Endothelin-B-receptor-selective antagonist inhibits endothelin-1 induced potentiation on the vasoconstriction to noradrenaline and angiotensin II.
OBJECTIVE
Endothelin-A-receptor-antagonists inhibit angiotensin II- and noradrenaline-induced vasoconstriction. Whether functional constrictive endothelin-B-receptors play a role in the endothelin-1-mediated potentiation of vasoconstriction to angiotensin II and noradrenaline is thus far unknown.


METHODS
We studied the effects of noradrenaline and angiotensin II (10 mol/l) in the presence of exogenous endothelin-1 (10 mol/l) with and without selective endothelin-B-receptor-blockade by BQ-788 (10 mol/l) and dual receptor blockade with BQ-788 and the endothelin-A-selective antagonist BQ-123 (10 mol/l) in 14 healthy male volunteers (aged 20-28). Studies were performed in the human skin microcirculation under in vivo conditions using laser-Doppler flowmetry and double injection technique. The area under the time-response curve of all doses was calculated.


RESULTS
Endothelin-1 potentiated the effects of angiotensin II and noradrenaline (-944 +/- 139 perfusion units (PU), P < 0.01; -926 +/- 117 PU, P < 0.05, respectively). In the presence of BQ-788, the potentiating effect of endothelin-1 was significantly blunted (-624 +/- 132 PU, P < 0.01; -549 +/- 136 PU, P < 0.01, respectively). In the presence of BQ-123 and BQ-788 the vasoconstriction was fully inhibited (431 +/- 108 PU, P < 0.001 and 421 +/- 86 PU, P < 0.001, respectively).


CONCLUSIONS
These data suggest that functional vasoconstrictive endothelin-B receptors on vascular smooth muscle cells may contribute to the potentiating effects of high local concentrations of endothelin-1 on the vasoconstriction to noradrenaline and angiotensin II in human microcirculation.
Gössl
Mario
M
West German Heart Center Essen, Division of Cardiology, University Hospital Essen, Germany.
Mitchell
Anna
A
Lerman
Amir
A
Opazo Saez
Anabelle
A
Schäfers
Rafael F
RF
Erbel
Raimund
R
Philipp
Thomas
T
Wenzel
René R
RR
D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine