J. Funder
Feb 1, 2009
Citations
4
Influential Citations
142
Citations
Quality indicators
Journal
Hypertension
Abstract
Translational research is usually taken to mean the application of laboratory discovery to clinical practice. Like languages or enzymes, however, translation is a 2-way street, and in the field of aldosterone and mineralocorticoid receptors (MR), there are a number of examples where clinical studies have prompted reconsideration of the basic biology. For example, in essential hypertensive subjects the distinction between the antihypertensive and electrolyte effects of the selective MR antagonist eplerenone has been interpreted as evidence against a primary renal role for aldosterone/MR activation in raising blood pressure.1 Similarly, the finding of an S810L MR mutant receptor causing juvenile hypertension exacerbated by pregnancy2 prompted a reconsideration of the order of branching of the MR/glucocorticoid receptor (GR)/progesterone receptor (PR)/androgen receptor (AR) subfamily of steroid hormone receptors from a common primordial ancestral protein.3 These studies and their implications for the basic biology of aldosterone action have been discussed elsewhere.4 The present review focuses on the clinical study (Randomized ALdactone Evaluation Study [RALES]5) that prompted this process of re-examination almost a decade ago. The rationale for this study, in patients with New York Heart Association class III heart failure, was that previous clinical studies had shown that plasma aldosterone levels could break through prolonged angiotensin-converting enzyme inhibition and angiotensin II type 1 blockade; in addition, early laboratory studies by Brilla and Weber6 had shown that exogenous aldosterone plus normal saline as drinking solution produced cardiac hypertrophy and fibrosis in uninephrectomized rats. The outcomes of RALES were remarkable. The trial was halted just more than half way through the projected period of recruitment on the basis of the divergence between the 2 groups: 1 treated with standard of care (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc) plus placebo and the other with standard of care plus spironolactone. …