Endothelins and their inhibition in the human skin microcirculation: ET[1-31], a new vasoconstrictor peptide.
OBJECTIVE
Endothelin-1 (ET-1([1-21])) is an extremely potent vasoconstrictor in the human skin microcirculation and is generated from larger precursor peptides. The aims of the present study were to assess the vasoactive effects of these precursors as well as endothelin blockade in the human skin microcirculation, in vivo.


METHODS
Six healthy volunteers received intradermal injections of a range of doses of big ET-1([1-38]), ET-1([1-31]), ET-1([1-21]), BQ-123 (ET(A) receptor antagonist), BQ-788 (ET(B) receptor antagonist), phosphoramidon [endothelin converting enzyme (ECE) inhibitor] or saline control (0.9%). Skin blood flow (SBF) was measured using standard laser Doppler flowmetry.


RESULTS
Big ET-1([1-38]), ET-1([1-31]) and ET-1([1-21]) reduced SBF when compared with saline control (P < 0.01 for all). Big ET-1([1-38]) and ET-1([1-31]) were less potent than ET-1([1-21]) as defined by skin vasoconstriction. Phosphoramidon, BQ-123 and BQ-788, given alone, all caused vasodilatation in the human skin microcirculation (P < 0.01 for all).


CONCLUSIONS
In the human skin microcirculation, big ET-1([1-38]) and ET-1([1-31]) are less potent vasoconstrictors than ET-1([1-21]). The effects of big ET-1([1-38]) and phosphoramidon suggest the presence of endogenous ECE activity in the skin. In contrast to skeletal muscle resistance vessels, ET-1([1-21]) contributes to the maintenance of skin microvascular tone through both ET(A) and ET(B) receptor-mediated vasoconstriction.
Leslie
Stephen J
SJ
Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.
Rahman
Mamun Q
MQ
Denvir
Martin A
MA
Newby
David E
DE
Webb
David J
DJ
D000328:Adult; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors*
D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D014662:Vasoconstrictor Agents; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)