Simpson and Tait identified and studied the effects of aldosterone in the early 1950’s.1 Much of the early investigations of aldosterone related to its effects on the renal distal tubular exchange of intratubular sodium for secreted potassium and hydrogen ions. Soon after the discovery of aldosterone a syndrome was described as primary aldosteronism, or Conn’s syndrome. The excessive production of aldosterone resulted from an aldosterone-producing adrenal adenoma. In 1957 Conn’s syndrome was associated with resistant hypertension.2 Over forty years later aldosterone’s role in heart failure was evaluated in a large randomized-controlled trial (Randomized Aldactone Evaluation Study).3 In this study the mineralocorticoid receptor antagonist, spironolactone, reduced morbidity and mortality in patients with severe systolic dysfunction. More recently aldosterone has been implicated in the pathogenesis of the metabolic syndrome. Sowers and colleagues published a narrative review of the emerging clinical implications of aldosterone.4 Specifically, the authors reviewed the role of aldosterone in the metabolic syndrome, in resistant hypertension, as well as its association with cardiovascular and renal disease.
Aldosterone’s effect on insulin resistance was first seen in patients with Conn’s syndrome. In patients undergoing resection of discreet adrenal adenomas, blood insulin and glucose levels were reduced. Numerous mechanisms of aldosterone-induced glucose intolerance have been proposed. Some of the most interesting hypotheses relate to the interactions between aldosterone and adipose tissue. Human adipocytes produce a mineralocorticoid-releasing factor that in turn stimulates adrenal aldosterone production. In support of this, obesity has been shown to increase aldosterone production. Additionally, hyperaldosteronism is associated with the development of the metabolic syndrome. Lastly, mineralocorticoid receptor blockade has been shown to improve insulin sensitivity.
“Resistant hypertension” is defined by some as hypertension requiring a rational regimen of more than 3 drugs to control blood pressure. The prevalence of primary aldosteronism in patients with resistant hypertension is approximately 20% versus 1% of unselected hypertensive patients. Importantly, individuals with resistant hypertension, but without primary aldosteronism, still have higher levels of aldosterone than controls. This secondary aldosteronism may produce higher levels of aldosterone than in patients with primary aldosteronism.
Aldosterone is also associated with the development of chronic kidney disease (CKD) in patients with obesity, diabetes, and hypertension. Renin-angiotensin system blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (ARBs) are considered the standard of care to prevent or slow the progression of renal disease. However, these regimens have not been very successful in preventing the progression of CKD. Clinical trials evaluating surrogate outcomes such as microalbuminuria or glomerular filtration rate have shown incremental benefit with the addition of a mineralocorticoid receptor blocker (mostly spironolactone) to ACE inhibitors or ARBs.
It is clear that aldosterone is implicated in the metabolic syndrome, resistant hypertension, cardiovascular, and renal disease. There are good data supporting the use of spironolactone in patients with depressed left ventricular systolic function or in patients with primary aldosteronism. Mineralocorticoid receptor blockade may be beneficial in other conditions such as the metabolic syndrome, resistant ...