Endothelin-A receptor antagonist inhibits angiotensin II and noradrenaline in man.

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.
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.
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).
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.
AuthorsR R Wenzel, J Rüthemann, H Bruck, R F Schäfers, M C Michel, T Philipp
JournalBritish journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 52 Issue 2 Pg. 151-7 (Aug 2001) ISSN: 0306-5251 [Print] England
PMID11488771 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antihypertensive Agents
  • BQ 788
  • Endothelin Receptor Antagonists
  • Oligopeptides
  • Peptides, Cyclic
  • Piperidines
  • Receptor, Endothelin A
  • Vasoconstrictor Agents
  • Angiotensin II
  • cyclo(Trp-Asp-Pro-Val-Leu)
  • Norepinephrine
  • Adult
  • Angiotensin II (antagonists & inhibitors, pharmacology)
  • Antihypertensive Agents (pharmacology)
  • Endothelin Receptor Antagonists
  • Humans
  • Laser-Doppler Flowmetry
  • Male
  • Microcirculation (drug effects)
  • Norepinephrine (antagonists & inhibitors, pharmacology)
  • Oligopeptides (pharmacology)
  • Peptides, Cyclic (pharmacology)
  • Piperidines (pharmacology)
  • Receptor, Endothelin A
  • Skin Physiological Phenomena
  • Vasoconstriction (drug effects)
  • Vasoconstrictor Agents (pharmacology)

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