Endothelin-A receptor antagonist inhibits angiotensin II and noradrenaline in man.
OBJECTIVE
Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear.


METHODS
We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique.


RESULTS
BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001).


CONCLUSIONS
ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.
Wenzel
R R
RR
Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Essen, Germany. rene@rrwenzel.de
Rüthemann
J
J
Bruck
H
H
Schäfers
R F
RF
Michel
M C
MC
Philipp
T
T
D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012879:Skin Physiological Phenomena; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine