Endothelin antagonists for chronic heart failure: do they have a role?

Over the last two decades, the vascular endothelium has been shown to produce a variety of vasoactive substances that are crucial for the regulation of vascular tone, both in health and disease. This concept emerged in 1980, with the discovery of endothelium-derived relaxing factor, later characterized as nitric oxide. In 1985 Hickey et al. reported the existence of a vasoconstricting factor derived from cultured bovine endothelial cells. Yanagisawa et al. were, however, the first to purify, sequence and clone the 21 amino acid structure of endothelin (ET) and its mRNA from the culture supernatant of porcine aortic endothelial cells in 1988. The authors stated that ‘endothelin, having a potent, strong and characteristically long-lasting vasoconstrictor activity, may be important in systemic blood pressure and/or local blood flow: disturbances in the control of endothelin production could contribute to the pathogenesis of hypertension and that of pathological vascular spasm’. Since that original report remarkable advances have been made in our understanding of the molecular basis of ET biosynthesis and action. ET has been implicated as playing an important physiological role in cardiovascular regulation and a putative pathophysiological role in a wide range of disease states, including chronic heart failure. The aim of this review article is to focus on the role of endothelin in chronic heart failure and in particular, the potential therapeutic benefits of ET receptor antagonists for patients with chronic heart failure.