Does Aldosterone Cause Hypertension by a Non-Renal Mechanism?

Background Shortly after the structure of aldosterone (aldo) was determined (1) in 1952, its effect on the kidney to cause sodium (Na) retention and potassium (K) and hydrogen ion (H) excretion were characterized (2,3). Although the ability of aldo to effect many transporting epithelia is now well known, it is this effect on the kidney to retain sodium which is felt to play an important role in Na retention to cause edema and, in some settings, hypertension (HBP).

Aldo was shown by Edelman (4) to bind to a specific receptor and then be transported into the nucleus of aldo responsive cells and subsequently lead to the production of aldo-induced proteins. The first aldo receptor antagonist )ARA(, spironolactone, has been used clinically for over 30 years in the management of edema and in the past few years a new agent Eplerenone, which is structurally similar to spironolactone, but without the side effect of gynecomastia, has come into clinical use in the USA and in Israel.

Treatment of HBP is usually directed at the cause of the HBP if it is known, for example, removal of tumors releasing catecholamines and correcting renal artery stenosis. If HBP is due to primary aldosteronism, then surgical removal of the tumor, or use of an ARA is usually effective (5,6). When the cause of the HBP is not known, traditionally called essential hypertension, therapy today frequently involves drugs that interfere with the RAS (7), but until recently the addition of an ARA was not usually included. Recently studies by Epstein and others (8,9) have shown that the addition of an ARA to the drug management of what has been considered essential HPB can further reduce HBP by over 10 mmHg, thus suggesting that the addition of an ARA to the routine tools available to treat HBP is important. Although the mechanism by which this addition of an ARA lowers HBP is not clear, the obvious suggestion is that by blocking the effect of aldo on the kidney to reabsorb Na there is an increased excretion of Na which is responsible for the lowering of HBP.

In patients with end-stage renal disease (ESRD), at the time they start dialysis HBP is common and has been attributed to volume overload or an active RAS (10). Early in the history of hemodialysis the potential for the RAS to be involved in causing HBP was unclear, but studies with saralasin (11,12), a competitive angiotensin II antagonist, clearly showed that in dialysis patients with elevated plasma renin levels the renin was involved in causing HBP by leading to the generation of angiotensin II. Although a number of other mechanisms apart from volume and angiotensin II have been considered, there is little evidence today that any, including aldo, play a regular role in causing HBP in the dialysis setting.

Because of the possibility that aldosterone may contribute to the HBP of patients on dialysis, independent of an effect on sodium excretion (since such patients excrete little urine), this protocol is designed to test this possibility by administering an ARA to patients on chronic dialysis with HBP. A positive result would strongly suggest that there is an effect to lower HBP independent of sodium excretion. Such a result would be indicative of a non-Na mechanism for ARA to lower HBP in dialysis patients, but would also suggest the possibility of ARA acting by a non-Na mechanism in lowering HBP in essential HBP.