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

• Published in: British journal of pharmacology Vol. 153; no. 6; pp. 1105 - 1119
• Main Authors: Kirkby, N S, Hadoke, P W F, Bagnall, A J, Webb, D J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; cardiovascular disease; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - physiopathology; clinical trials; Controlled Clinical Trials as Topic; Drug Delivery Systems; ECE inhibitors; Endothelin Receptor Antagonists; Endothelin-1 - drug effects; Endothelin-1 - metabolism; Endothelin-Converting Enzymes; endothelin‐1; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Pharmacology. Drug treatments; Receptors, Endothelin - physiology; Reviews; Human; ECE inhibitors; endothelin receptor antagonists; Targeted therapy; Clinical trial; Cardiovascular disease; Endothelin 1; Inhibitor; clinical trials; Antagonist; endothelin-1; Endothelin receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707516

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 ETA 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.
British Journal of Pharmacology (2008) 153, 1105–1119; doi:10.1038/sj.bjp.0707516; published online 29 October 2007