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(-)Doxazosin is a necessary component for the hypotensive effect of (±)doxazosin during long-term administration in conscious rats

Aim: Doxazosin is a racemic mixture of (–)doxazosin and (+)doxazosin that is currently used as an add-on therapy for hypertension. In this study we investigated the contribution of each enantiomer to the hypotensive action of long-term administration of (±)doxazosin in conscious rats. Methods: Blood...

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Published in:Acta pharmacologica Sinica 2014-01, Vol.35 (1), p.48-57
Main Authors: Zhao, Jing, Kong, De-zhi, Li, Qing, Zhen, Ya-qin, Wang, Miao, Zhao, Yan, Wang, Dong-kai, Ren, Lei-ming
Format: Article
Language:English
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Summary:Aim: Doxazosin is a racemic mixture of (–)doxazosin and (+)doxazosin that is currently used as an add-on therapy for hypertension. In this study we investigated the contribution of each enantiomer to the hypotensive action of long-term administration of (±)doxazosin in conscious rats. Methods: Blood pressure of conscious SD rats was measured using a volume pressure recording system. The rats were orally administered (–)doxazosin, (+)doxazosin, or (±)doxazosin (8 mg·kg-1·d-1) for 12 weeks. Plasma concentrations of the agents were analyzed with HPLC. The effect of the agents on α1-adrenoceptor was examined in isolated rat caudal artery preparations. Results: Treatment of conscious rats with a single dose of (±)doxazosin (8 mg/kg) did not affected DBP and MBP, but significantly decreased SBP by 11.9% 4 h after the administration. Long-term treatment of conscious rats with (±)doxazosin significantly decreased SBP, DBP and MBP with a maximal decrease of SBP by 29.3% 8 h after the last administration. The rank order of the hypotensive actions caused by long-term treatment in conscious rats was (±)doxazosin〉(+)doxazosin〉〉(–)doxazosin. However, the pKB values for inhibiting NA-induced contraction of isolated rat caudal artery were (+)doxazosin (8.995)〉(±)doxazosin (8.694)〉(–)doxazosin (8.032). The plasma concentrations of (–)doxazosin, (+)doxazosin, and (±)doxazosin were 18.26±3.55, 177.11±20.66, and 113.18±13.21 ng/mL, respectively, 8 h after the last administration of these agents. Conclusion: Long-term treatment with (±)doxazosin produces potent hypotensive action in conscious rats that seems to result from synergic interaction of the two enantiomers.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2013.154