, which had initially decreased with the initiation of ACE inhibitors, were found to be back to baseline levels or above initial levels at the end of the study.[5,6] It has been suggested that non-renin mediated sources of angiotensin II generation and/or increased intracellular potassium concentration may have contributed to the rise in aldosterone in these studies despite inhibition of the ACE or blockade of its receptor.[7]

Aldosterone has been shown to be involved in the process of LVH; in the canine model of CHF, eplerenone has been shown to cause reversal of LVH and remodeling of the left ventricle.[8] Moreover, these effects on the myocardium are independent of blood pressure (BP) reduction, thus establishing a role for selective ARB in preventing or possibly reversing cardiovascular injury.[9] Recent observations have further suggested that aldosterone blockade can also lead to an improvement in endothelial function,[10] as well as having an anti-fibrotic effect on the heart, aorta, and vasculature.[9]

Observations from recent studies with the specific aldosterone blocker, eplerenone, in hypertensive patients will be reviewed. These observations include a dose-ranging comparison of eplerenone with placebo and spironolactone, a comparison of antihypertensive efficacy between eplerenone and losartan in black and white hypertensives and in subjects with low-renin hypertension, combination studies with ACE inhibitors and ARBs, studies in diabetics with proteinuria, in CHF, and in isolated systolic hypertension.

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