Escape from the sodium-retaining effects of mineralocorticoids

Abstract

The prolonged administration of pharmacologic doses of mineralocorticoids to normal subjects results in hypokalemia, metabolic alkalosis, polydipsia, polyuria, and transient sodium retention. Although this review will focus on sodium metabolism, increased water turnover was, in retrospect, the first part of this constellation to be recognized. Ragan et al [1], in 1940, demonstrated that the chronic injection of deoxycorticosterone acetate (DOCA) produced a syndrome of polydipsia and polyuria in normal animals. These authors state that their results could have been anticipated from the earlier work of Teel [2], Wermer [3], and also Silvette and Britton [4]. Most importantly, Ragan et al [1] demonstrated that there was no striking accumulation of extracellular fluid or congestive heart failure when DOCA was administered to normal dogs; that is, sodium retention was only transient, whereas the hypokalemia was persistent, finally leading to paralysis and death of the animal. Clinton and Thorn, in 1943, extended these observations by demonstrating that the chronic administration of DOCA increased plasma volume of normal subjects by 6% [5]. In 1950, Daughaday and MacBryde evaluated the effects of DOCA administration with both deprivation and abundance of sodium in the diet [6]. Urine sodium excretion remained negligible during DOCA treatment when the diet contained 3mEq of sodium per day. DOCA was administered again in the presence of 203mEq of sodium per day in the diet. Following an initial period of sodium retention, sodium balance was restored, a finding similar to that reported for the chronic administration of cortisone and ACTH [7]. Although renal sodium excretion was high when sodium balance was restored, the concentration of sodium in sweat was low, indicating a continuing effect of the hormone. Relman and Schwartz, who also studied the effects of DOCA during variations of sodium intake, concluded that the from the sodium-retaining effect of DOCA was the result of regulatory mechanisms which override the hormonal effect on the renal tubule [8]. The term escape was introduced into the literature in this context. Because the term has been widely used and provides a convenient description of the phenomenon, we will use the term as an abbreviation in this review.