Vasoconstrictor effect of endothelin-1 in human skin: role of ET A and ET B receptors

• Published in: American journal of physiology. Heart and circulatory physiology 1999-02, Vol.276 (2), p.H359-H367
• Main Authors: Lipa, Joan E, Neligan, Peter C, Perreault, Therese M, Baribeau, Johanne, Levine, Ronald H, Knowlton, Robert J, Pang, Cho Y
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.1999.276.2.H359

The aim of this project was to investigate the role of ET and ET receptors in the mediation of endothelin (ET)-1-induced vasoconstriction in human skin. This information should provide important insights into the design of pharmacological intervention against skin vasospasm induced by ET-1 in peripheral vascular disease or surgical trauma. Vasoconstriction in response to intra-arterial drug infusion in isolated perfused human skin flaps (8 × 18 cm) derived from dermolipectomy specimens was assessed by studying changes in skin perfusion and perfusion pressure under constant flow rate in each drug treatment ( n = 4). It was observed that ET-1 (10 to 10 M) and norepinephrine (NE, 10 to 10 M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 ∼200-fold higher than NE. The ET -receptor antagonist BQ-123 but not the ET -receptor antagonist BQ-788 blocked the vasoconstrictor effect of ET-1. This observation was confirmed by studying skin perfusion using the dermofluorometry technique. In addition, ET -receptor agonists BQ-3020 and sarafotoxin S6c (10 to 10 M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10 M of N -nitro-l-arginine methyl ester and indomethacin. Furthermore, results from saturable and competitive ET-1 radioligand membrane receptor binding assays revealed that high-affinity and capacity binding sites are predominantly the ET receptor subtype in endothelium-denuded skin arteries and veins of 0.5-1.5 mm diameter, with an ET -to-ET receptor ratio of 83:17 in arteries ( n= 5) and 78:22 in veins ( n = 7). Results from the present functional and radioligand receptor binding studies clearly indicate that ET-1 is a very potent vasoconstrictor in human skin and its vasoconstrictor effect is primarily mediated by ET receptors, with no significant participation from ET receptors.