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Endothelin system: area of research and therapeutics

Endothelial cells play a key role in the regulation of vascular tone by the production of mediators such as prostacyclins, nitric oxide and endothelins (ETs). These mediators have opposing roles on the whole vascular bed, including smooth muscle cells, matrix and fibroblasts, as well as platelets and inflammatory pathways. The endothelins are a family of peptides secreted by various cells and tissues in the human. This family consists of 3 isopeptides: ET-l, 2, and 3 in humans which mediate their actions via two ET receptor subtypes: ET and ET . These ETs play an important role in A B human physiology and in the pathophysiology of vasospastic conditions, renal failure, chronic heart failure, atherosclerotic conditions, essential and pulmonary hypertension, pain, malignancy, etc. Accordingly, ET receptor antagonists have been developed rapidly, mostly for the treatment of cardiovascular diseases. But as research progressed, these ET antagonists proved to be disappointing in many clinical trials. This article will focus on the developments in the endothelin field, with special emphasis on the ET-1 antagonists, their clinical use and the shift of research target from ET receptors to endothelin converting enzyme (ECE). Selective inhibitors of ECE along with dual & even triple enzyme inhibitors have come into research..