Mechanisms for Mineralocorticoid-driven Age-related Hypertension: Potential Therapeutic Role of Mineralocorticoid Receptor Antagonists and Aldosterone Synthase Inhibitors

Abstract

Hypertension prevalence rises dramatically with advancing age, is not well controlled with current therapy, and contributes substantially to cardiovascular, renal and neurologic disorders that are common in the elderly. The renin-angiotensin-aldosterone system is a hormonal pathway with multiorgan involvement critical to controlling blood pressure. The production of the steroid hormone aldosterone and the activation state of its mineralocorticoid receptor (MR) are important clinical targets for hypertension treatment and cardiorenal disease prevention. This review summarizes studies demonstrating that aging is associated with: 1) dysregulation of adrenal aldosterone production by autonomous aldosterone producing adrenal cells and, when co-morbid with obesity, by factors released from adipose tissue that promote adrenal aldosterone production; 2) increased expression of the MR due to oxidative stress- and inflammation-activated transcription factors; and 3) aldosterone-independent MR activation by oxidative stress-activated Rac1, angiotensin-II signaling, and declining expression of the cortisol-inactivating enzyme 11bHSD2. Together, these data support the concept that elderly individuals are at high risk for mineralocorticoid-driven hypertension and associated cardiovascular, renal, and neurologic disease. The review further describes the different classes of agents that inhibit this pathway, including traditional steroidal MR antagonists (sMRAs), newer nonsteroidal (nsMRAs) and aldosterone synthase inhibitors (ASIs), comparing their modes of action. The sMRAs and nsMRAs have different degrees of MR selectivity and potency, yet they all block MR activation by aldosterone, cortisol, and ligand-independent mechanisms. The ASIs block aldosterone production in the adrenal gland and attenuate aldosterone-mediated MR effects. All three drug classes raise potassium proportional to the degree of renal MR inhibition. Trials are summarized showing efficacy of the new agents in reducing MR activation, aldosterone production, blood pressure and adverse cardiorenal outcomes. Head-to-head studies in older individuals are needed to determine the relative efficacy of aldosterone synthase versus MR inhibition for blood pressure control to improve outcomes in the elderly and very old.