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)
Wenzel
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Division of Cardiology, University Hospital, Inselspital, Bern, Switzerland.
Noll
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Lüscher
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TF
D000328:Adult; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; C082887:PD 145065; D008012:Lidocaine; D009638:Norepinephrine