Endothelin receptor antagonists inhibit endothelin in human skin microcirculation

Endothelin is a potent vasoconstrictor peptide produced by endothelial cells, but its role in physiology and disease is uncertain. We investigated the influence of the endothelin-A-selective receptor antagonist PD 147953 and the nonselective endothelin receptor antagonist PD 145065 on the effects of endothelin-1 and endothelin-3 in the skin microcirculation of healthy volunteers, using laser Doppler flowmetry. A double injection model was developed, allowing simultaneous injection of two substances, ie, agonist and antagonist or saline. The injection of saline led to a well-defined vasodilation at the injection site (maximum increase, from 19 +/- 2 to 97 +/- 15 perfusion units at 6 minutes; P < .001; n = 10). Endothelin-1 (10(-12) mol) decreased blood flow (difference from saline control, -79 +/- 14 perfusion units; P < .001; n = 11) within the injection wheal (diameter, 4 to 5 mm), while endothelin-3 had no effect. In the surrounding area (at 8 mm from the injection site), both endothelin-1 (+116 +/- 32 perfusion units; P < .001; n = 11) and endothelin-3 (+59 +/- 16 perfusion units; P < .001; n = 11) markedly increased blood flow. Both endothelin receptor antagonists slightly increased blood flow (maximum difference from control, +56 +/- 18 [PD 147953] and +31 +/- 10 [PD 145065] perfusion units; P < .05; n = 8) and inhibited endothelin-1-induced (P < .01) vasoconstriction. The vasoconstriction to norepinephrine was not affected by the endothelin antagonist PD 147953. Endothelin-1- and endothelin-3-induced vasodilation in the surrounding area were also inhibited by both endothelin antagonists or by lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)