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

Abstract

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.

Figure 1

Changes in systolic blood pressure (A), diastolic blood pressure (B) and mean blood pressure (C) in nonfasted conscious rats after a single administration of 8 mg/kg (±)doxazosin. The data are expressed as the mean±SEM. n=6. ^bP<0.05 vs baseline.

Figure 2

The plasma concentration of (±)doxazosin after a single administration of 8 mg/kg (±)doxazosin in fasted and nonfasted conscious rats. The data are expressed as the mean±SEM. n=4.

Figure 3

Changes in systolic (A), diastolic (B) and mean blood pressure (C) in nonfasted conscious rats after the long-term administration of (−)doxazosin, (+)doxazosin, and (±)doxazosin (8 mg/kg, once daily for 12 weeks, respectively). The data are expressed as the mean±SEM. n=10. ^bP<0.05, ^cP<0.01 vs baseline. ^eP<0.05, ^fP<0.01 vs control.

Figure 4

Decreases in the systolic (A), diastolic (B) and mean blood pressure (C) 8 h after the last administration of (−)doxazosin, (+)doxazosin, and (±)doxazosin. ^bP<0.05, ^cP<0.01 vs control. ^eP<0.05, ^fP<0.01 vs (±)doxazosin.

Figure 5

Typical HPLC chromatograms obtained from a blank plasma sample determined using an achiral column (A); a rat plasma sample collected after the oral administration of a racemic doxazosin and determined using an achiral column (B); a blank plasma sample determined using a chiral column (C); the rat plasma sample aliquoted from that for (B) and determined by a chiral column (D). Peaks: 1) prazosin, 2) doxazosin, 3) (−)doxazosin, and 4) (+)doxazosin. For more experimental details, refer to the Materials and methods section.

Figure 6

Plasma concentrations of (−)doxazosin, (+)doxazosin, and (±)doxazosin 8 h after the last administration of (−)doxazosin, (+)doxazosin, and (±)doxazosin. Data are expressed as the mean±SEM. n=10. ^bP<0.05, ^cP<0.01 vs (+)doxazosin. ^fP<0.01 vs (−)doxazosin.

Figure 7

The effects of (−)doxazosin (A), (+)doxazosin (B), and (±)doxazosin (C) on the contractile responses to NA in the isolated caudal artery of the rat. Points represent the mean values and vertical bars show the SEM. n=6.