Acute dilation to α 2-adrenoceptor antagonists uncovers dual constriction and dilation mediated by arterial α 2- adrenoceptors

P. A. Crassous, S. Flavahan, N. A. Flavahan

Research output: Contribution to journalArticle

Abstract

Background and purpose: In mouse tail arteries, selective α 2-adrenoceptor antagonism with rauwolscine caused powerful dilation during constriction to the α 1-adrenoceptor agonist phenylephrine. This study therefore assessed phenylephrine's selectivity at vascular α-adrenoceptors and the mechanlsm(s) underlying dilation to rauwolscine. Experimental approach: Mouse isolated tail arteries were assessed using a pressure myograph. Key results: The α 2-adrenoceptor agonist UK14, 304 caused low-maximum constriction that was inhibited by rauwolscine (3 × 10 -8 M) but not by the selective α 1-adrenoceptor antagonist prazosin (10 -7 M). Concentration-effect curves to phenylephrine, cirazoline or noradrenaline were unaffected by rauwolscine but were inhibited by prazosin, which was more effective at high compared with low levels of constriction. In the presence of prazosin, rauwolscine inhibited the curves and was more effective at low compared with high levels of constriction. Although rauwolscine alone did not affect concentration-effect curves to phenylephrine, noradrenaline or cirazoline, it caused marked transient dilation when administered during constriction to these agonists. Dilation was mimicked by another α 2-adrenoceptor antagonist (RX821002, 3 × 10 -8 M), was dependent on agonist selectivity, and did not occur during adrenoceptor-independent constriction (U46619). During constriction to UK14, 304 plus U46619, rauwolscine or rapid removal of UK14, 304 caused transient dilation that virtually abolished the combined constriction. Endothelial denudation reduced these dilator responses. Conclusions and implications: Inhibition of α 2-adrenoceptors caused transient dilation that was substantially greater than the contribution of α 2- adrenoceptors to the constriction. This reflects a slowly reversing α 2-adrenoceptor-mediated endotheliumdependent dilation and provides a rapid, sensitive test of α 2-adrenoceptor activity. This approach also clearly emphasizes the poor selectivity of phenylephrine at vascular α-adrenoceptors.

Original languageEnglish (US)
Pages (from-to)1344-1355
Number of pages12
JournalBritish Journal of Pharmacology
Volume158
Issue number5
DOIs
StatePublished - Dec 4 2009

Keywords

  • Cirazoline
  • Endothelium
  • Phenylephrine
  • α -adrenoceptors
  • α -adrenoceptors

ASJC Scopus subject areas

  • Pharmacology

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