Endothelin receptor antagonists: a place in the management of essential hypertension?

The endothelin system is a potent endothelial system that controls vascular tone and regulates regional blood flow [1]. Today, three isoforms of the endothelin peptide have been described (endothelin-1, -2 and -3) but most biological effects of endothelin are mediated by the 21 amino acid endothelin-1. In addition to its vascular properties, endothelin influences cell proliferationand extracellularmatrix synthesis and contributes to the homeostasis of water and electrolytes by direct effects on the kidney [1]. Endothelin acts through the activation of two specific G-protein-coupled receptors, i.e. endothelin Type A (ETA) and endothelin Type B (ETB) receptors. Stimulation of vascular ETA receptors induces vasoconstriction, whereas activation of vascular ETB receptors promotes vasodilatation. Therefore, the impact of endothelin on vascular tone will depend on the balance between the ETA and ETB receptor activation. Since its discovery, the endothelin system has been implicated in the pathophysiology of several diseases including essential arterial hypertension, pulmonary hypertension, congestive heart failure, acute kidney injury and more recently the progression of chronic kidney diseases (CKDs) [2–5]. Since 1992, several peptidic and non-peptidic endothelin receptor antagonists have been synthesized (Table 1) [6]. Animal studies using these antagonists have provided promising results in different indications but today, except for the management of pulmonary hypertension, the clinical development of endothelin receptor antagonists has been relatively slow and their use for the management of essential arterial hypertension is still under investigation. The purpose of this review is to discuss the potential role of endothelin receptor antagonists in the management of arterial essential hypertension and perhaps in the prevention of the progression of CKDs.