The use of so called “knockout” mice in scientific research continues to produce surprises. Deficient in a particular molecule as a result of targeted mutagenesis, they allow scientists to study the essential physiological role of the absent molecule. Such has been the case with the endothelins, vasoactive peptide mediators whose discovery in 1988 was a highpoint in vascular biology.1 Humans have three endothelin isoforms, endothelins 1,2, and 3,2 and two endothelin receptor subtypes, endothelins A and B, whose functions remain to be completely elucidated. Endothelin-1 is the most potent vasoconstrictor substance yet described,1 and the major focus in endothelin research has been to investigate its role in the regulation of normal systemic and regional vascular tone.2 In the intense research activity that followed discovery of endothelin-1 it soon became apparent that endothelins did not function as classical circulating humoral factors, but rather as locally acting autocrine or paracrine factors. Surprisingly, the endothelins were also found to be synthesised by a variety …