Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade

M C Verhaar, F E Strachan, D E Newby, N L Cruden, H A Koomans, T J Rabelink, D J Webb

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET(A) receptors are clear, the contribution from endothelial and vascular smooth muscle ET(B) receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET(A) and ET(B) receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET(A)-selective receptor antagonist BQ-123.

METHODS AND RESULTS: Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (P=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (P<.001) with coinfusion of the ET(B) receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (P<.001).

CONCLUSIONS: Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET(B) receptor antagonism either alone or on a background of ET(A) antagonism causes local vasoconstriction, indicating that ET(B) receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Original languageEnglish
Pages (from-to)752-6
Number of pages5
JournalCirculation
Volume97
Issue number8
DOIs
Publication statusPublished - 3 Mar 1998

Keywords

  • Adult
  • Endothelin Receptor Antagonists
  • Female
  • Forearm
  • Humans
  • Male
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Oligopeptides
  • Peptides, Cyclic
  • Piperidines
  • Prostaglandins
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Regional Blood Flow
  • Vasodilation
  • Vasodilator Agents

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