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Am J Physiol Heart Circ Physiol 276: H359-H367, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 2, H359-H367, February 1999

Vasoconstrictor effect of endothelin-1 in human skin: role of ETA and ETB receptors

Joan E. Lipa1,2, Peter C. Neligan1,2, Therese M. Perreault3, Johanne Baribeau3, Ronald H. Levine2, Robert J. Knowlton2, and Cho Y. Pang1,2,4

1 Research Institute, The Hospital for Sick Children and Departments of 2 Surgery and 4 Physiology, University of Toronto, Toronto, Ontario M5G 1X8; and 3 Division of Newborn Medicine, The Montreal Children's Hospital, Montreal, Quebec, H3H 1P3 Canada

The aim of this project was to investigate the role of ETA and ETB 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 (10-10 to 10-8 M) and norepinephrine (NE, 10-8 to 10-5 M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 ~200-fold higher than NE. The ETA-receptor antagonist BQ-123 but not the ETB-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, ETB-receptor agonists BQ-3020 and sarafotoxin S6c (10-9 to 10-6 M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10-5 M of Nomega -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 ETA receptor subtype in endothelium-denuded skin arteries and veins of 0.5-1.5 mm diameter, with an ETA-to-ETB 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 ETA receptors, with no significant participation from ETB receptors.

vasoconstriction


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