The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

Abstract

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

Figure 1

Generation and action of endothelin-1 (ET-1) in the vascular wall. The 21-amino-acid peptide, ET-1, is the eventual product of a gene on chromosome 6 that encodes preproET-1 protein. This is converted to proET-1 on secretion into the cytoplasm, which itself undergoes enzymatic cleavage by a furin-like endopeptidase to form big ET-1. ET-1 is generated from big ET-1 by endothelin-converting enzymes (ECEs) and is excreted predominantly abluminally into the vessel wall. Alternative enzymatic pathways may also process big ET-1 to yield bioactive 31- and 32-amino acid isoforms. ET-1 stimulates contraction, proliferation and migration of vascular cells by a direct action on VSMC ET_A and, to a lesser extent, VSMC ET_B receptors. In addition, ET-1 also induces indirect relaxation and anti-proliferation by stimulation of ET_B receptors on the endothelium. These actions may be mediated by the release of several distinct dilator compounds (nitric oxide, endothelium-derived hyperpolarizing factor and prostaglandins) but the precise combination of these factors varies between vascular beds. The principal pharmacological approaches in modulating the action of ET-1 are (1) inhibition of synthesis with ECE inhibitors or dual ECE/neutral endopeptidase (NEP) inhibitors and (2) blockade of receptors using antagonists that are selective for either ET_A or ET_B receptor subtypes or nonselective. EDRF, endothelium-derived relaxing factor.