Selective and mixed endothelin receptor antagonism in cardiovascular disease

Within five years of discovering endothelin (ET-1) in 1988, the first report of an orally available ET receptor antagonist was published. Within twelve years, bosentan, the first ET receptor antagonist to gain marketing authorisation, was made available for the treatment of pulmonary artery hypertension (PAH). Since this milestone in ET biology, several ET receptor antagonists have been developed, principally to target cardiovascular disease states. ET-1 acts through two receptors - ETA and ETB, Currently, the mixed antagonist, bosentan, and the selective ETA antagonist, sitaxsentan, are both licensed for the treatment of PAH, and clinical trials with these and other agents are ongoing for many diseases, including scleroderma, diabetic nephropathy and prostate cancer. Although there has been no argument about the importance of blocking ETA receptors, there remains a long-running debate as to whether additional ETB antagonism is of benefit, and this is the topic of the following review.