Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1

1 The potential vasodilator function of the peptide ghrelin, recently identified as the endogenous ligand of the growth hormone secretagogue orphan receptor (GHS-R), was investigated in human endothelium-denuded internal mammary artery. The peptide endothelin-1 (ET-1) is a potent and long-lasting vasoconstrictor. Comparisons were made with established and putative endogenous vasodilators to determine if any could reverse ET-1-induced vasoconstriction in this vessel. 2 Ghrelin (0.1 - 300 nm) potently dilated 10 nm ET-1-induced constrictions (pD(2) 8.39 +/- 0.29; E-MAX 63 +/- 5.6%; n = 9/14, responders/total). 3 ANP (pD2 7.75 +/- 0.14; E-MAX 106 +/- 2.0; n = 5/5) and CGRP (pD, 8.08 +/- 0.17; E-MAX 76 +/- 15% n = 5/6) both produced complete reversal of the constrictor response to ET-1 (E-MAX not significantly different from 100%, P > 0.05 one-sample t-test). 4 The following caused partial reversal of the ET-I response: Adrenomedullin (n = 9/9) and two peptides derived from proadrenomedullin, PAMP-12 (n = 6/7) and PAMP-20 (n = 9/9) (pD, values 7.63 +/- 0.28, 7.97 +/- 0.23 and 8.51 +/- 0.29; E-MAX 58 +/- 7.3, 54 +/- 10 and 51 +/- 7.8% respectively). Unexpectedly, amylin was only 2 fold less potent than CGRP, although there was less than 50% reversal of the ET-1 constriction (pD(2) 7.86 +/- 0.30; E-MAX 41 +/- 5.4%; n = 7/9). CNP (n = 6/6) also partially reversed constrictions to ET-1 (E-MAX 53 +/- 6.3; pD, 8.07 +/- 0.38). 5 BNP (n = 415) and PGI(2) (n = 6/8) were weak vasodilators, since concentration-response curves failed to reach a maximum within the range tested. PGE, caused a small dilatation in some vessels (EMAX 17 +/- 2.1%; pD, 8.63 +/- 0.36; n = 4/8). 6 We have demonstrated ghrelin to be an effective, endothelium-independent vasodilator of the long-lasting constrictor ET-1 in human arteries producing responses similar to those of adrenomedullin (P > 0.05, ANOVA).