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

Zhao, Jing; Kong, De-zhi; Li, Qing; Zhen, Ya-qin; Wang, Miao; Zhao, Yan; Wang, Dong-kai; Ren, Lei-ming
January 2014
Acta Pharmacologica Sinica;Jan2014, Vol. 35 Issue 1, p48
Academic Journal
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.


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