The discovery in 1988 of endothelin-1 (ET-1) by Yanagisawa and colleagues in Japan represented a landmark in the field of cardiovascular research.¹ A combination of molecular and pharmacological approaches revealed ET-1 as the most powerful vasoconstrictor yet identified in biological systems. Since its discovery, a great deal of effort has been made towards gaining a better understanding of the key roles—developmental, physiological, and pathological—played by this peptide, particularly with regard to the cardiovascular system. In this review, we will describe current knowledge on the endothelin system and focus on the cardiovascular effects of ET-1 and its antagonism. We will review the evidence for the two therapeutic areas mainly investigated, pulmonary arterial hypertension and heart failure, as well as outline its important role in hypertension, renal dysfunction, and atherosclerosis.

MOLECULAR BIOLOGY OF ENDOTHELIN-1

Endothelin synthesis and clearance

The endothelin family consists of three closely related peptides, ET-1, ET-2, and ET-3, each 21 amino acids in length and derived from separate genes. ET-1_[1–21] is the main isoform produced in the cardiovascular system and about which most is known; ET-2 is mainly produced within the kidney and intestine, whereas ET-3 is predominantly found within the central nervous system (tables 1 and 2). However, the roles of ET-2 and ET-3, except in embryonic development, remain unclear.

ET-1 is not stored and released but instead generated in response to a range of stimuli, which vary between different tissues (fig 1).² It is generated mainly in endothelial cells of blood vessels and requires several processing steps before the mature peptide is formed (fig 1). The final step in the ET-1 pathway involves cleavage of the 38 amino acid “big ET-1” by the highly selective membrane bound metalloproteinase, endothelin converting enzyme (ECE-1). ECE independent pathways of ET-1 formation have also …