Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

Rajiv Agarwal; Peter Kolkhof; George Bakris; Johann Bauersachs; Hermann Haller; Takashi Wada; Faiez Zannad


Eur Heart J. 2021;42(2):152-161. 

In This Article

Discovery of the Pro-inflammatory and Pro-fibrotic Effects of Aldosterone and the Development of Spironolactone

The purification of deoxycorticosterone acetate (DOCA)[5] facilitated experiments to gain insights into its physiology and pharmacology as a potent MR agonist. In 1938, Thorn et al.[6] demonstrated that dogs treated with DOCA had sodium chloride retention and potassium diuresis (Figure 1). In the same year, Thorn and Engel[7] noted progesterone as a potential adrenal replacement therapy, but these experiments were marred by the large supplies of progesterone needed. Progesterone was not recognized as an MRA until 1955; this finding provided an explanation for the escape from aldosterone-induced sodium retention during pregnancy.[8]

Figure 1.

Key studies in the history of mineralocorticoid receptor antagonists.

In 1943, Selye et al.[9] performed seminal experiments noting the central importance of MR agonists on target organ damage. A 2 × 2 factorial trial of salt and DOCA was performed in rats (aldosterone was unavailable at the time). Malignant hypertension, produced by DOCA and salt in combination, was associated with inflammation and fibrosis in various organs (i.e. malignant nephrosclerosis, cardiac hypertrophy, rigid aorta, and oedematous pancreatitis).[9] While increased blood pressure (BP) and salt were necessary, it was inflammation and fibrosis that caused organ damage. These historical findings have been replicated with aldosterone in models demonstrating reactive and progressive interstitial and perivascular fibrosis, such as perivascular coronary fibrosis in rats.[10]

In 1957, two separate papers provided early examples of bench-to-bedside and academia–industry collaboration.[11,12] The first was a preclinical study showing aldosterone antagonism by new steroidal drugs SC-5233 and SC-8109 (modified from progesterone with relative activities 7.5 and 26.8, respectively).[11] The second was a clinical paper by Liddle[12] demonstrating that SC-5233 caused potassium retention and sodium secretion both in a patient with congestive heart failure (HF) and in DOCA-treated patients with Addison's disease.

SC-5233 and SC-8109 use was limited by the need for subcutaneous administration. This barrier was surmounted in 1957 by the synthesis of an active steroidal MRA, spironolactone, that could be administered orally. This important discovery facilitated implementation in clinical trials,[13] and within 3 years of its synthesis, the US Food and Drug Administration approved spironolactone, which had a 46-fold more potent oral activity than SC-5233. Spironolactone was launched as a diuretic for the management of oedematous conditions, primary aldosteronism, and essential hypertension.[14]

Following the discovery and availability of spironolactone, Selye demonstrated attenuation of aldosterone effects and salt on cardiac necrosis using spironolactone in animals. In the presence of a high-salt diet, spironolactone provided a 40% risk reduction in cardiac necrosis but demonstrated complete protection (100% risk reduction) in the absence of salt; this animal model shows that both a low-salt diet and spironolactone are required to observe the full treatment benefits of MR antagonism.[15] The pharmacology and science of MRAs is beyond the scope of this work but is reviewed elsewhere.[16]