Vasoconstrictor activity of novel endothelin peptide, ET‐1 (1 – 31) , in human mammary and coronary arteries in vitro

The ability of the putative chymase product of big endothelin‐1 (big ET‐1), ET‐1 (1 – 31) , to constrict isolated endothelium‐denuded preparations of human coronary and internal mammary artery was determined. pD 2 values in coronary and mammary artery respectively were 8.21±0.12 ( n =14) and 8.55±0.11 ( n =12) for ET‐1, 6.74±0.11 ( n =16) and 7.10±0.08 ( n =16) for ET‐1 (1 – 31) and 6.92±0.10 ( n =15) and 7.23±0.11 ( n =12) for big ET‐1. ET‐1 (1 – 31) was significantly less potent than ET‐1 ( P <0.001, Student's t ‐test) and equipotent with big ET‐1. Vasoconstrictor responses to 100 – 700 n M ET‐1 (1 – 31) were significantly ( P <0.05, Student's paired t ‐test) attenuated by the ET A antagonist PD156707 (100 n M ). There was no effect of the ECE inhibitor PD159790 (30 μ M ), the ECE/NEP inhibitor phosphoramidon (100 μ M ) or the serine protease inhibitor chymostatin (100 μ M ) on ET‐1 (1 – 31) responses in either artery. Radioimmunoassay detected significant levels of mature ET in the bathing medium of coronary (1.6±0.5 n M , n =14) and mammary (2.1±0.6 n M , n =14) arteries, suggesting that conversion of ET‐1 (1 – 31) to ET‐1 contributed to the observed vasoconstriction. ET‐1 (1 – 31) competed for specific [ 125 I]‐ET‐1 binding to ET A and ET B receptors in human left ventricle with a pooled K D of 71.6±7.0 n M ( n =3). Therefore, in human arteries the novel peptide ET‐1 (1 – 31) mediated vasoconstriction via activation of the ET A receptor. The conversion of ET‐1 (1 – 31) to ET‐1, by an as yet unidentified protease, must contribute wholly or partly to the observed constrictor response. Chymase generated ET‐1 (1 – 31) may therefore represent an alternative precursor for ET‐1 production in the human vasculature.British Journal of Pharmacology (2001) 134 , 1360–1366; doi: 10.1038/sj.bjp.0704384