Aldosterone breakthrough during RAS blockade: a role for endothelins and their antagonists?

Activation of the renin-angiotensin system (RAS), with ensuing aldosterone excess, detrimentally affects outcome in patients with hypertension and heart failure (HF). RAS blockade with angiotensin (Ang) 1-converting enzyme inhibitors (ACEIs) or Ang II type 1 receptor blockers (ARBs) is beneficial in such conditions. However, aldosterone secretion can persist despite these treatments. Hence, mechanisms besides Ang II acquire the role of aldosterone secretagogue. The RALES and EPHESUS studies have shown that this aldosterone "escape" or "breakthrough" is an important factor, because it is a determinant of outcome in HF patients. Endothelin (ET)-1, which stimulates aldosterone secretion via both A (ETA) and B (ETB) receptor subtypes, and which is increased in HF, is a candidate for the "aldosterone breakthrough." Moreover, the novel ET peptide ET-1(1-31) is involved in adrenocortical growth. Therefore, findings suggesting a role for the ET-1 system as an aldosterone secretagogue, along with the potential usefulness of endothelin antagonists for the prevention of "aldosterone breakthrough," are discussed.