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Acute dilation to alpha(2)-adrenoceptor antagonists uncovers dual constriction and dilation mediated by arterial alpha(2)-adrenoceptors.

Authors
Crassous-PA; Flavahan-S; Flavahan-NA
Source
Br J Pharmacol 2009 Nov; 158(5):1344-1355
NIOSHTIC No.
20036435
Abstract
BACKGROUND AND PURPOSE: In mouse tail arteries, selective alpha(2)-adrenoceptor antagonism with rauwolscine caused powerful dilation during constriction to the alpha(1)-adrenoceptor agonist phenylephrine. This study therefore assessed phenylephrine's selectivity at vascular alpha-adrenoceptors and the mechanism(s) underlying dilation to rauwolscine. EXPERIMENTAL APPROACH: Mouse isolated tail arteries were assessed using a pressure myograph. KEY RESULTS: The alpha(2)-adrenoceptor agonist UK14,304 caused low-maximum constriction that was inhibited by rauwolscine (3 x 10(-8) M) but not by the selective alpha(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 alpha(2)-adrenoceptor antagonist (RX821002, 3 x 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 alpha(2)-adrenoceptors caused transient dilation that was substantially greater than the contribution of alpha(2)-adrenoceptors to the constriction. This reflects a slowly reversing alpha(2)-adrenoceptor-mediated endothelium-dependent dilation and provides a rapid, sensitive test of alpha(2)-adrenoceptor activity. This approach also clearly emphasizes the poor selectivity of phenylephrine at vascular alpha-adrenoceptors.
Keywords
Blood-vessels; Cell-biology; Cell-differentiation; Cell-function; Cell-transformation; Circulatory-system; Laboratory-animals; Laboratory-testing; Muscle-cells; Nerve-function; Nerves; Author Keywords: alpha1-adrenoceptors; alpha2-adrenoceptors; endothelium; phenylephrine; cirazoline
Contact
Nicholas A Flavahan, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Ross Research Building, Room 370, 720 Rutland Ave, Baltimore, MD 21205
CODEN
BJPCBM
Publication Date
20091101
Document Type
Journal Article
Email Address
nflavah1@jhmi.edu
Funding Type
Grant
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008531
Issue of Publication
5
ISSN
0007-1188
Priority Area
Construction; Manufacturing
Source Name
British Journal of Pharmacology
State
MD; OH
Performing Organization
Johns Hopkins University
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