Aldosterone was isolated 52 yr ago and characterized by its ability to promote sodium flux across epithelia. Generations of physicians have thus been taught a relatively straightforward physiology of aldosterone. Levels are elevated via the renin-angiotensin system in response to sodium deficiency or lowered circulating volume; it then acts to retain fluid and electrolytes in the kidney and colon, in a classic homeostatic feedback loop. A year or two later, they were taught in the wards that primary aldosteronism was a rare (1%) cause of essential hypertension, and that it reflected simple disruption of the feedback loop. Autonomous aldosterone secretion promoted fluid and electrolyte retention and an increase in blood volume; the increased blood volume triggered an increase in cardiac output; the increased cardiac output was then reflexly normalized, at the expense of increased peripheral resistance. Much has changed since we did Physiology 101. It is now increasingly accepted, for example, that primary aldosteronism represents 8–13% of nonselected essential hypertension, across a range of studies in many different countries: given the prevalence of hypertension, this is thus no longer a boutique disorder (1). Secondly, on the basis of abnormal aldosterone to renin ratios, as evidence of autonomous secretion of aldosterone within normal plasma levels, another approximately 25% of unselected so-called essential hypertensives may evolve into primary aldosteronism, with plasma aldosterone levels that are absolutely as well as relatively elevated (1).

What has also changed is the pathophysiology of mineralocorticoid receptors (MR) and the demonstrated benefits of MR blockade in heart failure and hypertension. In progressive New York Heart Association (NYHA) class III heart failure, spironolactone, at an average daily dose of 26 mg in addition to standard of care, produced a 30% improvement in survival, with 35% fewer hospital admissions (2). Eplerenone, the MR-selective antagonist, similarly improved mortality and morbidity when added to standard of care in patients with heart failure after myocardial infarction (3). The combination of eplerenone and the angiotensin-converting enzyme inhibitor Enalapril was shown to be superior, in terms of reversing left ventricular hypertrophy and proteinuria, to maximal doses of either agent alone, with no further effect on blood pressure in essential hypertensive patients (4). Finally, in dose titration studies of eplerenone in essential hypertensives, no correlation was found at any dose between responder/nonresponder status (in terms of attaining goal