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

• Published in: Acta pharmacologica Sinica Vol. 35; no. 1; pp. 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: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2014
• Subjects: Administration, Oral; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - blood; Blood Pressure - drug effects; Blood Pressure - physiology; Consciousness - drug effects; Consciousness - physiology; Doxazosin - administration & dosage; Doxazosin - blood; Heart Rate - drug effects; Heart Rate - physiology; Male; Original; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors; 口服给药; 外消旋混合物; 多沙唑嗪; 大鼠; 成分; 肾上腺素能受体; 降血压作用; 高效液相色谱法
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2013.154

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.