Dual Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibition

Abstract

See related article, pp 755–763 The endothelin (ET) family consists of three 21-amino acid peptides (ET-1, ET-2, and ET-3) with powerful vasoconstrictor and pressor properties.1 Of the 3 peptides, ET-1 is the major vascular isoform and of most importance in the cardiovascular system.2 The gene product is the 212-amino acid preproET-1. This is cleaved to Big-ET-1, after which an ET-converting enzyme (ECE), of which there are several isoforms, catalyzes the generation of the biologically active ET-1 and a C-terminal fragment. ET-1 has 2 distinct binding sites, the ETA and the ETB receptors.3,4 ET receptors are expressed by a wide variety of cells and tissues. Within the vasculature, ETA and ETB receptors located on vascular smooth muscle cells mediate the vasoconstrictor effects of ET-1.5 ETB receptors are also found on vascular endothelial cells, where their activation results in vasodilation mediated mainly by NO.6 In addition, ETB receptors have a major role in clearance of circulating ET-1. The ET system is upregulated in a number of cardiovascular diseases, and its antagonism has shown promising therapeutic potential. Similar to angiotensin II, there are 2 pharmacological mechanisms for inhibiting the actions of ET-1, either at the point of its binding to its cognate receptors or by blocking its generation. Much of the work on ET blocking strategies has focused on the first of these. The last 10 years have seen the clinical development of a large number of selective ETA receptor and mixed ETA/B receptor antagonists (see Table in Reference7). The major clinical problem …