多沙唑嗪对清醒大鼠血压的影响及其相关机制的分析
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摘要
多沙唑嗪作为抗高血压治疗的辅助用药，临床常用其消旋体，其分子结构中含有一个手性碳原子和一对对映体。我们曾报道左旋多沙唑嗪、右旋多沙唑嗪和消旋多沙唑嗪降低麻醉大鼠血压的强度序列为左旋多沙唑嗪<消旋多沙唑嗪<右旋多沙唑嗪。然而，在清醒大鼠长期给予消旋多沙唑嗪的降压效应中，左旋多沙唑嗪和右旋多沙唑嗪两对映体所发挥的作用尚不清楚。本研究目的是，观察连续12周灌胃给予左旋多沙唑、右旋多沙唑嗪和消旋多沙唑嗪（8mg/kg），清醒大鼠动脉血压的变化；观察左旋多沙唑嗪、右旋多沙唑嗪和消旋多沙唑嗪连续12周灌胃给药时，大鼠进食量、体重增长、肝脏与肾脏功能的改变；采用高效液相色谱仪及FLD荧光检测器，分析连续12周灌胃给药后，多沙唑嗪及其对映体在最大降压作用时的血药浓度；采用大鼠离体尾动脉实验，比较左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪对血管α1肾上腺素受体的阻断作用。
第一部分多沙唑嗪对映体长期灌胃给药对清醒大鼠动脉血压的影响
大鼠适应性饲养1周后，随机分为溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组以及消旋多沙唑嗪组，每组10只。左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组均灌胃给予相应的药物（8mg/kg），溶媒对照组灌胃给予等容积溶媒。给药容积为10ml/kg，每周给药7天，连续12周。于连续灌胃给药11周后，每天每组随机抽取2只未禁食大鼠测量血压。读取给药前0时、药后2小时、4小时、8小时、12小时的收缩压、舒张压、平均动脉压和心率。
1多沙唑嗪对映体连续给药12周对未禁食清醒大鼠收缩压、舒张压和平均动脉压的影响。
与给药前相比，溶媒对照组大鼠的收缩压、舒张压和平均动脉压于给溶媒后2、4、8、12小时无显著性改变（P>0.05）。消旋多沙唑嗪组大鼠的收缩压在给药后2小时（123.03±3.63mmHg）、4小时（123.93±6.53mmHg）、8小时（102.15±3.68mmHg）以及12小时（113.86±5.28mmHg）均显著低于药前收缩压（144.57±4.18mmHg，P<0.01）。长期给予消旋多沙唑嗪及其对映体降低未禁食清醒大鼠舒张压与平均动脉压的作用与其降低收缩压的作用相似。与溶媒对照组相比，消旋多沙唑嗪组大鼠的收缩压、舒张压及平均动脉压显著降低（P<0.01）。与消旋多沙唑嗪相似，右旋多沙唑嗪组大鼠的收缩压、舒张压及平均动脉压在末次给药后2小时、4小时、8小时、12小时，均显著低于药前值（P<0.05或P<0.01）。但是，右旋多沙唑嗪组大鼠收缩压、舒张压及平均动脉压的最大降幅（药后8小时）显著小于消旋多沙唑嗪(P<0.05)。末次给药后8小时，左旋多沙唑嗪组大鼠的收缩压（112.67±6.56mmHg）、舒张压（72.34±4.24mmHg）及平均动脉压（85.46±4.96mmHg）与药前值（132.81±4.83mmHg、87.15±3.58mmHg、102.00±3.96mmHg）相比，轻微但显著性降低(P<0.05或P<0.01)。但是，与溶媒对照组相比，左旋多沙唑嗪组大鼠收缩压、舒张压及平均动脉压的最大降幅（8小时）无显著改变(P>0.05)。
2多沙唑嗪对映体连续灌胃给药12周对未禁食清醒大鼠心率的影响
与给药前相比，末次给药后2、4、8、12小时，溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠的心率无显著改变(P>0.05)。但是，与溶媒对照组相比，消旋多沙唑嗪组大鼠的心率，于给药后8小时(336.61±16.57bpm比427.43±34.4bpm)和12小时(332.24±22.68bpm比435.15±25.85bpm)，显著加快(P<0.05或P<0.01)。
第二部分多沙唑嗪对映体长期灌胃给药对大鼠一般状况的影响
大鼠适应性饲养1周后，随机分为溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组以及消旋多沙唑嗪组，每组10只。左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠均灌胃给予相应的药物（8mg/kg），溶媒对照组大鼠灌胃给予等容积溶媒。给药容积为10ml/kg，每周给药7天，连续12周。观察多沙唑嗪对映体长期灌胃给药对清醒大鼠进食量、体重增长及血液生化指标的影响。
1多沙唑嗪对映体连续灌胃给药12周对大鼠体重的影响
灌胃给予溶媒、左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪之前（0周），各组大鼠体重无显著性差异（P>0.05）。溶媒对照组大鼠在实验第3周（449.2±12.38g）、6周（489.8±14.55g）、9周（516.2±14.04g）以及12周（539.7±14.69g）时的体重显著高于0周时的体重（359.9±6.98g；P<0.01）。与给药前的大鼠体重相比，左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪各组大鼠，在灌胃给药后的第3周、6周、9周和12周时的体重均显著增加（P<0.01）。双因素方差分析结果表明，左旋多沙唑嗪、右旋多沙唑嗪或消旋多沙唑嗪组的大鼠体重（第3周、6周、9周和12周），与同时期溶媒对照组相比，均未见显著差异（P>0.05）。
2多沙唑嗪对映体连续灌胃给药12周对大鼠进食量的影响
与溶媒对照组大鼠0周时的进食量（25.75±0.25g）相比，给药前（0周）左旋多沙唑嗪（24.77±0.57g）、右旋多沙唑嗪（25.32±0.48g）以及消旋多沙唑嗪（26.50±0.50g）各组大鼠的进食量无显著性差异（P>0.05）。统计分析结果表明，除第10周以外，其他各周（第1周至第12周）左旋多沙唑嗪、右旋多沙唑嗪或消旋多沙唑嗪组大鼠的进食量，与同时期溶媒对照组相比未见显著差异（P>0.05）。左旋多沙唑嗪组以及右旋多沙唑嗪组大鼠在10周时的进食量与溶媒对照组相比显著增加（P<0.05）。
3多沙唑嗪对映体连续灌胃给药12周对大鼠肾功能的影响
溶媒对照组大鼠灌胃给予溶媒12周后，大鼠肾功能生化指标中的肌酐（CRTN）、尿酸（UA）、尿素（UREA）水平分别为：33.20±1.15μmol/L、70.80±9.31μmol/L、5.28±0.27mmol/L。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，大鼠肾功能生化指标中的肌酐、尿酸、尿素水平未见显著性改变（P>0.05）。
4多沙唑嗪对映体连续给药12周对大鼠肝功能的影响
溶媒对照组大鼠灌胃给予溶媒12周后，大鼠肝功能生化指标中的丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、总蛋白（TP）、白蛋白（ALB）、球蛋白（GLO）水平及白蛋白/球蛋白比值（A/G）分别为：36.30±3.56U/L、154.30±19.42U/L、57.31±1.71g/L、28.67±0.77g/L、28.64±1.06g/L以及1.00±0.02。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，大鼠肝功能生化指标中的丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、总蛋白、白蛋白、球蛋白水平以及白蛋白/球蛋白比值均无显著性改变（P>0.05）。
5多沙唑嗪对映体连续灌胃给药12周对大鼠血糖及血脂水平的影响
溶媒对照组灌胃给予溶媒12周后，大鼠血糖（GLU）、胆固醇（T-CHO）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、极低密度脂蛋白胆固醇（VLDL-C）水平分别为：5.85±0.38mmol/L、1.15±0.04mmol/L、0.37±0.05mmol/L、0.33±0.01mmol/L、0.24±0.02mmol/L以及0.17±0.02mmol/L。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，右旋多沙唑嗪组大鼠的HDL-C水平显著升高（P<0.01），左旋多沙唑嗪组大鼠的LDL-C水平显著降低（P<0.01）；各给药组的其他各项指标均未见显著性改变（P>0.05）。
连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，与溶媒对照组相比，左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠的肌酸激酶水平无显著性改变（P>0.05）。
第三部分大鼠口服多沙唑嗪对映体后最大降压作用时的血药浓度分析
本研究观察了消旋多沙唑嗪单次灌胃给药后，清醒大鼠降压作用的时效关系；分析了食物对消旋多沙唑嗪单次灌胃给药后血药浓度的影响；以及左旋多沙唑嗪、右旋多沙唑嗪和消旋多沙唑嗪连续12周灌胃给药时，3个药物末次给药后产生最大降压效果时（药后8小时）血药浓度的差异。
1消旋多沙唑嗪单次灌胃给药对清醒大鼠血压及心率的影响
在给予溶媒后2小时、4小时、8小时、12小时时，溶媒对照组清醒大鼠的收缩压、舒张压以及平均动脉压，与0小时相比无显著改变（P>0.05）。消旋多沙唑嗪给药组清醒大鼠的收缩压，与0小时相比显著降低（P<0.05），单次给药后4小时清醒大鼠收缩压降至最低值，下降了11.90%；舒张压和平均动脉压无显著改变（P>0.05）。
溶媒对照组清醒大鼠的心率，在给予溶媒后2小时、4小时、8小时、12小时时，与0小时相比无显著改变（P>0.05）。单次给予消旋多沙唑嗪后2小时、4小时、8小时、12小时时，清醒大鼠的心率与0小时相比无显著改变（P>0.05）；给药前与给药后2小时、4小时、8小时、12小时时，大鼠的心率分别为389.43±23.31、343.02±14.06、359.16±17.18、359.16±17.18和344.99±9.23（bpm）。与溶媒对照组相比，消旋多沙唑嗪给药组清醒大鼠的心率无显著改变（P>0.05）。
2食物对消旋多沙唑嗪单次灌胃给药后血药浓度的影响
禁食大鼠灌胃给予消旋多沙唑嗪后0.5小时，血药浓度迅速升高至254.61±27.69ng/mL，给药后1小时达峰值306.97±43.47ng/mL，给药后2小时仍维持在较高的浓度(296.10±40.97ng/mL)；之后血药浓度明显降低，给药后12小时降至30.22±16.53ng/mL。非禁食组大鼠灌胃给予相同剂量的药物后，0.5至2小时的血药浓度略低于禁食组大鼠，但是未见显著性差异（P>0.05）；此外，4至6小时的血药浓度呈一平台(170.75±27.05和169.87±40.29ng/mL)。禁食组与未禁食组大鼠给予消旋多沙唑嗪8小时的血药浓度分别为125.35±72.6ng/mL和125.799±33.7ng/mL。
3多沙唑嗪对映体末次给药产生最大降压效应时血药浓度的分析
末次灌胃给予左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪后8小时，各组大鼠的血药浓度分别为18.26±3.55ng/mL、177.11±20.66ng/mL和113.18±13.21ng/mL。灌胃给药后8小时，左旋多沙唑嗪与消旋多沙唑嗪的血药浓度显著低于右旋多沙唑嗪（P<0.05或P<0.01）；而且左旋多沙唑嗪血药浓度与右旋多沙唑嗪血药浓度的比值为0.1。将消旋多沙唑嗪灌胃给药大鼠的血浆药物进一步进行手性分离检测后发现，其中左旋多沙唑嗪的浓度为12.01±2.45ng/mL，右旋多沙唑嗪的浓度为96.56±9.94ng/mL,两者的比值为0.12。
第四部分多沙唑嗪对映体对大鼠离体尾动脉α1受体的阻断作用
我们采用大鼠离体尾动脉标本，探讨左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪对大鼠离体尾动脉α1受体的阻断作用。
1溶媒对NA诱发大鼠尾动脉收缩反应的影响
溶媒对照组中，建立5轮NA诱导的血管收缩反应量效曲线。第2轮作为对照，其他3轮在建立NA量效曲线前20min加入溶媒。研究结果表明，第2至第5轮NA量效曲线的Emax值分别为1.75±0.05g、1.76±0.07g、1.80±0.07g和1.93±0.06g；统计学分析结果显示，与对照组相比，后3轮NA量效曲线的Emax值和EC50值无显著改变（P>0.05）。在大鼠尾动脉，溶媒对NA量效曲线中各浓度点的血管收缩反应均无显著影响（P>0.05）。
2多沙唑嗪对映体对NA诱发大鼠尾动脉收缩反应的影响
NA（0.001-100μmol/L）可诱发大鼠尾动脉产生浓度依赖性收缩反应。在给予阻断剂左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪之前，各组间NA量效曲线的Emax值和EC50值无明显差异（P>0.05）。在建立第3、4、5轮NA量效曲线前20min，分别于浴槽中加入右旋多沙唑嗪或消旋多沙唑嗪0.001μmol/L、0.01μmol/L和0.1μmol/L。随着消旋多沙唑嗪浓度增加，NA量效曲线右移，Emax值不变（P>0.05）。Schild plot分析结果表明，消旋多沙唑嗪的作用属非竞争性拮抗，斜率（0.716±0.028）小于1（P<0.05）。右旋多沙唑嗪的作用与消旋多沙唑嗪相似，其斜率（0.647±0.018）亦小于1（P<0.05），属非竞争性拮抗。在建立第3、4、5轮NA量效曲线前20min分别给予左旋多沙唑嗪0.003μmol/L、0.03μmol/L和0.3μmol/L，随着左旋多沙唑嗪浓度增加，NA量效曲线右移，Emax值不变（P>0.05）。Schild plot分析结果表明，左旋多沙唑嗪的作用属非竞争性拮抗，斜率（0.607±0.028）小于1（P<0.05）。左旋多沙唑嗪的pKB值（8.032±0.039）显著小于右旋多沙唑嗪（8.995±0.032）及消旋多沙唑嗪（8.694±0.032）的pKB值（P<0.01），并且消旋多沙唑嗪的pKB值明显小于右旋多沙唑嗪的pKB值（P<0.01）。
结论
右旋多沙唑嗪阻断α1受体的作用显著强于消旋多沙唑嗪和左旋多沙唑嗪，但是清醒大鼠长期灌服消旋多沙唑嗪的降压作用显著强于右旋多沙唑嗪，而左旋多沙唑嗪长期给药未见明显降压作用。研究结果提示，左旋多沙唑嗪是抗高血压药消旋多沙唑嗪的必要成分，其中右旋多沙唑嗪兼具升高HDL-C的作用，左旋多沙唑嗪兼具降低LDL-C的作用。
Doxazosin currently used as add-on therapy for hypertension is racemicmixture of (-)doxazosin and (+)doxazation. Previously we reported that rankorder of acute hypotensive activity was (-)doxazosin <(±)doxazosin <(+)doxazosin in anesthetized rats. However, contributions of the twoenantiomers to hypotensive effect of long-term administration of (±)doxazosinin conscious animals are unknown. Here we observed hypotensive responsesto doxazosin enantiomers in conscious rats, and analyzed (±)doxazosin,(-)doxazosin and (+)doxazosin concentrations in plasma byHPLC-fluorescence method. α1-Adrenoceptor blocking activity of the3agentswas investigated in isolated rat caudal artery.
Part I Effects of long-term administrations of (-)doxazosin,(+)doxazosinand (±)doxazosin on blood pressure in conscious rats
Animals were allowed to habituate to the animal maintenance facilitiesfor a period of at least7days before the beginning of the experiments.40ratswere randomly divided into four groups of10each. Group I served as solventcontrol, and the rats in groups II, III and IV were administered orally8mg/kgof (-)doxazosin,(+)doxazosin and (±)doxazosin once daily for12weeks,respectively. During the11th week of drug administration, systolic bloodpressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP)and heart rate were measured at0,2,4,8and12h after a long-termadministration of8mg/kg (±)doxazosin in the conscious and nonfasted rats.The time required to complete the measurements in40animals was5days
1Effects of long-term administrations of doxazosin and its enantiomerson blood pressure in nonfasted conscious rats
The systolic blood pressure, diastolic blood pressure, mean bloodpressure did not change significantly at2,4,8and12h after solvent administration (P>0.05). In the rat treated with a long-term administration of(±)doxazosin for12weeks, the SBP decreased significantly at2h(123.03±3.63mmHg),4h (123.93±6.53mmHg),8h (102.15±3.68mmHg)and12h (113.86±5.28mmHg) after the last administration of8mg/kg(±)doxazosin, as compared to pre-drug baseline level (144.57±4.18mmHg;P<0.01). Hypotensive effects on DBP and MBP by long-term administrationof (±)doxazosin were similar to that on SBP. The results of statisticalcomparison between solvent group and (±)doxazosin group also indicatedsignificant hypotensive effects on SBP, DBP and MBP by (±)doxazosin.(+)Doxazosin had similar hypotensive effects as (±)doxazosin, but themaximal decreases (8h after the last administration) in SBP, DBP and MBPinduced by (+)doxazosin were significantly smaller than that by (±)doxazosinat the same dose (P<0.05). A long-term administration of (-)doxazosinproduced significant, but mild, hypotensive effects on the SBP (112.67±6.56mmHg), DBP (72.34±4.24mmHg) and MBP (85.46±4.96mmHg)8h after thelast administration, as compared to pre-drug baseline levels (132.81±4.83mmHg,87.15±3.58mmHg and102.00±3.96mmHg)(P<0.05and0.01).However, the maximal decreases (8h after the last administration) in SBP,DBP and MBP induced by (-)doxazosin were not significantly different fromthat by solvent (P>0.05).
2Effects of long-term administrations of doxazosin and its enantiomerson heart rate in nonfasted conscious rats
A long-term administration of (-)doxazosin,(+)doxazosin or(±)doxazosin did not affect HR significantly, as compared to pre-drug baselinelevel (P>0.05), however results of statistical comparison between solventgroup and (±)doxazosin group indicated a significant positive chronotropiceffect at8h (336.61±16.57bpm vs427.43±34.4bpm)and12h (332.24±22.68bpm vs435.15±25.85bpm) after the last administration of (±)doxazosin(P<0.05and0.01).
Part II Effects of long-term administrations of doxazosin and itsenantiomers on general situation of the rat
Animals were allowed to habituate to the animal maintenance facilitiesfor a period of at least7days before the beginning of the experiments.40ratswere randomly divided into four groups of10each. Group I served as solventcontrol, and the rats in groups II, III and IV were administered orally8mg/kgof (-)doxazosin,(+)doxazosin and (±)doxazosin once daily for12weeks,respectively. Effect of long-term administrations of doxazosin and itsenantiomers on general situation were observed.
1Effects of long-term administrations of doxazosin and its enantiomerson rat body weight
Before long-term oral administrations of solvent,(-)doxazosin,(+)doxazosin and (±)doxazosin, the body weights of4groups were notsignificantly different from each other (P>0.05). Body weights of the solventgroup at the end of the3rd,6th,9th and12th week were449.2±12.38g,489.8±14.55g,516±14.04g and539.7±14.69g, which were significantlygreater than the body weight (359.9±6.98g) before administration of thesolvent (P<0.01). Long-term administrations of (-)doxazosin,(+)doxazosinand (±)doxazosin for12weeks did not significantly affect body weight gain ofthe rat (P>0.05).
2Effects of long-term administrations of doxazosin and its enantiomerson food consumption of the rats
Before long-term oral administrations of solvent,(-)doxazosin,(+)doxazosin and (±)doxazosin, the food consumption of the4groups was notsignificantly different from each other (P>0.05). There was no significantdifference in food consumption among solvent,(-)doxazosin,(+)doxazosinand (±)doxazosin groups during the12week (except at the10th week)(P>0.05). Food consumption of the (-)doxazosin group or (+)doxazosin groupwas significantly greater than solvent group at the end of the10th week(P<0.05). There was no significant difference in food consumption between(±)doxazosin group and solvent group.
3Effects of long-term administrations of doxazosin and its enantiomers onkidney function
CRTN, UA and UREA levels of solvent group after a long-termadministration were33.2±1.15μmol/L,70.80±9.31μmol/L and5.28±0.27mmol/L. A long-term administration (12weeks) of (-)doxazosin,(+)doxazosinor (±)doxazosin did not affect the level of CRTN, UA, UREA significantly, ascompared to solvent group (P>0.05).
4Effects of long-term administrations of doxazosin and its enantiomerson liver function
ALT, AST, TP, ALB, GLO and A/G levels of solvent group after along-term administration were36.30±3.56U/L,154.30±19.42U/L,57.31±1.71g/L,28.67±0.77g/L,28.64±1.06g/L and1.00±0.02. A long-termadministration (12weeks) of (-)doxazosin,(+)doxazosin or (±)doxazosin didnot affect the levels of ALT, AST, TP, ALB, GLO and A/G significantly, ascompared to solvent group (P>0.05).
5Effects of long-term administrations of doxazosin and its enantiomerson GLU and serum lipid levels (T-CHO、TG、HDL-C、LDL-C、VLDL-C)
GLU, T-CHO, TG, HDL-C, LDL-C and VLDL-C levels of solvent groupafter a long-term administration were5.85±0.38mmol/L,1.15±0.04mmol/L,0.37±0.05mmol/L,0.33±0.01mmol/L,0.24±0.02mmol/L and0.17±0.02mmol/L. The level of GLU was not changed by the agents. Serum T-CHOlevel, TG level and VLDL-C level of the rats in solvent group,(-)doxazosingroup,(+)doxazosin group and (±)doxazosin group were not significantlydifferent from each other (P>0.05). A long-term treatment with (+)doxazosinincreased HDL-C level, and a long-term treatment with (-)doxazosindecreased LDL-C level significantly (P<0.01).
A long-term administration (12weeks) of (-)doxazosin,(+)doxazosin or(±)doxazosin did not affect the level of CK significantly, as compared tosolvent group (P>0.05).
Part III Plasma drug concentrations corresponding to maximalhypotensive responses to doxazosin and its enantiomers orallyadministered in the rat
Time-dependent hypotensive effects and maximum hypotensive effect induced by single oral administration of8mg/kg (±)doxazosin were studied.To clarify the possible influence of fasting state on plasma drug concentration,a difference in plasma drug concentration-time curves between fasted andnonfasted rats was studied. We measured the plasma concentrationscorresponding to maximal hypotensive responses to (-)doxazosin,(+)doxazosin and (±)doxazosin for long-term administration by HPLC.
1Changes in blood pressure and heart rate in conscious rats after a singleadministration of (±)doxazosin
The systolic blood pressure, diastolic blood pressure, mean bloodpressure and heart rate did not change significantly at2,4,8and12h aftersolvent administration (P>0.05). The SBP in rats treated with8mg/kg(±)doxazosin decreased significantly4h after administration, as compared topre-drug baseline level (P<0.05), but there was no significant differencebetween each individual datum (racemic doxazosin group) and its respectivecontrol value (solvent group). A single administration of (±)doxazosin did notaffect HR significantly (P>0.05), and the values of HR were389.43±23.31,343.02±14.06,359.16±17.18,359.16±17.18and344.99±9.23(bpm) beforeand2h,4h,8h,12h after the administration, respectively
2Effect of food on the plasma drug concentrations measured after asingle administration of (±)doxazosin
Plasma (±)doxazosin concentration quickly increased to254.61±27.69ng/ml at0.5h, then reached its peak level (306.97±43.47ng/ml) at1h afteroral administration in fasted rats. Its concentration was still maintained at ahigher level (296.10±40.97ng/ml) at2h, and decreased to30.22±16.53ng/mlat12h in fasted rats. Although the plasma concentration of (±)doxazosin innonfasted rats was slightly lower than that in fasted rats0.5h,1h and2h afteroral administration of the same dose, drug concentration-time curve for(±)doxazosin in fasted rats was not significantly different from that innonfasted rats (P>0.05). In addition, stable (±)doxazosin concentrations weremaintained at4h (170.75±27.05ng/ml) and6h (169.87±40.29ng/ml) afteroral administration in nonfasted rats.
3Analysis of plasma drug concentrations corresponding to maximalhypotensive responses to the last administration of doxazosin enantiomers inthe rat
Plasma drug concentrations were measured8h after the lastadministration of (-)doxazosin,(+)doxazosin and (±)doxazosin, and theconcentration of (-)doxazosin,(+)doxazosin or (±)doxazosin was18.26±3.55ng/ml,177.11±20.66ng/ml or113.18±13.21ng/ml. The concentrations of(-)doxazosin and (±)doxazosin were significantly lower than (+)doxazosin(P<0.05and0.01), and the concentration ratio of (-)doxazosin/(+)doxazosinwas0.10. A chiral separation of (±)doxazosin-containing plasma samples wasfurther performed, and the (-)doxazosin and (+)doxazosin components were12.01±2.45ng/ml and96.56±9.94ng/ml, respectively. The concentration ratioof (-)doxazosin/(+)doxazosin in plasma from the rats orally administered(±)doxazosin was0.12.
Part Ⅳ α1-Adrenoceptor blocking activity of doxazosin and itsenantiomers in the isolated rat caudal artery
In solvent control group, there were no significant differences in Emaxvalues among the second, third, fourth and fifth set of concentration-responsecurves for NA (1.75±0.05g,1.76±0.07g,1.80±0.07g and1.93±0.06g;P>0.05), and EC50values for NA calculated from the4concentration-responsecurves were not significantly different from each other (data not shown).Before treatment with (-)doxazosin,(+)doxazosin and (±)doxazosin, thevalues of Emax or EC50obtained from the concentration-response curves forNA were not significantly different from each other (P>0.05).(-)Doxazosin(0.003,0.03and0.3μmol/L),(+)doxazosin and (±)doxazosin (0.001,0.01and0.1μmol/L) produced a shift to the right of the concentration-response curvesfor NA (Figure8) without significant changes in the Emax values (P>0.05).Slope of the Schild plot for (-)doxazosin,(+)doxazosin or (±)doxazosin(0.607±0.028,0.647±0.018or0.716±0.028) was significantly different fromunity (P<0.05), indicating that the three agents non-competitively inhibited theconcentration-response curves for NA in the isolated rat caudal artery. The pKBvalue of (-)doxazosin (8.032±0.039) was significantly smaller (P<0.01)than that of (+)doxazosin (8.995±0.032) or (±)doxazosin (8.694±0.032), andthe pKBvalue of (±)doxazosin was significantly smaller than that of(+)doxazosin (P<0.01).
Conclusion
The effect of (+)doxazosin against α1-adrenoceptor is significantly higherthan that of (-)doxazosin and (±)doxazosin. However the hypotensive effect of(±)doxazosin of long-term administration higher than (+)doxazosin inconscious rats. The hypotensive effect of (-)doxazosin were not significantlydifferent from that by solvent. These results suggest that (-)doxazosincomponent is absolutely necessary to ensure the potent hypotensive effect ofracemic doxazosin administered for12weeks in conscious rats. And(+)doxazosin increased HDL-C level while (-)doxazosin decreased LDL-Clevel significantly.
第一部分多沙唑嗪对映体长期灌胃给药对清醒大鼠动脉血压的影响
大鼠适应性饲养1周后，随机分为溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组以及消旋多沙唑嗪组，每组10只。左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组均灌胃给予相应的药物（8mg/kg），溶媒对照组灌胃给予等容积溶媒。给药容积为10ml/kg，每周给药7天，连续12周。于连续灌胃给药11周后，每天每组随机抽取2只未禁食大鼠测量血压。读取给药前0时、药后2小时、4小时、8小时、12小时的收缩压、舒张压、平均动脉压和心率。
1多沙唑嗪对映体连续给药12周对未禁食清醒大鼠收缩压、舒张压和平均动脉压的影响。
与给药前相比，溶媒对照组大鼠的收缩压、舒张压和平均动脉压于给溶媒后2、4、8、12小时无显著性改变（P>0.05）。消旋多沙唑嗪组大鼠的收缩压在给药后2小时（123.03±3.63mmHg）、4小时（123.93±6.53mmHg）、8小时（102.15±3.68mmHg）以及12小时（113.86±5.28mmHg）均显著低于药前收缩压（144.57±4.18mmHg，P<0.01）。长期给予消旋多沙唑嗪及其对映体降低未禁食清醒大鼠舒张压与平均动脉压的作用与其降低收缩压的作用相似。与溶媒对照组相比，消旋多沙唑嗪组大鼠的收缩压、舒张压及平均动脉压显著降低（P<0.01）。与消旋多沙唑嗪相似，右旋多沙唑嗪组大鼠的收缩压、舒张压及平均动脉压在末次给药后2小时、4小时、8小时、12小时，均显著低于药前值（P<0.05或P<0.01）。但是，右旋多沙唑嗪组大鼠收缩压、舒张压及平均动脉压的最大降幅（药后8小时）显著小于消旋多沙唑嗪(P<0.05)。末次给药后8小时，左旋多沙唑嗪组大鼠的收缩压（112.67±6.56mmHg）、舒张压（72.34±4.24mmHg）及平均动脉压（85.46±4.96mmHg）与药前值（132.81±4.83mmHg、87.15±3.58mmHg、102.00±3.96mmHg）相比，轻微但显著性降低(P<0.05或P<0.01)。但是，与溶媒对照组相比，左旋多沙唑嗪组大鼠收缩压、舒张压及平均动脉压的最大降幅（8小时）无显著改变(P>0.05)。
2多沙唑嗪对映体连续灌胃给药12周对未禁食清醒大鼠心率的影响
与给药前相比，末次给药后2、4、8、12小时，溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠的心率无显著改变(P>0.05)。但是，与溶媒对照组相比，消旋多沙唑嗪组大鼠的心率，于给药后8小时(336.61±16.57bpm比427.43±34.4bpm)和12小时(332.24±22.68bpm比435.15±25.85bpm)，显著加快(P<0.05或P<0.01)。
第二部分多沙唑嗪对映体长期灌胃给药对大鼠一般状况的影响
大鼠适应性饲养1周后，随机分为溶媒对照组、左旋多沙唑嗪组、右旋多沙唑嗪组以及消旋多沙唑嗪组，每组10只。左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠均灌胃给予相应的药物（8mg/kg），溶媒对照组大鼠灌胃给予等容积溶媒。给药容积为10ml/kg，每周给药7天，连续12周。观察多沙唑嗪对映体长期灌胃给药对清醒大鼠进食量、体重增长及血液生化指标的影响。
1多沙唑嗪对映体连续灌胃给药12周对大鼠体重的影响
灌胃给予溶媒、左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪之前（0周），各组大鼠体重无显著性差异（P>0.05）。溶媒对照组大鼠在实验第3周（449.2±12.38g）、6周（489.8±14.55g）、9周（516.2±14.04g）以及12周（539.7±14.69g）时的体重显著高于0周时的体重（359.9±6.98g；P<0.01）。与给药前的大鼠体重相比，左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪各组大鼠，在灌胃给药后的第3周、6周、9周和12周时的体重均显著增加（P<0.01）。双因素方差分析结果表明，左旋多沙唑嗪、右旋多沙唑嗪或消旋多沙唑嗪组的大鼠体重（第3周、6周、9周和12周），与同时期溶媒对照组相比，均未见显著差异（P>0.05）。
2多沙唑嗪对映体连续灌胃给药12周对大鼠进食量的影响
与溶媒对照组大鼠0周时的进食量（25.75±0.25g）相比，给药前（0周）左旋多沙唑嗪（24.77±0.57g）、右旋多沙唑嗪（25.32±0.48g）以及消旋多沙唑嗪（26.50±0.50g）各组大鼠的进食量无显著性差异（P>0.05）。统计分析结果表明，除第10周以外，其他各周（第1周至第12周）左旋多沙唑嗪、右旋多沙唑嗪或消旋多沙唑嗪组大鼠的进食量，与同时期溶媒对照组相比未见显著差异（P>0.05）。左旋多沙唑嗪组以及右旋多沙唑嗪组大鼠在10周时的进食量与溶媒对照组相比显著增加（P<0.05）。
3多沙唑嗪对映体连续灌胃给药12周对大鼠肾功能的影响
溶媒对照组大鼠灌胃给予溶媒12周后，大鼠肾功能生化指标中的肌酐（CRTN）、尿酸（UA）、尿素（UREA）水平分别为：33.20±1.15μmol/L、70.80±9.31μmol/L、5.28±0.27mmol/L。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，大鼠肾功能生化指标中的肌酐、尿酸、尿素水平未见显著性改变（P>0.05）。
4多沙唑嗪对映体连续给药12周对大鼠肝功能的影响
溶媒对照组大鼠灌胃给予溶媒12周后，大鼠肝功能生化指标中的丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、总蛋白（TP）、白蛋白（ALB）、球蛋白（GLO）水平及白蛋白/球蛋白比值（A/G）分别为：36.30±3.56U/L、154.30±19.42U/L、57.31±1.71g/L、28.67±0.77g/L、28.64±1.06g/L以及1.00±0.02。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，大鼠肝功能生化指标中的丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、总蛋白、白蛋白、球蛋白水平以及白蛋白/球蛋白比值均无显著性改变（P>0.05）。
5多沙唑嗪对映体连续灌胃给药12周对大鼠血糖及血脂水平的影响
溶媒对照组灌胃给予溶媒12周后，大鼠血糖（GLU）、胆固醇（T-CHO）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、极低密度脂蛋白胆固醇（VLDL-C）水平分别为：5.85±0.38mmol/L、1.15±0.04mmol/L、0.37±0.05mmol/L、0.33±0.01mmol/L、0.24±0.02mmol/L以及0.17±0.02mmol/L。与溶媒对照组相比，连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，右旋多沙唑嗪组大鼠的HDL-C水平显著升高（P<0.01），左旋多沙唑嗪组大鼠的LDL-C水平显著降低（P<0.01）；各给药组的其他各项指标均未见显著性改变（P>0.05）。
连续灌胃给予左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪12周后，与溶媒对照组相比，左旋多沙唑嗪组、右旋多沙唑嗪组及消旋多沙唑嗪组大鼠的肌酸激酶水平无显著性改变（P>0.05）。
第三部分大鼠口服多沙唑嗪对映体后最大降压作用时的血药浓度分析
本研究观察了消旋多沙唑嗪单次灌胃给药后，清醒大鼠降压作用的时效关系；分析了食物对消旋多沙唑嗪单次灌胃给药后血药浓度的影响；以及左旋多沙唑嗪、右旋多沙唑嗪和消旋多沙唑嗪连续12周灌胃给药时，3个药物末次给药后产生最大降压效果时（药后8小时）血药浓度的差异。
1消旋多沙唑嗪单次灌胃给药对清醒大鼠血压及心率的影响
在给予溶媒后2小时、4小时、8小时、12小时时，溶媒对照组清醒大鼠的收缩压、舒张压以及平均动脉压，与0小时相比无显著改变（P>0.05）。消旋多沙唑嗪给药组清醒大鼠的收缩压，与0小时相比显著降低（P<0.05），单次给药后4小时清醒大鼠收缩压降至最低值，下降了11.90%；舒张压和平均动脉压无显著改变（P>0.05）。
溶媒对照组清醒大鼠的心率，在给予溶媒后2小时、4小时、8小时、12小时时，与0小时相比无显著改变（P>0.05）。单次给予消旋多沙唑嗪后2小时、4小时、8小时、12小时时，清醒大鼠的心率与0小时相比无显著改变（P>0.05）；给药前与给药后2小时、4小时、8小时、12小时时，大鼠的心率分别为389.43±23.31、343.02±14.06、359.16±17.18、359.16±17.18和344.99±9.23（bpm）。与溶媒对照组相比，消旋多沙唑嗪给药组清醒大鼠的心率无显著改变（P>0.05）。
2食物对消旋多沙唑嗪单次灌胃给药后血药浓度的影响
禁食大鼠灌胃给予消旋多沙唑嗪后0.5小时，血药浓度迅速升高至254.61±27.69ng/mL，给药后1小时达峰值306.97±43.47ng/mL，给药后2小时仍维持在较高的浓度(296.10±40.97ng/mL)；之后血药浓度明显降低，给药后12小时降至30.22±16.53ng/mL。非禁食组大鼠灌胃给予相同剂量的药物后，0.5至2小时的血药浓度略低于禁食组大鼠，但是未见显著性差异（P>0.05）；此外，4至6小时的血药浓度呈一平台(170.75±27.05和169.87±40.29ng/mL)。禁食组与未禁食组大鼠给予消旋多沙唑嗪8小时的血药浓度分别为125.35±72.6ng/mL和125.799±33.7ng/mL。
3多沙唑嗪对映体末次给药产生最大降压效应时血药浓度的分析
末次灌胃给予左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪后8小时，各组大鼠的血药浓度分别为18.26±3.55ng/mL、177.11±20.66ng/mL和113.18±13.21ng/mL。灌胃给药后8小时，左旋多沙唑嗪与消旋多沙唑嗪的血药浓度显著低于右旋多沙唑嗪（P<0.05或P<0.01）；而且左旋多沙唑嗪血药浓度与右旋多沙唑嗪血药浓度的比值为0.1。将消旋多沙唑嗪灌胃给药大鼠的血浆药物进一步进行手性分离检测后发现，其中左旋多沙唑嗪的浓度为12.01±2.45ng/mL，右旋多沙唑嗪的浓度为96.56±9.94ng/mL,两者的比值为0.12。
第四部分多沙唑嗪对映体对大鼠离体尾动脉α1受体的阻断作用
我们采用大鼠离体尾动脉标本，探讨左旋多沙唑嗪、右旋多沙唑嗪以及消旋多沙唑嗪对大鼠离体尾动脉α1受体的阻断作用。
1溶媒对NA诱发大鼠尾动脉收缩反应的影响
溶媒对照组中，建立5轮NA诱导的血管收缩反应量效曲线。第2轮作为对照，其他3轮在建立NA量效曲线前20min加入溶媒。研究结果表明，第2至第5轮NA量效曲线的Emax值分别为1.75±0.05g、1.76±0.07g、1.80±0.07g和1.93±0.06g；统计学分析结果显示，与对照组相比，后3轮NA量效曲线的Emax值和EC50值无显著改变（P>0.05）。在大鼠尾动脉，溶媒对NA量效曲线中各浓度点的血管收缩反应均无显著影响（P>0.05）。
2多沙唑嗪对映体对NA诱发大鼠尾动脉收缩反应的影响
NA（0.001-100μmol/L）可诱发大鼠尾动脉产生浓度依赖性收缩反应。在给予阻断剂左旋多沙唑嗪、右旋多沙唑嗪及消旋多沙唑嗪之前，各组间NA量效曲线的Emax值和EC50值无明显差异（P>0.05）。在建立第3、4、5轮NA量效曲线前20min，分别于浴槽中加入右旋多沙唑嗪或消旋多沙唑嗪0.001μmol/L、0.01μmol/L和0.1μmol/L。随着消旋多沙唑嗪浓度增加，NA量效曲线右移，Emax值不变（P>0.05）。Schild plot分析结果表明，消旋多沙唑嗪的作用属非竞争性拮抗，斜率（0.716±0.028）小于1（P<0.05）。右旋多沙唑嗪的作用与消旋多沙唑嗪相似，其斜率（0.647±0.018）亦小于1（P<0.05），属非竞争性拮抗。在建立第3、4、5轮NA量效曲线前20min分别给予左旋多沙唑嗪0.003μmol/L、0.03μmol/L和0.3μmol/L，随着左旋多沙唑嗪浓度增加，NA量效曲线右移，Emax值不变（P>0.05）。Schild plot分析结果表明，左旋多沙唑嗪的作用属非竞争性拮抗，斜率（0.607±0.028）小于1（P<0.05）。左旋多沙唑嗪的pKB值（8.032±0.039）显著小于右旋多沙唑嗪（8.995±0.032）及消旋多沙唑嗪（8.694±0.032）的pKB值（P<0.01），并且消旋多沙唑嗪的pKB值明显小于右旋多沙唑嗪的pKB值（P<0.01）。
结论
右旋多沙唑嗪阻断α1受体的作用显著强于消旋多沙唑嗪和左旋多沙唑嗪，但是清醒大鼠长期灌服消旋多沙唑嗪的降压作用显著强于右旋多沙唑嗪，而左旋多沙唑嗪长期给药未见明显降压作用。研究结果提示，左旋多沙唑嗪是抗高血压药消旋多沙唑嗪的必要成分，其中右旋多沙唑嗪兼具升高HDL-C的作用，左旋多沙唑嗪兼具降低LDL-C的作用。
Doxazosin currently used as add-on therapy for hypertension is racemicmixture of (-)doxazosin and (+)doxazation. Previously we reported that rankorder of acute hypotensive activity was (-)doxazosin <(±)doxazosin <(+)doxazosin in anesthetized rats. However, contributions of the twoenantiomers to hypotensive effect of long-term administration of (±)doxazosinin conscious animals are unknown. Here we observed hypotensive responsesto doxazosin enantiomers in conscious rats, and analyzed (±)doxazosin,(-)doxazosin and (+)doxazosin concentrations in plasma byHPLC-fluorescence method. α1-Adrenoceptor blocking activity of the3agentswas investigated in isolated rat caudal artery.
Part I Effects of long-term administrations of (-)doxazosin,(+)doxazosinand (±)doxazosin on blood pressure in conscious rats
Animals were allowed to habituate to the animal maintenance facilitiesfor a period of at least7days before the beginning of the experiments.40ratswere randomly divided into four groups of10each. Group I served as solventcontrol, and the rats in groups II, III and IV were administered orally8mg/kgof (-)doxazosin,(+)doxazosin and (±)doxazosin once daily for12weeks,respectively. During the11th week of drug administration, systolic bloodpressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP)and heart rate were measured at0,2,4,8and12h after a long-termadministration of8mg/kg (±)doxazosin in the conscious and nonfasted rats.The time required to complete the measurements in40animals was5days
1Effects of long-term administrations of doxazosin and its enantiomerson blood pressure in nonfasted conscious rats
The systolic blood pressure, diastolic blood pressure, mean bloodpressure did not change significantly at2,4,8and12h after solvent administration (P>0.05). In the rat treated with a long-term administration of(±)doxazosin for12weeks, the SBP decreased significantly at2h(123.03±3.63mmHg),4h (123.93±6.53mmHg),8h (102.15±3.68mmHg)and12h (113.86±5.28mmHg) after the last administration of8mg/kg(±)doxazosin, as compared to pre-drug baseline level (144.57±4.18mmHg;P<0.01). Hypotensive effects on DBP and MBP by long-term administrationof (±)doxazosin were similar to that on SBP. The results of statisticalcomparison between solvent group and (±)doxazosin group also indicatedsignificant hypotensive effects on SBP, DBP and MBP by (±)doxazosin.(+)Doxazosin had similar hypotensive effects as (±)doxazosin, but themaximal decreases (8h after the last administration) in SBP, DBP and MBPinduced by (+)doxazosin were significantly smaller than that by (±)doxazosinat the same dose (P<0.05). A long-term administration of (-)doxazosinproduced significant, but mild, hypotensive effects on the SBP (112.67±6.56mmHg), DBP (72.34±4.24mmHg) and MBP (85.46±4.96mmHg)8h after thelast administration, as compared to pre-drug baseline levels (132.81±4.83mmHg,87.15±3.58mmHg and102.00±3.96mmHg)(P<0.05and0.01).However, the maximal decreases (8h after the last administration) in SBP,DBP and MBP induced by (-)doxazosin were not significantly different fromthat by solvent (P>0.05).
2Effects of long-term administrations of doxazosin and its enantiomerson heart rate in nonfasted conscious rats
A long-term administration of (-)doxazosin,(+)doxazosin or(±)doxazosin did not affect HR significantly, as compared to pre-drug baselinelevel (P>0.05), however results of statistical comparison between solventgroup and (±)doxazosin group indicated a significant positive chronotropiceffect at8h (336.61±16.57bpm vs427.43±34.4bpm)and12h (332.24±22.68bpm vs435.15±25.85bpm) after the last administration of (±)doxazosin(P<0.05and0.01).
Part II Effects of long-term administrations of doxazosin and itsenantiomers on general situation of the rat
Animals were allowed to habituate to the animal maintenance facilitiesfor a period of at least7days before the beginning of the experiments.40ratswere randomly divided into four groups of10each. Group I served as solventcontrol, and the rats in groups II, III and IV were administered orally8mg/kgof (-)doxazosin,(+)doxazosin and (±)doxazosin once daily for12weeks,respectively. Effect of long-term administrations of doxazosin and itsenantiomers on general situation were observed.
1Effects of long-term administrations of doxazosin and its enantiomerson rat body weight
Before long-term oral administrations of solvent,(-)doxazosin,(+)doxazosin and (±)doxazosin, the body weights of4groups were notsignificantly different from each other (P>0.05). Body weights of the solventgroup at the end of the3rd,6th,9th and12th week were449.2±12.38g,489.8±14.55g,516±14.04g and539.7±14.69g, which were significantlygreater than the body weight (359.9±6.98g) before administration of thesolvent (P<0.01). Long-term administrations of (-)doxazosin,(+)doxazosinand (±)doxazosin for12weeks did not significantly affect body weight gain ofthe rat (P>0.05).
2Effects of long-term administrations of doxazosin and its enantiomerson food consumption of the rats
Before long-term oral administrations of solvent,(-)doxazosin,(+)doxazosin and (±)doxazosin, the food consumption of the4groups was notsignificantly different from each other (P>0.05). There was no significantdifference in food consumption among solvent,(-)doxazosin,(+)doxazosinand (±)doxazosin groups during the12week (except at the10th week)(P>0.05). Food consumption of the (-)doxazosin group or (+)doxazosin groupwas significantly greater than solvent group at the end of the10th week(P<0.05). There was no significant difference in food consumption between(±)doxazosin group and solvent group.
3Effects of long-term administrations of doxazosin and its enantiomers onkidney function
CRTN, UA and UREA levels of solvent group after a long-termadministration were33.2±1.15μmol/L,70.80±9.31μmol/L and5.28±0.27mmol/L. A long-term administration (12weeks) of (-)doxazosin,(+)doxazosinor (±)doxazosin did not affect the level of CRTN, UA, UREA significantly, ascompared to solvent group (P>0.05).
4Effects of long-term administrations of doxazosin and its enantiomerson liver function
ALT, AST, TP, ALB, GLO and A/G levels of solvent group after along-term administration were36.30±3.56U/L,154.30±19.42U/L,57.31±1.71g/L,28.67±0.77g/L,28.64±1.06g/L and1.00±0.02. A long-termadministration (12weeks) of (-)doxazosin,(+)doxazosin or (±)doxazosin didnot affect the levels of ALT, AST, TP, ALB, GLO and A/G significantly, ascompared to solvent group (P>0.05).
5Effects of long-term administrations of doxazosin and its enantiomerson GLU and serum lipid levels (T-CHO、TG、HDL-C、LDL-C、VLDL-C)
GLU, T-CHO, TG, HDL-C, LDL-C and VLDL-C levels of solvent groupafter a long-term administration were5.85±0.38mmol/L,1.15±0.04mmol/L,0.37±0.05mmol/L,0.33±0.01mmol/L,0.24±0.02mmol/L and0.17±0.02mmol/L. The level of GLU was not changed by the agents. Serum T-CHOlevel, TG level and VLDL-C level of the rats in solvent group,(-)doxazosingroup,(+)doxazosin group and (±)doxazosin group were not significantlydifferent from each other (P>0.05). A long-term treatment with (+)doxazosinincreased HDL-C level, and a long-term treatment with (-)doxazosindecreased LDL-C level significantly (P<0.01).
A long-term administration (12weeks) of (-)doxazosin,(+)doxazosin or(±)doxazosin did not affect the level of CK significantly, as compared tosolvent group (P>0.05).
Part III Plasma drug concentrations corresponding to maximalhypotensive responses to doxazosin and its enantiomers orallyadministered in the rat
Time-dependent hypotensive effects and maximum hypotensive effect induced by single oral administration of8mg/kg (±)doxazosin were studied.To clarify the possible influence of fasting state on plasma drug concentration,a difference in plasma drug concentration-time curves between fasted andnonfasted rats was studied. We measured the plasma concentrationscorresponding to maximal hypotensive responses to (-)doxazosin,(+)doxazosin and (±)doxazosin for long-term administration by HPLC.
1Changes in blood pressure and heart rate in conscious rats after a singleadministration of (±)doxazosin
The systolic blood pressure, diastolic blood pressure, mean bloodpressure and heart rate did not change significantly at2,4,8and12h aftersolvent administration (P>0.05). The SBP in rats treated with8mg/kg(±)doxazosin decreased significantly4h after administration, as compared topre-drug baseline level (P<0.05), but there was no significant differencebetween each individual datum (racemic doxazosin group) and its respectivecontrol value (solvent group). A single administration of (±)doxazosin did notaffect HR significantly (P>0.05), and the values of HR were389.43±23.31,343.02±14.06,359.16±17.18,359.16±17.18and344.99±9.23(bpm) beforeand2h,4h,8h,12h after the administration, respectively
2Effect of food on the plasma drug concentrations measured after asingle administration of (±)doxazosin
Plasma (±)doxazosin concentration quickly increased to254.61±27.69ng/ml at0.5h, then reached its peak level (306.97±43.47ng/ml) at1h afteroral administration in fasted rats. Its concentration was still maintained at ahigher level (296.10±40.97ng/ml) at2h, and decreased to30.22±16.53ng/mlat12h in fasted rats. Although the plasma concentration of (±)doxazosin innonfasted rats was slightly lower than that in fasted rats0.5h,1h and2h afteroral administration of the same dose, drug concentration-time curve for(±)doxazosin in fasted rats was not significantly different from that innonfasted rats (P>0.05). In addition, stable (±)doxazosin concentrations weremaintained at4h (170.75±27.05ng/ml) and6h (169.87±40.29ng/ml) afteroral administration in nonfasted rats.
3Analysis of plasma drug concentrations corresponding to maximalhypotensive responses to the last administration of doxazosin enantiomers inthe rat
Plasma drug concentrations were measured8h after the lastadministration of (-)doxazosin,(+)doxazosin and (±)doxazosin, and theconcentration of (-)doxazosin,(+)doxazosin or (±)doxazosin was18.26±3.55ng/ml,177.11±20.66ng/ml or113.18±13.21ng/ml. The concentrations of(-)doxazosin and (±)doxazosin were significantly lower than (+)doxazosin(P<0.05and0.01), and the concentration ratio of (-)doxazosin/(+)doxazosinwas0.10. A chiral separation of (±)doxazosin-containing plasma samples wasfurther performed, and the (-)doxazosin and (+)doxazosin components were12.01±2.45ng/ml and96.56±9.94ng/ml, respectively. The concentration ratioof (-)doxazosin/(+)doxazosin in plasma from the rats orally administered(±)doxazosin was0.12.
Part Ⅳ α1-Adrenoceptor blocking activity of doxazosin and itsenantiomers in the isolated rat caudal artery
In solvent control group, there were no significant differences in Emaxvalues among the second, third, fourth and fifth set of concentration-responsecurves for NA (1.75±0.05g,1.76±0.07g,1.80±0.07g and1.93±0.06g;P>0.05), and EC50values for NA calculated from the4concentration-responsecurves were not significantly different from each other (data not shown).Before treatment with (-)doxazosin,(+)doxazosin and (±)doxazosin, thevalues of Emax or EC50obtained from the concentration-response curves forNA were not significantly different from each other (P>0.05).(-)Doxazosin(0.003,0.03and0.3μmol/L),(+)doxazosin and (±)doxazosin (0.001,0.01and0.1μmol/L) produced a shift to the right of the concentration-response curvesfor NA (Figure8) without significant changes in the Emax values (P>0.05).Slope of the Schild plot for (-)doxazosin,(+)doxazosin or (±)doxazosin(0.607±0.028,0.647±0.018or0.716±0.028) was significantly different fromunity (P<0.05), indicating that the three agents non-competitively inhibited theconcentration-response curves for NA in the isolated rat caudal artery. The pKBvalue of (-)doxazosin (8.032±0.039) was significantly smaller (P<0.01)than that of (+)doxazosin (8.995±0.032) or (±)doxazosin (8.694±0.032), andthe pKBvalue of (±)doxazosin was significantly smaller than that of(+)doxazosin (P<0.01).
Conclusion
The effect of (+)doxazosin against α1-adrenoceptor is significantly higherthan that of (-)doxazosin and (±)doxazosin. However the hypotensive effect of(±)doxazosin of long-term administration higher than (+)doxazosin inconscious rats. The hypotensive effect of (-)doxazosin were not significantlydifferent from that by solvent. These results suggest that (-)doxazosincomponent is absolutely necessary to ensure the potent hypotensive effect ofracemic doxazosin administered for12weeks in conscious rats. And(+)doxazosin increased HDL-C level while (-)doxazosin decreased LDL-Clevel significantly.
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3de álvaro F, Hernández-Presa MA. Effect of doxazosingastrointestinal therapeutic system on patients with uncontrolledhypertension: The ASOCIA study. Journal of CardiovascularPharmacology,2006,47(2):271-276
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1Fukiyama K, Omae T, Iimura O, et al. A double-blind comparativestudy of doxazosin and prazosin in the treatment of essentialhypertension. American Heart Journal,1991,121(1):317-322
2Sega R, Marazzi M, Bombelli M, et al. Comparison of the newalpha1-blocker alfuzosin with propranolol as first-line therapy inhypertension. Pharmacological Research,1991,24(1):41-52
3Itskovitz H. Alpha1-blockade for the treatment of hypertension: amegastudy of terazosin in2214clinical practice settings. ClinicalTherapeutics,1994,16(3):490
4Joglekar S, Nanivadekar A. A randomized, controlled, multicenterstudy to compare prazosin GITS with enalapril in hypertensivepatients with diabetes mellitus. Bombay Hypertension Study Group.The Journal of the Association of Physicians of India,1998:52
5Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of mildhypertension studyfinal results. JAMA: the journal of the AmericanMedical Association,1993,270(6):713-724
6Os I, Stokke HP. Effects of doxazosin in the gastrointestinaltherapeutic system formulation versus doxazosin standard andplacebo in mild-to-moderate hypertension. Journal of CardiovascularPharmacology,1999,33(5):791-797
7Calvo C, Gil-Extremera B, Gomez-Fernández P, Masramon X, PueyoC, Armada B.Doxazosin GITS versus standard doxazosin in mild tomoderate hypertension. International Journal of Cardiology,2005,101:97-104
8Os I. Comparison of doxazosin GITS and standard doxazosin in thetreatment of high blood pressure. International Journal of ClinicalPharmacology and Therapeutics,2006,44(3):99-106
9Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to thetherapeutic regimen of hypertensive patients inadequately controlledwith other antihypertensive medications: a randomized,placebo-controlled study. American Journal of Hypertension,2000,13(5):468-474
10Steers W, Kirby R. Clinical ease of using doxazosin in BPH patientswith and without hypertension. Prostate Cancer and ProstaticDiseases,2005,8(2):152-157.
11Lemmer B, Nold G. Effect of doxazosin GITS on24-hour bloodpressure profile in patients with stage1to stage2primaryhypertension. Blood Pressure Monitoring,2003,8(3):119-125
12Lehtonen A. Doxazosin effects on insulin and glucose in hypertensivepatients. American Heart Journal,1991,121(4):1307-1311
13Lehtonen A, V h talo M. Effect of doxazosin on insulin sensitivity inhypertensive non-insulin dependent diabetic patients. EuropeanJournal of Clinical Pharmacology,1992,43(4):365-368.
14Maheux P, Facchini F, Jeppesen J, et al. Changes in Glucose, Insulin,Lipid, Lipoprotein, and Apoprotein Concentrations and Insulin Actionin Doxazosin-Treated Patients With Hypertension ComparisonBetween Nondiabetic Individuals and Patients WithNon–Insulin-Dependent Diabetes Mellitus. American Journal ofHypertension,1994,7(5):416-424
15Levy D, Walmsley P, Levenstein M. Principal results of theHypertension and Lipid Trial (HALT): a multicenter study ofdoxazosin in patients with hypertension. American Heart Journal,1996,131(5):966-973
16Grimm Jr RH, Flack JM, Grandits GA, et al. Long-term effects onplasma lipids of diet and drugs to treat hypertension. JAMA: thejournal of the American Medical Association,1996,275(20):1549-1556
17LUDVIG ND, WESTLIE L. A5-year comparison of doxazosin andatenolol in patients with mild-to-moderate hypertension: effects onblood pressure, serum lipids, and coronary heart disease risk. Bloodpressure,1998,7(1):39-45
18Hirano T, Yoshino G, Kashiwazaki K, et al. Doxazosin reducesprevalence of small dense low density lipoprotein and remnant-likeparticle cholesterol levels in nondiabetic and diabetic hypertensivepatients. American journal of hypertension,2001,14(9):908-913
19Kinoshita M, Shimazu N, Fujita M, et al. Doxazosin, anα1-adrenergic antihypertensive agent, decreases serum oxidized LDL.American Journal of Hypertension,2001,14(3):267-270
20Hobbs FR, Khan T, Collins B. Doxazosin versus bendrofluazide: acomparison of the metabolic effects in British South Asians withhypertension. The British Journal of General Practice,2005,55(515):437
21Derosa G, Cicero AF, D’Angelo A, et al. Synergistic effect ofdoxazosin and acarbose in improving metabolic control in patientswith impaired glucose tolerance. Clinical Drug Investigation,2006,26(9):529-539
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1Fukiyama K, Omae T, Iimura O, et al. A double-blind comparativestudy of doxazosin and prazosin in the treatment of essentialhypertension. American Heart Journal,1991,121(1):317-322
2Sega R, Marazzi M, Bombelli M, et al. Comparison of the newalpha1-blocker alfuzosin with propranolol as first-line therapy inhypertension. Pharmacological research,1991,24(1):41-52
3Itskovitz H. Alpha1-blockade for the treatment of hypertension: amegastudy of terazosin in2214clinical practice settings. Clinicaltherapeutics,1994,16(3):490-504
4Joglekar S, Nanivadekar A. A randomized, controlled, multicenterstudy to compare prazosin GITS with enalapril in hypertensivepatients with diabetes mellitus. Bombay Hypertension Study Group.The Journal of the Association of Physicians of India,1998, Suppl1:52-62
5Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of mildhypertension studyfinal results. JAMA: the journal of the AmericanMedical Association,1993,270(6):713-724
6Os I, Stokke HP. Effects of doxazosin in the gastrointestinaltherapeutic system formulation versus doxazosin standard andplacebo in mild-to-moderate hypertension. Journal of cardiovascularpharmacology,1999,33(5):791-797
7Calvo C, Gil-Extremera B, Gomez-Fernández P, et al. DoxazosinGITS versus standard doxazosin in mild to moderate hypertension.International journal of cardiology,2005,101(1):97-104
8Os I. Comparison of doxazosin GITS and standard doxazosin in thetreatment of high blood pressure. International journal of clinicalpharmacology and therapeutics,2006,44(3):99-106
9Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to thetherapeutic regimen of hypertensive patients inadequately controlledwith other antihypertensive medications: a randomized,placebo-controlled study. American journal of hypertension,2000,13(5):468-474
10Steers W, Kirby R. Clinical ease of using doxazosin in BPH patientswith and without hypertension. Prostate cancer and prostatic diseases,2005,8(2):152-157
11Lemmer B, Nold G. Effect of doxazosin GITS on24-hour bloodpressure profile in patients with stage1to stage2primaryhypertension. Blood Pressure Monitoring,2003,8(3):119-125
12Lehtonen A. Doxazosin effects on insulin and glucose in hypertensivepatients. American Heart Journal,1991,121(4):1307-1311
13Lehtonen A, V h talo M. Effect of doxazosin on insulin sensitivity inhypertensive non-insulin dependent diabetic patients. Europeanjournal of clinical pharmacology,1992,43(4):365-368
14Maheux P, Facchini F, Jeppesen J, et al. Changes in Glucose, Insulin,Lipid, Lipoprotein, and Apoprotein Concentrations and Insulin Actionin Doxazosin-Treated Patients With Hypertension ComparisonBetween Nondiabetic Individuals and Patients WithNon–Insulin-Dependent Diabetes Mellitus. American Journal ofHypertension,1994,7(5):416-424
15Levy D, Walmsley P, Levenstein M. Principal results of theHypertension and Lipid Trial (HALT): a multicenter study ofdoxazosin in patients with hypertension. American Heart Journal,1996,131(5):966-973
16Grimm Jr RH, Flack JM, Grandits GA, et al. Long-term effects onplasma lipids of diet and drugs to treat hypertension. JAMA: thejournal of the American Medical Association,1996,275(20):1549-1556
17LUDVIG ND, WESTLIE L. A5-year comparison of doxazosin andatenolol in patients with mild-to-moderate hypertension: effects onblood pressure, serum lipids, and coronary heart disease risk. Bloodpressure,1998,7(1):39-45
18Hirano T, Yoshino G, Kashiwazaki K, et al. Doxazosin reducesprevalence of small dense low density lipoprotein and remnant-likeparticle cholesterol levels in nondiabetic and diabetic hypertensivepatients. American Journal of Hypertension,2001,14(9):908-913
19Kinoshita M, Shimazu N, Fujita M, et al. Doxazosin, anα1-adrenergic antihypertensive agent, decreases serum oxidized LDL.American Journal of Hypertension,2001,14(3):267-270
20Hobbs FR, Khan T, Collins B. Doxazosin versus bendrofluazide: acomparison of the metabolic effects in British South Asians withhypertension. The British Journal of General Practice,2005,55(515):437-443
21Derosa G, Cicero AF, D’Angelo A, et al. Synergistic effect ofdoxazosin and acarbose in improving metabolic control in patientswith impaired glucose tolerance. Clinical Drug Investigation,2006,26(9):529-539
22Lepor H. Role of alpha‐adrenergic blockers in the treatment ofbenign prostatic hyperplasia. The Prostate,1990,17(S3):75-84
23Nazarko L. Benign prostatic hyperplasia: Diagnosis and treatment.Nursing&Residential Care,2004,6(10):485-487
24ALLHAT Officers and Coordinators for the ALLHATT CollaborativeResearch Group. Diuretic versus α-blocker as first-stepantihypertensive therapy. Final results from the Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).Hypertension.2003;42:239-246
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11Niu CQ, Zhao D, Jia XM, et al. α1-Adrenoceptor antagonist profile ofdoxazosin and its enantiomers in isolated rabbit blood vessels. Chin JPharmacol Toxicol,2003,17(5):354-359
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13Aukes AM, Vitullo L, Zeeman GG, et al. Pregnancy prevents hypertensiveremodeling and decreases myogenic reactivity in posterior cerebral arteriesfrom Dahl salt-sensitive rats: a role in eclampsia? Am J Physiol Heart CircPhysiol,2007,292: H1071-H1076
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1Fukiyama K, Omae T, Iimura O, et al. A double-blind comparativestudy of doxazosin and prazosin in the treatment of essentialhypertension. American Heart Journal,1991,121(1):317-322
2Sega R, Marazzi M, Bombelli M, et al. Comparison of the newalpha1-blocker alfuzosin with propranolol as first-line therapy inhypertension. Pharmacological Research,1991,24(1):41-52
3Itskovitz H. Alpha1-blockade for the treatment of hypertension: amegastudy of terazosin in2214clinical practice settings. ClinicalTherapeutics,1994,16(3):490
4Joglekar S, Nanivadekar A. A randomized, controlled, multicenterstudy to compare prazosin GITS with enalapril in hypertensivepatients with diabetes mellitus. Bombay Hypertension Study Group.The Journal of the Association of Physicians of India,1998:52
5Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of mildhypertension studyfinal results. JAMA: the journal of the AmericanMedical Association,1993,270(6):713-724
6Os I, Stokke HP. Effects of doxazosin in the gastrointestinaltherapeutic system formulation versus doxazosin standard andplacebo in mild-to-moderate hypertension. Journal of CardiovascularPharmacology,1999,33(5):791-797
7Calvo C, Gil-Extremera B, Gomez-Fernández P, Masramon X, PueyoC, Armada B.Doxazosin GITS versus standard doxazosin in mild tomoderate hypertension. International Journal of Cardiology,2005,101:97-104
8Os I. Comparison of doxazosin GITS and standard doxazosin in thetreatment of high blood pressure. International Journal of ClinicalPharmacology and Therapeutics,2006,44(3):99-106
9Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to thetherapeutic regimen of hypertensive patients inadequately controlledwith other antihypertensive medications: a randomized,placebo-controlled study. American Journal of Hypertension,2000,13(5):468-474
10Steers W, Kirby R. Clinical ease of using doxazosin in BPH patientswith and without hypertension. Prostate Cancer and ProstaticDiseases,2005,8(2):152-157.
11Lemmer B, Nold G. Effect of doxazosin GITS on24-hour bloodpressure profile in patients with stage1to stage2primaryhypertension. Blood Pressure Monitoring,2003,8(3):119-125
12Lehtonen A. Doxazosin effects on insulin and glucose in hypertensivepatients. American Heart Journal,1991,121(4):1307-1311
13Lehtonen A, V h talo M. Effect of doxazosin on insulin sensitivity inhypertensive non-insulin dependent diabetic patients. EuropeanJournal of Clinical Pharmacology,1992,43(4):365-368.
14Maheux P, Facchini F, Jeppesen J, et al. Changes in Glucose, Insulin,Lipid, Lipoprotein, and Apoprotein Concentrations and Insulin Actionin Doxazosin-Treated Patients With Hypertension ComparisonBetween Nondiabetic Individuals and Patients WithNon–Insulin-Dependent Diabetes Mellitus. American Journal ofHypertension,1994,7(5):416-424
15Levy D, Walmsley P, Levenstein M. Principal results of theHypertension and Lipid Trial (HALT): a multicenter study ofdoxazosin in patients with hypertension. American Heart Journal,1996,131(5):966-973
16Grimm Jr RH, Flack JM, Grandits GA, et al. Long-term effects onplasma lipids of diet and drugs to treat hypertension. JAMA: thejournal of the American Medical Association,1996,275(20):1549-1556
17LUDVIG ND, WESTLIE L. A5-year comparison of doxazosin andatenolol in patients with mild-to-moderate hypertension: effects onblood pressure, serum lipids, and coronary heart disease risk. Bloodpressure,1998,7(1):39-45
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21Derosa G, Cicero AF, D’Angelo A, et al. Synergistic effect ofdoxazosin and acarbose in improving metabolic control in patientswith impaired glucose tolerance. Clinical Drug Investigation,2006,26(9):529-539
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1Fukiyama K, Omae T, Iimura O, et al. A double-blind comparativestudy of doxazosin and prazosin in the treatment of essentialhypertension. American Heart Journal,1991,121(1):317-322
2Sega R, Marazzi M, Bombelli M, et al. Comparison of the newalpha1-blocker alfuzosin with propranolol as first-line therapy inhypertension. Pharmacological research,1991,24(1):41-52
3Itskovitz H. Alpha1-blockade for the treatment of hypertension: amegastudy of terazosin in2214clinical practice settings. Clinicaltherapeutics,1994,16(3):490-504
4Joglekar S, Nanivadekar A. A randomized, controlled, multicenterstudy to compare prazosin GITS with enalapril in hypertensivepatients with diabetes mellitus. Bombay Hypertension Study Group.The Journal of the Association of Physicians of India,1998, Suppl1:52-62
5Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of mildhypertension studyfinal results. JAMA: the journal of the AmericanMedical Association,1993,270(6):713-724
6Os I, Stokke HP. Effects of doxazosin in the gastrointestinaltherapeutic system formulation versus doxazosin standard andplacebo in mild-to-moderate hypertension. Journal of cardiovascularpharmacology,1999,33(5):791-797
7Calvo C, Gil-Extremera B, Gomez-Fernández P, et al. DoxazosinGITS versus standard doxazosin in mild to moderate hypertension.International journal of cardiology,2005,101(1):97-104
8Os I. Comparison of doxazosin GITS and standard doxazosin in thetreatment of high blood pressure. International journal of clinicalpharmacology and therapeutics,2006,44(3):99-106
9Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to thetherapeutic regimen of hypertensive patients inadequately controlledwith other antihypertensive medications: a randomized,placebo-controlled study. American journal of hypertension,2000,13(5):468-474
10Steers W, Kirby R. Clinical ease of using doxazosin in BPH patientswith and without hypertension. Prostate cancer and prostatic diseases,2005,8(2):152-157
11Lemmer B, Nold G. Effect of doxazosin GITS on24-hour bloodpressure profile in patients with stage1to stage2primaryhypertension. Blood Pressure Monitoring,2003,8(3):119-125
12Lehtonen A. Doxazosin effects on insulin and glucose in hypertensivepatients. American Heart Journal,1991,121(4):1307-1311
13Lehtonen A, V h talo M. Effect of doxazosin on insulin sensitivity inhypertensive non-insulin dependent diabetic patients. Europeanjournal of clinical pharmacology,1992,43(4):365-368
14Maheux P, Facchini F, Jeppesen J, et al. Changes in Glucose, Insulin,Lipid, Lipoprotein, and Apoprotein Concentrations and Insulin Actionin Doxazosin-Treated Patients With Hypertension ComparisonBetween Nondiabetic Individuals and Patients WithNon–Insulin-Dependent Diabetes Mellitus. American Journal ofHypertension,1994,7(5):416-424
15Levy D, Walmsley P, Levenstein M. Principal results of theHypertension and Lipid Trial (HALT): a multicenter study ofdoxazosin in patients with hypertension. American Heart Journal,1996,131(5):966-973
16Grimm Jr RH, Flack JM, Grandits GA, et al. Long-term effects onplasma lipids of diet and drugs to treat hypertension. JAMA: thejournal of the American Medical Association,1996,275(20):1549-1556
17LUDVIG ND, WESTLIE L. A5-year comparison of doxazosin andatenolol in patients with mild-to-moderate hypertension: effects onblood pressure, serum lipids, and coronary heart disease risk. Bloodpressure,1998,7(1):39-45
18Hirano T, Yoshino G, Kashiwazaki K, et al. Doxazosin reducesprevalence of small dense low density lipoprotein and remnant-likeparticle cholesterol levels in nondiabetic and diabetic hypertensivepatients. American Journal of Hypertension,2001,14(9):908-913
19Kinoshita M, Shimazu N, Fujita M, et al. Doxazosin, anα1-adrenergic antihypertensive agent, decreases serum oxidized LDL.American Journal of Hypertension,2001,14(3):267-270
20Hobbs FR, Khan T, Collins B. Doxazosin versus bendrofluazide: acomparison of the metabolic effects in British South Asians withhypertension. The British Journal of General Practice,2005,55(515):437-443
21Derosa G, Cicero AF, D’Angelo A, et al. Synergistic effect ofdoxazosin and acarbose in improving metabolic control in patientswith impaired glucose tolerance. Clinical Drug Investigation,2006,26(9):529-539
22Lepor H. Role of alpha‐adrenergic blockers in the treatment ofbenign prostatic hyperplasia. The Prostate,1990,17(S3):75-84
23Nazarko L. Benign prostatic hyperplasia: Diagnosis and treatment.Nursing&Residential Care,2004,6(10):485-487
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