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Acute dilation to α 2 ‐adrenoceptor antagonists uncovers dual constriction and dilation mediated by arterial α 2 ‐adrenoceptors
Author(s) -
Crassous PA,
Flavahan S,
Flavahan NA
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00403.x
Subject(s) - rauwolscine , prazosin , constriction , phenylephrine , medicine , antagonist , vasoconstriction , endocrinology , yohimbine , agonist , chemistry , vascular smooth muscle , receptor , blood pressure , smooth muscle
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 mechanism(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 endothelium‐dependent 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.