多沙唑嗪对映体缓解下尿道阻力的立体选择性及其作用机制
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摘要
下尿路症状(lower urinary tract symptoms,LUTS)和良性前列腺增生(benign prostatic hyperplasia,BPH)是老年男性常见病症,严重影响患者生活质量,已成为全球性的公共健康问题。治疗BPH/LUTS以外科手术为佳,但手术在不同程度上给病人带来损伤,如术后尿失禁、阳痿、逆向射精或术后复发等。因此,对于轻、中度BPH/LUTS患者,使用安全有效的药物治疗,已成为重要研究课题。目前,BPH/LUTS的治疗药物分为三类,即α1受体阻断剂、5α还原酶抑制剂和植物治疗药。
多沙唑嗪(doxazosin,DOX)是喹啉类、长效、选择性α1受体阻断剂,临床使用其消旋体(racemic-doxazosin, rac-DOX)。临床研究结果表明,rac-DOX可降低排尿阻力,提高最大尿流率,缓解BPH/LUTS症状。但是,rac-DOX常引起头昏、头疼、无力和体位性低血压等不良反应而影响其临床应用。因此,选择α1受体阻断剂治疗BPH/LUTS,应考虑药物的“尿路选择性”。在rac-DOX的分子结构中存在一个手性C原子和一对光学异构体。国内、外学者利用HPLC技术对rac-DOX进行了手性拆分,并制备了其单一对映体S-DOX和R-DOX。对S-DOX、R-DOX和rac-DOX进行的药理学研究发现,S-DOX、R-DOX和rac-DOX对人体前列腺α1受体的亲和力明显高于α2受体,且三者对α1受体的亲和力无显著性差异;S-DOX、R-DOX和rac-DOX均能竞争性对抗苯肾上腺素诱导的人离体前列腺平滑肌收缩反应,三者pA2值无显著性差异。但是,我室对兔离体胸主动脉和颈总动脉的研究发现,S-DOX拮抗去甲肾上腺素诱发血管收缩的pA2值显著小于R-DOX和rac-DOX,说明S-DOX对兔血管α1受体的选择性明显低于R-DOX和rac-DOX。上述结果提示,S-DOX可能成为心血管副作用较小的BPH/LUTS治疗药物。
本文进一步观察了S-DOX、R-DOX和rac-DOX十二指肠给药对大鼠血压和膀胱排尿功能的影响,以及不同给药途径对豚鼠膀胱排尿功能的影响;建立了大鼠膀胱出口梗阻模型,观察了S-DOX、R-DOX和rac-DOX对出口梗阻膀胱离体平滑肌的作用;同时,本文还建立了丙酸睾酮诱导去势大鼠前列腺增生模型,并就S-DOX和rac-DOX对增生前列腺的组织形态学变化及细胞增殖与凋亡进行了研究。
第一部分多沙唑嗪对映体十二指肠给药对大鼠血压和膀胱排尿功能的影响
本研究观察了S-DOX、R-DOX和rac-DOX十二指肠给药对麻醉大鼠血压和膀胱排尿功能的影响。采用八道生理记录仪记录麻醉大鼠颈总动脉血压、心率、膀胱排尿压以及排尿间隔的变化,收集并测量排尿量,以探讨S-DOX、R-DOX和rac-DOX对大鼠血压和膀胱排尿功能的选择性作用。
1多沙唑嗪对映体对大鼠颈总动脉血压及心率的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.1～3.0 mg·kg-1),均剂量依赖性降低麻醉大鼠颈总动脉收缩压、舒张压和平均动脉压;1.0 mg·kg-1时三者对平均动脉压的降低幅度分别达到26.9±8.2 %、40.5±8.8 %和43.1±7.7 %;三者降低平均动脉压的ED30值依次为1.7±0.8、0.5±0.6、0.5±0.4 mg·kg-1;S-DOX降低收缩压、舒张压和平均动脉压的作用均明显弱于R-DOX和rac-DOX (P<0.05),R-DOX和rac-DOX的降压作用无显著差异(P>0.05)。rac-DOX在1.0、3.0 mg·kg-1剂量时均可抑制麻醉大鼠心率,而S-DOX和R-DOX仅在3.0 mg·kg-1剂量时对心率有抑制作用。
2多沙唑嗪对映体对大鼠膀胱排尿功能的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.1～3.0 mg·kg-1),均剂量依赖性降低麻醉大鼠膀胱排尿压;三种药物对排尿压的最大降低幅度分别为13.4±5.7 %、14.5±11.0 %和10.9±7.6 %;三者降低排尿压的作用无显著差异(P>0.05);R-DOX可显著缩短排尿间隔并减少排尿量(P<0.05),S-DOX和rac-DOX对排尿间隔和排尿量无明显影响(P>0.05)。
上述结果表明,与R-DOX和rac-DOX相比,S-DOX在保留降低大鼠膀胱排尿压作用的同时,减轻了对血压、心率和膀胱排尿间隔的不良影响。
第二部分多沙唑嗪对映体不同给药途径对豚鼠膀胱排尿功能的影响
本研究观察了S-DOX、R-DOX和rac-DOX十二指肠给药和静脉注射对麻醉豚鼠膀胱排尿功能的影响。采用八道生理记录仪连续记录给药前、后麻醉豚鼠膀胱排尿压、排尿阈值压及排尿间隔的变化,收集并测量排尿量,以比较S-DOX、R-DOX和rac-DOX不同给药途径对豚鼠膀胱排尿功能的作用。
1多沙唑嗪对映体十二指肠给药对豚鼠膀胱排尿功能的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.08～2.4 mg·kg-1),均剂量依赖性降低麻醉豚鼠膀胱排尿压;在0.8 mg·kg-1和2.4 mg·kg-1剂量时,S-DOX、R-DOX和rac-DOX对排尿压的降低幅度无显著差异(P >0.05)。十二指肠给予S-DOX对麻醉豚鼠排尿阈值压、排尿间隔及排尿量均无显著影响(P>0.05);R-DOX和rac-DOX则可显著降低排尿阈值压(P <0.05),在2.4 mg·kg-1剂量时均显著缩短排尿间隔(P<0.05),在0.8 mg·kg-1和2.4 mg·kg-1剂量时均显著减少排尿量(P<0.05)。
2多沙唑嗪对映体静脉注射对豚鼠膀胱排尿功能的影响
静脉注射S-DOX、R-DOX和rac-DOX(0.008～0.8 mg·kg-1),均剂量依赖性降低麻醉豚鼠膀胱排尿压,对膀胱排尿压的最大降低幅度依次为14.9±7.8 %、19.2±14.4 %和19.3±9.8 %,三者对排尿压的作用强度无显著性差异(P>0.05)。静脉注射S-DOX、R-DOX和rac-DOX对麻醉豚鼠排尿阈值压无显著影响(P>0.05),均能延长麻醉豚鼠膀胱排尿间隔(P<0.05),S-DOX和R-DOX尚能增加麻醉豚鼠膀胱排尿量(P<0.05)。
上述结果表明,十二指肠或静脉注射给予S-DOX,均可降低麻醉豚鼠膀胱排尿压;与R-DOX和rac-DOX相比,S-DOX对膀胱排尿阈值压、排尿间隔和排尿量无不良影响。
第三部分多沙唑嗪对映体对膀胱出口梗阻大鼠离体膀胱平滑肌的作用
本研究观察了S-DOX、R-DOX和rac-DOX对膀胱出口梗阻大鼠离体膀胱平滑肌的作用。建立膀胱出口梗阻大鼠模型;连续灌胃给予S-DOX、R-DOX和rac-DOX(3.0 mg·kg-1)2周后处死动物,制备离体膀胱体平滑肌标本,按累积给药法建立卡巴胆碱(0.01～100μmol·L-1)收缩反应量效曲线和异丙肾上腺素(0.01～300μmol·L-1)舒张反应量效曲线。
1多沙唑嗪对映体对大鼠膀胱体湿重的影响
与假手术组(89±8 mg)相比,模型组大鼠膀胱体湿重(111±18 mg)明显增加(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体湿重无明显改变(P>0.05)。
2多沙唑嗪对映体对大鼠膀胱体平滑肌收缩反应的影响
与假手术组相比,模型组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应明显增强(P<0.01),其量效曲线左移,Emax变大(P<0.01),EC50变小(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应明显降低(P<0.01),其Emax值明显减小(P<0.01),而EC50值明显增大(P<0.01)。与假手术组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应无明显改变(P>0.05)。
3多沙唑嗪对映体对大鼠膀胱体平滑肌舒张反应的影响
与假手术组相比,模型组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应明显增强(P<0.01),其量效曲线左移,Emax变大(P<0.01),EC50变小(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应明显降低(P<0.01),其Emax值明显减小(P<0.01),而EC50值明显增大(P<0.01)。与假手术组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应无明显改变(P>0.05)。
综上所述,灌胃给予S-DOX、R-DOX和rac-DOX,可使膀胱出口梗阻大鼠离体膀胱体平滑肌对卡巴胆碱的过度收缩反应和异丙肾上腺素的过度舒张反应恢复正常,三者作用强度无显著差异。
第四部分S-多沙唑嗪对前列腺增生大鼠前列腺组织形态学的影响
本部分实验观察了S-DOX和rac-DOX对前列腺增生大鼠前列腺组织形态学的影响。建立丙酸睾酮诱导去势大鼠前列腺增生模型;连续灌胃给予S-DOX(0.3、1.0、3.0 mg·kg-1)和rac-DOX(1.0 mg·kg-1)30天后处死动物;测量前列腺体积并称量湿重;光镜观察前叶及后侧叶前列腺组织形态学变化;以图像分析系统进行组织计量学分析。
1 S-DOX对前列腺体积和湿重的影响
与假手术组相比,模型组大鼠前列腺体积、体积指数、各叶湿重及湿重指数均明显增大(P<0.01)。与模型组相比,S-DOX大剂量组前列腺体积指数显著减小(P<0.05)。rac-DOX组和S-DOX小、中剂量组上述各项指标与模型组相比无显著性差异(P>0.05)。
2 S-DOX对前列腺组织形态学的影响
模型组大鼠前叶及后侧叶前列腺腺上皮细胞增生,腺腔明显扩张。与模型组相比,S-DOX各剂量组和rac-DOX组大鼠前叶前列腺腺上皮细胞增生程度和腺腔扩张程度明显减轻;S-DOX各剂量组和rac-DOX组大鼠后侧叶前列腺上皮细胞增生程度和腺腔扩张程度略有减轻。
3 S-DOX对前列腺组织作用的计量学测量
与假手术组相比,模型组大鼠前叶及后侧叶前列腺腺腔最大直径、周长、面积及腺上皮细胞高度明显增大(P<0.01)。与模型组相比,S-DOX(1.0、3.0 mg·kg-1)可明显减小大鼠前叶及后侧叶前列腺腺腔最大直径、周长、面积及腺上皮细胞高度(P<0.05,P<0.01);rac-DOX(1.0 mg·kg-1)可减小后侧叶前列腺腺腔周长(P<0.05),亦可减小前叶及后侧叶上皮细胞高度(P<0.01),对前叶和后侧叶前列腺腺腔最大直径和面积无明显影响(P>0.05)。
上述结果表明,灌胃给予S-DOX和rac-DOX,可抑制丙酸睾酮诱导去势大鼠前列腺增生;S-DOX抗前列腺增生作用优于同等剂量的rac-DOX。
第五部分S-多沙唑嗪对前列腺增生大鼠前列腺细胞增殖与凋亡的影响
本部分实验观察了S-DOX和rac-DOX对前列腺增生大鼠前列腺细胞增殖与凋亡的影响。建立丙酸睾酮诱导去势大鼠前列腺增生模型;连续灌胃给予S-DOX(0.3,1.0和3.0 mg·kg-1)和rac-DOX(1.0 mg·kg-1)30天后处死动物;分离前叶及后侧叶前列腺组织,采用流式细胞术定量检测前列腺细胞增殖周期百分率、凋亡百分率及Bcl-2和Bax蛋白表达,以进一步分析S-DOX抗前列腺增生的作用机制。
1 S-DOX对大鼠前叶前列腺细胞增殖周期及凋亡的影响
与假手术组相比,模型组大鼠S期、G2/M期细胞周期百分率及增殖指数显著增高(P<0.05);与模型组相比,S-DOX各剂量组和rac-DOX组大鼠细胞增殖周期时相分布及增殖指数无明显改变(P>0.05)。S-DOX小剂量组、S-DOX中剂量组、S-DOX大剂量组和rac-DOX组细胞凋亡百分率依次为7.90±3.91 %、8.26±4.21 %、8.33±4.49 %和8.29±1.59 %,明显高于模型组的4.42±1.08 %(P<0.05,P<0.01)。
2 S-DOX对大鼠后侧叶前列腺细胞增殖周期及凋亡的影响
与模型组相比,S-DOX各剂量组及rac-DOX组大鼠细胞增殖周期时相分布、增殖指数及细胞凋亡百分率均无明显改变(P>0.05)。
3 S-DOX对大鼠前叶前列腺细胞Bcl-2和Bax蛋白含量的影响
与假手术组相比,模型组大鼠Bcl-2蛋白FI值及Bcl-2/Bax值明显增高(P<0.05);与模型组相比,S-DOX各剂量组及rac-DOX组大鼠Bcl-2蛋白FI值、Bax蛋白FI值及Bcl-2/Bax值均无明显改变(P>0.05)。
4 S-DOX对大鼠后侧叶前列腺细胞Bcl-2和Bax蛋白含量的影响
与模型组相比,S-DOX各剂量组及rac-DOX组大鼠Bcl-2蛋白FI值、Bax蛋白FI值及Bcl-2/Bax值均无明显改变(P>0.05)。
综上所述,灌胃给予S-DOX和rac-DOX,可促进丙酸睾酮诱导前列腺增生大鼠前叶前列腺细胞凋亡,但对前列腺细胞的增殖周期无明显影响。S-DOX和rac-DOX促进前列腺增生大鼠前列腺细胞凋亡的作用可能与Bcl-2和Bax蛋白表达水平的改变无关。
结论
十二指肠给予S-DOX、R-DOX和rac-DOX,均可剂量依赖性降低麻醉大鼠和豚鼠的膀胱排尿压,S-DOX降低排尿压的作用强度与rac-DOX相同;与R-DOX和rac-DOX相比,S-DOX对排尿间隔和排尿量无不良影响,对血压和心率的抑制作用较弱。
S-DOX、R-DOX和rac-DOX可使膀胱出口梗阻大鼠离体膀胱体平滑肌对卡巴胆碱的过度收缩反应和异丙肾上腺素的过度舒张反应恢复正常,三者作用强度无显著差异。
组织病理学结果表明,S-DOX和rac-DOX对丙酸睾酮诱导去势大鼠前列腺增生均有抑制作用;S-DOX抗前列腺增生作用优于同等剂量的rac-DOX。促进前列腺细胞凋亡是S-DOX和rac-DOX抗前列腺增生的作用机制之一。
Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are the most common urogenital disorders in ageing male. Patients with BPH/LUTS are suffering serious troubles on the quality of life, and BPH/LUTS have become a public health problem in the world. Surgical therapy seems to be the best option to treat BPH/LUTS, but it might cause some impairment to patients, such as uroclepsia, erectile dysfunction, retrograde ejaculation or relapse. Accordingly, it is becoming a considerable issue to develop safe and effective therapeutic agents treating the mild and intermediate BPH/LUTS. At present, therapeutic drugs to treat BPH/LUTS includeα1-adrenoceptor antagonists, 5α-reductase inhibitors and phytotherapeutic agents.
Doxazosin (DOX), a quinazoline derivative, is a long acting selectiveα1-adrenoceptor antagonist, and racemic-doxazosin (rac-DOX) is the current medication of DOX for the clinical treatment of BPH/LUTS. Several clinical studies have demonstrated that rac-DOX produces a decrease in urethral resistance and an increase in maximal urinary flow rate with a corresponding improvement in lower urinary tract symptoms in BPH patients. However, rac-DOX is limited in the clinical application for BPH/LUTS due to its common adverse effects of dizziness, headache, adynamia and orthostatic hypotension. Therefore, the urinary tract selectivity should be necessarily considered whenα1-adrenoceptor antagonists are used for the BPH/LUTS patients. In chemical structure, rac-DOX has a chiral carbon with two optical isomers, i.e. R- and S-forms. It was reported that S-doxazosin (S-DOX) and R-doxazosin (R-DOX) were prepared using chiral mobile phase HPLC. In a pharmacological study using the human isolated prostate tissue, S-DOX, R-DOX and rac-DOX were showed to have higher affinity for α1-adrenoceptors thanα2-adrenoceptors, and no significant differences inα1-adrenoceptor affinity were found among the three compounds. Furthermore, S-DOX, R-DOX and rac-DOX all competitively antagonized the phenylephrine-induced constractile responses in the human isolated prostate with no significant differences in their pA2 values among S-DOX, R-DOX and rac-DOX. Recently, a study in our laboratory showed that S-DOX, R-DOX and rac-DOX all competitively inhibited the norepinephrine-induced constractile responses in the rabbit thoracic aorta and carotid artery, but the pA2 value of S-DOX was significantly lower than that of R-DOX or rac-DOX, indicating that the affinity of S-DOX againstα1-adrenoceptors was significantly lower than that of R-DOX or rac-DOX in the rabbit isolated blood vessels. Therefore, it is reasonable to suggest that S-DOX is a potentially therapeutic agent improving BPH/LUTS with minor cardiovascular adverse effects.
In the present experiments, the effects of intraduodenal administration of S-DOX, R-DOX and rac-DOX on the rat carotid blood pressure and urinary bladder function, and the effects of S-DOX, R-DOX and rac-DOX by different routes of administration on the guinea pig urinary bladder function were observed. A rat model of partial outlet obstruction of urinary bladder was established and the effects of S-DOX, R-DOX and rac-DOX on the detrusor smooth muscle in vitro were investigated. Furthermore, a prostatic hyperplasia model induced by testosterone propionate in the castrated rat was made, and the effects of S-DOX and rac-DOX on prostatic histomorphology, cell proliferation and apoptosis were investigated.
PartⅠEffects of intraduodenal administration of doxazosin enantiomers on blood pressure and urinary bladder function in rats
We observed the effects of intraduodenal administration of S-DOX, R-DOX and rac-DOX on the carotid blood pressure and urinary bladder function in anesthetized rats. The parameters of carotid blood pressure, heart rate, vesical micturition pressure and intercontraction interval in anesthetized rats were recorded with an ADInstruments PowerLab/8sp data recording and analysis system, and the vesical micturition volume was measured, in order to investigate the selective effects of S-DOX, R-DOX and rac-DOX on the carotid blood pressure and urinary bladder function in rats.
1 Effects of doxazosin enantiomers on the carotid blood pressure and heart rate in rats
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.1~3.0 mg·kg-1) decreased the systolic blood pressure, diastolic blood pressure and mean arterial blood pressure significantly in the anesthetized rats in a dose-dependent manner. The inhibition of mean arterial pressure by S-DOX, R-DOX and rac-DOX at 1.0 mg·kg-1 was 26.9±8.2 %, 40.5±8.8 % and 43.1±7.7 %, respectively. The ED30 values of decreasing mean arterial blood pressure by S-DOX, R-DOX and rac-DOX were 1.7±0.8, 0.5±0.6 and 0.5±0.4 mg·kg-1. S-DOX had a weaker inhibitory effect on the carotid blood pressure in comparison with R-DOX and rac-DOX (P<0.05), but no significantly different effects were observed between R-DOX and rac-DOX on the carotid blood pressure (P>0.05). rac-DOX produced a significant inhibition on the heart rate at 1.0 and 3.0 mg·kg-1, but S-DOX and R-DOX reduced the heart rate only at 3.0 mg·kg-1.
2 Effects of doxazosin enantiomers on the urinary bladder function in rats
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.1~3.0 mg·kg-1) decreased the vesical micturition pressure dose-dependently in the anesthetized rats. The maximal inhibition of vesical micturition pressure by S-DOX, R-DOX and rac-DOX was 13.4±5.7 %, 14.5±11.0 % and 10.9±7.6 %, and their inhibitory potency on the vesical micturition pressure was not significantly different from each other (P>0.05). However, R-DOX, not S-DOX and rac-DOX, decreased the intercontraction interval and vesical micturition volume significantly (P<0.05).
These results indicate that S-DOX administered intraduodenally retains the beneficial action on vesical micturition pressure and improves the adverse effects on blood pressure, heart rate and intercontraction interval in comparison with R-DOX and rac-DOX in the anesthetized rats.
PartⅡEffects of doxazosin enantiomers by different routes of administration on urinary bladder function in guinea pigs
We observed the effects of intraduodenal and intravenous administration of S-DOX, R-DOX and rac-DOX on the urinary bladder function in anesthetized guinea pigs. The vesical micturition pressure, micturition threshold pressure and intercontraction interval in the anesthetized guinea pigs were recorded using an ADInstruments PowerLab/8sp data recording and analysis system, and the vesical micturition volume was measured, in order to investigate the effects of S-DOX, R-DOX and rac-DOX on the urinary bladder function by different routes of administration.
1 Effects of intraduodenal administration of doxazosin enantiomers on the urinary bladder function in guinea pigs
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.08~2.4 mg·kg-1) decreased the vesical micturition pressure dose-dependently in the anesthetized guinea pigs. No significantly different effects on the vesical micturition pressure were observed among S-DOX, R-DOX and rac-DOX at 0.8 and 2.4 mg·kg-1 (P>0.05). S-DOX administered intraduodenally did not affect the micturition threshold pressure, intercontraction interval and vesical micturition volume significantly (P>0.05), but R-DOX and rac-DOX significantly depressed the micturition threshold pressure (P<0.05). R-DOX and rac-DOX also markedly decreased the intercontraction interval at 2.4 mg·kg-1 (P<0.05), and reduced the vesical micturition volume at 0.8 and 2.4 mg·kg-1(P<0.05).
2 Effects of intravenous administration of doxazosin enantiomers on the urinary bladder function in guinea pigs
S-DOX, R-DOX and rac-DOX administered intravenously (0.008~0.8 mg·kg-1) decreased the vesical micturition pressure in a dose-dependent manner in the anesthetized guinea pigs. The maximal inhibition of vesical micturition pressure by S-DOX, R-DOX and rac-doxazosin administered intravenously was 14.9±7.8 %, 19.2±14.4 % and 19.3±9.8 %, and their inhibitory potency on the vesical micturition pressure was not significantly different from each other (P>0.05). S-DOX, R-DOX and rac-DOX administered intravenously increased the intercontraction interval significantly (P<0.05), and S-DOX and R-DOX also increased the vesical micturition volume markedly (P<0.05). None of the three agents administered intravenously affected the micturition threshold pressure significantly (P>0.05).
These results indicate that S-DOX, administered intraduodenally or intravenously, produces a decrease in the vesical micturition pressure with less adverse effects on the micturition threshold pressure, intercontraction interval and vesical micturition volume in comparison with R-DOX and rac-DOX in the anesthetized guinea pigs.
PartⅢEffects of doxazosin enantiomers on the bladder strips from rats of partial outlet obstruction of urinary bladder
We investigated the effects of S-DOX, R-DOX and rac-DOX on the detrusor smooth muscle preparations from the rats with partial outlet obstruction of urinary bladder. A rat model of partial outlet obstruction of urinary bladder was established and S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) were administered intragastrically to the respective groups for 2 weeks. After the rats were killed, the detrusor smooth muscle strips were prepared and the responses to carbachol (0.01~100μmol·L-1) and isoprenaline (0.01~300μmol·L-1) in the detrusor smooth muscle preparations were observed.
1 Bladder wet weight of rats treated with doxazosin enantiomers
The bladder wet weight (111±18 mg) of the obstructed model group was significantly increased in comparison with the sham-operated rats (89±8 mg, P<0.01). There were no significant changes in the bladder wet weight of the obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks in comparison with that of obstructed model group (P>0.05).
2 Contractile responses to carbachol in the detrusor smooth muscle preparations from rats treated with doxazosin enantiomers
In comparison with sham-operated rats, the contractile responses to carbachol in the detrusor smooth muscle preparations obtained from obstructed model rats were significantly enhanced (P<0.01), and the concentration-response curve for carbachol was shifted to the left in a parallel manner, with an increase in Emax value and a decrease in EC50 value of carbachol (P<0.01). Contractile responses to carbachol in the detrusor smooth muscle preparations obtained from obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks were significantly depressed (P<0.01). The Emax and EC50 values of carbachol in the three groups treated with doxazosin enantiomers were significantly different from that in obstructed model group (P<0.01), but not different from that in sham-operated group.
3 Relaxant responses to isoprenaline in the detrusor smooth muscle preparations from rats treated with doxazosin enantiomers
In comparison with sham-operated rats, the relaxant responses to isoprenaline in the detrusor smooth muscle preparations obtained from obstructed model rats were significantly enhanced (P<0.01), and the concentration-response curve for isoprenaline was shifted to the left in a parallel manner, with an increase in Emax value and a decrease in EC50 value of isoprenaline (P<0.01). Relaxant responses to isoprenaline in the detrusor smooth muscle preparations obtained from obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks were significantly depressed (P<0.01). The Emax and EC50 values of isoprenaline in the three groups treated with doxazosin enantiomers were significantly different from that in obstructed model group (P<0.01), but not different from that in sham-operated group.
These results indicate that S-DOX, R-DOX and rac-DOX are able to reverse abnormal increased responses to carbachol and isoprenaline to normal levels in the detrusor smooth muscle preparations obtained from the outlet obstructed bladder of rats, and the potencies of the three agents are not different from each other. PartⅣEffects of S-doxazosin on experimental prostatic hyperplasia in rats: quantitative evaluation of prostatic histomorphology
We observed the effects of S-DOX and rac-DOX on experimental prostatic hyperplasia in rats using a method of quantitative evaluation of prostatic histomorphology. A prostatic hyperplasia model was established in the castrated rat treated with testosterone propionate, and S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were administered intragastrically for 30 days. After the rats were killed, the prostate was dissected and weighed, and the prostate volume was measured. The morphological changes in the anterior lobe and posterolateral lobe of the rat prostate were observed under light microscope, and their quantitative measurements were done by an image analysis system.
1 Effects of S-DOX on the volume and wet weight of the rat prostate
In comparison with the sham-operated rats, the volume, volume index, wet weight and wet weight index of the prostate in the castrated model rats were significantly increased (P<0.01). In comparison with the castrated model rats, treatment with S-DOX (3.0 mg·kg-1) produced a significant decrease in volume index of the prostate in castrated rats (P<0.05), but S-DOX (0.3, 1.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not affect the volume, volume index, wet weight and wet weight index of the prostate (P>0.05).
2 Morphological changes in prostate induced by S-DOX in prostatic hyperplasia of the rat
Epithelial cells in the anterior lobe and posterolateral lobe of the prostate in castrated model rats proliferated markedly, and glandular cavities of the prostate became enlarged significantly. In comparison with the castrated model rats, the proliferation of epithelial cells and enlargement of glandular cavities of the anterior lobe of the prostate were inhibited in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1). The morphological changes in posterolateral lobe of the prostate in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were similar to those of the anterior lobe in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1).
3 Quantitative evaluation of prostatic histomorphology in the prostatic hyperplasia rat treated with S-DOX
In comparison with the sham-operated rats, the maximal diameter, perimeter and area of the glandular cavity as well as the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats were significantly increased (P<0.01). In comparison with the castrated model rats, S-DOX (1.0, 3.0 mg·kg-1) significantly decreased the maximal diameter, perimeter and area of the glandular cavity as well as the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats (P<0.05, P<0.01). rac-DOX (1.0 mg·kg-1) significantly decreased the perimeter of the glandular cavity of the prostate posterolateral lobe and the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats (P<0.05, P<0.01) without effects on maximal diameter and area of the prostate glandular cavity (P>0.05).
Results of quantitative evaluation of prostatic histomorphology indicate that the inhibitory effects by S-DOX on prostatic hyperplasia of the prostate anterior and posterolateral lobes of the castrated rat treated with testosterone propionate are more potent than those by rac-DOX.
PartⅤEffects of S-doxazosin on cell proliferation and apoptosis of the prostate in prostatic hyperplasia of the rat
We studied the effects of S-DOX and rac-DOX on the cell proliferation and apoptosis of prostate in prostatic hyperplasia of the rat. A prostatic hyperplasia was induced by testosterone propionate in the castrated rat, and S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were administered intragastrically for 30 days. After the rats were killed, the anterior and posterolateral lobes of prostate were dissected, and the cell cycle phase distribution, apoptotic rate and expression of Bcl-2 and Bax proteins of prostatic cells were detected by FCM.
1 Effects of S-DOX on proliferation and apoptosis of the prostate anterior lobe cells in prostatic hyperplasia of the rat
In comparison with the sham-operated rats, the prostatic cells in S- and G2/M-phase of the cell cycle and the proliferation index of the prostatic cells in the castrated model rats were significantly increased (P<0.05). S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) had no significant influence on the distribution of cell cycle and proliferation index of the prostatic cells in prostatic hyperplasia of the rats. S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1), however, produced a slight and significant increase in the apoptotic rates by 7.90±3.91 %, 8.26±4.21 %, 8.33±4.49 % and 8.29±1.59 % (P<0.05, P<0.01) in prostatic hyperplasia of the rats in comparison with the castrated model rats by 4.42±1.08 %.
2 Effects of S-DOX on proliferation and apoptosis of the prostate posterolateral lobe cells in prostatic hyperplasia of the rat
S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the distribution of cell cycle, proliferation index and the apoptotic rate of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
3 Effects of S-DOX on the expression of Bcl-2 and Bax proteins of the prostate anterior lobe cells in prostatic hyperplasia of the rat
In comparison with the sham-operated rats, the fluorescence index of Bcl-2 protein and the Bcl-2/Bax ratio of the prostatic cells in the castrated model rats were significantly increased (P<0.05). S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the fluorescence indexes of Bcl-2 and Bax proteins and the Bcl-2/Bax ratio of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
4 Effects of S-DOX on the expression of Bcl-2 and Bax proteins of the prostate posterolateral lobe cells in prostatic hyperplasia of the rat
S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the fluorescence indexes of Bcl-2 and Bax proteins and the Bcl-2/Bax ratio of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
These results indicate that S-DOX and rac-DOX administered intragastrically produce a slight and significant increase in the apoptotic rate of the prostate anterior lobe cells in prostatic hyperplasia of the rat induced by testosterone propionate without effects on cell proliferation, and the apoptogenic role of S-DOX and rac-DOX may not be involved in a change in expression of Bcl-2 and Bax proteins.
Conclusion
S-DOX, R-DOX and rac-DOX administered intraduodenally decrease the vesical micturition pressure dose-dependently in the anesthetized rats and guinea pigs, and the inhibitory potencies on the vesical micturition pressure are not significantly different between S-DOX and rac-DOX. S-DOX has less adverse effects on intercontraction interval and vesical micturition volume, and weaker inhibitory effects on blood pressure and heart rate in comparison with R-DOX and rac-DOX.
S-DOX, R-DOX and rac-DOX are able to reverse abnormal increased responses to carbachol and isoprenaline to normal levels in the detrusor smooth muscle preparations obtained from the outlet obstructed bladder of rats, and the potencies of the three agents are not different from each other.
Histopathological examination findings indicate that S-DOX inhibits the prostatic hyperplasia induced by testosterone propionate in the castrated rat, and its effect is more potent than rac-DOX at the same dose. Promotion of prostatic cell apoptosis is one of the mechanisms of the inhibitory effect of S-DOX and rac-DOX on prostatic hyperplasia.
多沙唑嗪(doxazosin,DOX)是喹啉类、长效、选择性α1受体阻断剂,临床使用其消旋体(racemic-doxazosin, rac-DOX)。临床研究结果表明,rac-DOX可降低排尿阻力,提高最大尿流率,缓解BPH/LUTS症状。但是,rac-DOX常引起头昏、头疼、无力和体位性低血压等不良反应而影响其临床应用。因此,选择α1受体阻断剂治疗BPH/LUTS,应考虑药物的“尿路选择性”。在rac-DOX的分子结构中存在一个手性C原子和一对光学异构体。国内、外学者利用HPLC技术对rac-DOX进行了手性拆分,并制备了其单一对映体S-DOX和R-DOX。对S-DOX、R-DOX和rac-DOX进行的药理学研究发现,S-DOX、R-DOX和rac-DOX对人体前列腺α1受体的亲和力明显高于α2受体,且三者对α1受体的亲和力无显著性差异;S-DOX、R-DOX和rac-DOX均能竞争性对抗苯肾上腺素诱导的人离体前列腺平滑肌收缩反应,三者pA2值无显著性差异。但是,我室对兔离体胸主动脉和颈总动脉的研究发现,S-DOX拮抗去甲肾上腺素诱发血管收缩的pA2值显著小于R-DOX和rac-DOX,说明S-DOX对兔血管α1受体的选择性明显低于R-DOX和rac-DOX。上述结果提示,S-DOX可能成为心血管副作用较小的BPH/LUTS治疗药物。
本文进一步观察了S-DOX、R-DOX和rac-DOX十二指肠给药对大鼠血压和膀胱排尿功能的影响,以及不同给药途径对豚鼠膀胱排尿功能的影响;建立了大鼠膀胱出口梗阻模型,观察了S-DOX、R-DOX和rac-DOX对出口梗阻膀胱离体平滑肌的作用;同时,本文还建立了丙酸睾酮诱导去势大鼠前列腺增生模型,并就S-DOX和rac-DOX对增生前列腺的组织形态学变化及细胞增殖与凋亡进行了研究。
第一部分多沙唑嗪对映体十二指肠给药对大鼠血压和膀胱排尿功能的影响
本研究观察了S-DOX、R-DOX和rac-DOX十二指肠给药对麻醉大鼠血压和膀胱排尿功能的影响。采用八道生理记录仪记录麻醉大鼠颈总动脉血压、心率、膀胱排尿压以及排尿间隔的变化,收集并测量排尿量,以探讨S-DOX、R-DOX和rac-DOX对大鼠血压和膀胱排尿功能的选择性作用。
1多沙唑嗪对映体对大鼠颈总动脉血压及心率的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.1～3.0 mg·kg-1),均剂量依赖性降低麻醉大鼠颈总动脉收缩压、舒张压和平均动脉压;1.0 mg·kg-1时三者对平均动脉压的降低幅度分别达到26.9±8.2 %、40.5±8.8 %和43.1±7.7 %;三者降低平均动脉压的ED30值依次为1.7±0.8、0.5±0.6、0.5±0.4 mg·kg-1;S-DOX降低收缩压、舒张压和平均动脉压的作用均明显弱于R-DOX和rac-DOX (P<0.05),R-DOX和rac-DOX的降压作用无显著差异(P>0.05)。rac-DOX在1.0、3.0 mg·kg-1剂量时均可抑制麻醉大鼠心率,而S-DOX和R-DOX仅在3.0 mg·kg-1剂量时对心率有抑制作用。
2多沙唑嗪对映体对大鼠膀胱排尿功能的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.1～3.0 mg·kg-1),均剂量依赖性降低麻醉大鼠膀胱排尿压;三种药物对排尿压的最大降低幅度分别为13.4±5.7 %、14.5±11.0 %和10.9±7.6 %;三者降低排尿压的作用无显著差异(P>0.05);R-DOX可显著缩短排尿间隔并减少排尿量(P<0.05),S-DOX和rac-DOX对排尿间隔和排尿量无明显影响(P>0.05)。
上述结果表明,与R-DOX和rac-DOX相比,S-DOX在保留降低大鼠膀胱排尿压作用的同时,减轻了对血压、心率和膀胱排尿间隔的不良影响。
第二部分多沙唑嗪对映体不同给药途径对豚鼠膀胱排尿功能的影响
本研究观察了S-DOX、R-DOX和rac-DOX十二指肠给药和静脉注射对麻醉豚鼠膀胱排尿功能的影响。采用八道生理记录仪连续记录给药前、后麻醉豚鼠膀胱排尿压、排尿阈值压及排尿间隔的变化,收集并测量排尿量,以比较S-DOX、R-DOX和rac-DOX不同给药途径对豚鼠膀胱排尿功能的作用。
1多沙唑嗪对映体十二指肠给药对豚鼠膀胱排尿功能的影响
十二指肠给予S-DOX、R-DOX和rac-DOX(0.08～2.4 mg·kg-1),均剂量依赖性降低麻醉豚鼠膀胱排尿压;在0.8 mg·kg-1和2.4 mg·kg-1剂量时,S-DOX、R-DOX和rac-DOX对排尿压的降低幅度无显著差异(P >0.05)。十二指肠给予S-DOX对麻醉豚鼠排尿阈值压、排尿间隔及排尿量均无显著影响(P>0.05);R-DOX和rac-DOX则可显著降低排尿阈值压(P <0.05),在2.4 mg·kg-1剂量时均显著缩短排尿间隔(P<0.05),在0.8 mg·kg-1和2.4 mg·kg-1剂量时均显著减少排尿量(P<0.05)。
2多沙唑嗪对映体静脉注射对豚鼠膀胱排尿功能的影响
静脉注射S-DOX、R-DOX和rac-DOX(0.008～0.8 mg·kg-1),均剂量依赖性降低麻醉豚鼠膀胱排尿压,对膀胱排尿压的最大降低幅度依次为14.9±7.8 %、19.2±14.4 %和19.3±9.8 %,三者对排尿压的作用强度无显著性差异(P>0.05)。静脉注射S-DOX、R-DOX和rac-DOX对麻醉豚鼠排尿阈值压无显著影响(P>0.05),均能延长麻醉豚鼠膀胱排尿间隔(P<0.05),S-DOX和R-DOX尚能增加麻醉豚鼠膀胱排尿量(P<0.05)。
上述结果表明,十二指肠或静脉注射给予S-DOX,均可降低麻醉豚鼠膀胱排尿压;与R-DOX和rac-DOX相比,S-DOX对膀胱排尿阈值压、排尿间隔和排尿量无不良影响。
第三部分多沙唑嗪对映体对膀胱出口梗阻大鼠离体膀胱平滑肌的作用
本研究观察了S-DOX、R-DOX和rac-DOX对膀胱出口梗阻大鼠离体膀胱平滑肌的作用。建立膀胱出口梗阻大鼠模型;连续灌胃给予S-DOX、R-DOX和rac-DOX(3.0 mg·kg-1)2周后处死动物,制备离体膀胱体平滑肌标本,按累积给药法建立卡巴胆碱(0.01～100μmol·L-1)收缩反应量效曲线和异丙肾上腺素(0.01～300μmol·L-1)舒张反应量效曲线。
1多沙唑嗪对映体对大鼠膀胱体湿重的影响
与假手术组(89±8 mg)相比,模型组大鼠膀胱体湿重(111±18 mg)明显增加(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体湿重无明显改变(P>0.05)。
2多沙唑嗪对映体对大鼠膀胱体平滑肌收缩反应的影响
与假手术组相比,模型组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应明显增强(P<0.01),其量效曲线左移,Emax变大(P<0.01),EC50变小(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应明显降低(P<0.01),其Emax值明显减小(P<0.01),而EC50值明显增大(P<0.01)。与假手术组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对卡巴胆碱的收缩反应无明显改变(P>0.05)。
3多沙唑嗪对映体对大鼠膀胱体平滑肌舒张反应的影响
与假手术组相比,模型组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应明显增强(P<0.01),其量效曲线左移,Emax变大(P<0.01),EC50变小(P<0.01);与模型组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应明显降低(P<0.01),其Emax值明显减小(P<0.01),而EC50值明显增大(P<0.01)。与假手术组相比,模型+S-DOX组、模型+R-DOX组及模型+rac-DOX组大鼠膀胱体平滑肌对异丙肾上腺素的舒张反应无明显改变(P>0.05)。
综上所述,灌胃给予S-DOX、R-DOX和rac-DOX,可使膀胱出口梗阻大鼠离体膀胱体平滑肌对卡巴胆碱的过度收缩反应和异丙肾上腺素的过度舒张反应恢复正常,三者作用强度无显著差异。
第四部分S-多沙唑嗪对前列腺增生大鼠前列腺组织形态学的影响
本部分实验观察了S-DOX和rac-DOX对前列腺增生大鼠前列腺组织形态学的影响。建立丙酸睾酮诱导去势大鼠前列腺增生模型;连续灌胃给予S-DOX(0.3、1.0、3.0 mg·kg-1)和rac-DOX(1.0 mg·kg-1)30天后处死动物;测量前列腺体积并称量湿重;光镜观察前叶及后侧叶前列腺组织形态学变化;以图像分析系统进行组织计量学分析。
1 S-DOX对前列腺体积和湿重的影响
与假手术组相比,模型组大鼠前列腺体积、体积指数、各叶湿重及湿重指数均明显增大(P<0.01)。与模型组相比,S-DOX大剂量组前列腺体积指数显著减小(P<0.05)。rac-DOX组和S-DOX小、中剂量组上述各项指标与模型组相比无显著性差异(P>0.05)。
2 S-DOX对前列腺组织形态学的影响
模型组大鼠前叶及后侧叶前列腺腺上皮细胞增生,腺腔明显扩张。与模型组相比,S-DOX各剂量组和rac-DOX组大鼠前叶前列腺腺上皮细胞增生程度和腺腔扩张程度明显减轻;S-DOX各剂量组和rac-DOX组大鼠后侧叶前列腺上皮细胞增生程度和腺腔扩张程度略有减轻。
3 S-DOX对前列腺组织作用的计量学测量
与假手术组相比,模型组大鼠前叶及后侧叶前列腺腺腔最大直径、周长、面积及腺上皮细胞高度明显增大(P<0.01)。与模型组相比,S-DOX(1.0、3.0 mg·kg-1)可明显减小大鼠前叶及后侧叶前列腺腺腔最大直径、周长、面积及腺上皮细胞高度(P<0.05,P<0.01);rac-DOX(1.0 mg·kg-1)可减小后侧叶前列腺腺腔周长(P<0.05),亦可减小前叶及后侧叶上皮细胞高度(P<0.01),对前叶和后侧叶前列腺腺腔最大直径和面积无明显影响(P>0.05)。
上述结果表明,灌胃给予S-DOX和rac-DOX,可抑制丙酸睾酮诱导去势大鼠前列腺增生;S-DOX抗前列腺增生作用优于同等剂量的rac-DOX。
第五部分S-多沙唑嗪对前列腺增生大鼠前列腺细胞增殖与凋亡的影响
本部分实验观察了S-DOX和rac-DOX对前列腺增生大鼠前列腺细胞增殖与凋亡的影响。建立丙酸睾酮诱导去势大鼠前列腺增生模型;连续灌胃给予S-DOX(0.3,1.0和3.0 mg·kg-1)和rac-DOX(1.0 mg·kg-1)30天后处死动物;分离前叶及后侧叶前列腺组织,采用流式细胞术定量检测前列腺细胞增殖周期百分率、凋亡百分率及Bcl-2和Bax蛋白表达,以进一步分析S-DOX抗前列腺增生的作用机制。
1 S-DOX对大鼠前叶前列腺细胞增殖周期及凋亡的影响
与假手术组相比,模型组大鼠S期、G2/M期细胞周期百分率及增殖指数显著增高(P<0.05);与模型组相比,S-DOX各剂量组和rac-DOX组大鼠细胞增殖周期时相分布及增殖指数无明显改变(P>0.05)。S-DOX小剂量组、S-DOX中剂量组、S-DOX大剂量组和rac-DOX组细胞凋亡百分率依次为7.90±3.91 %、8.26±4.21 %、8.33±4.49 %和8.29±1.59 %,明显高于模型组的4.42±1.08 %(P<0.05,P<0.01)。
2 S-DOX对大鼠后侧叶前列腺细胞增殖周期及凋亡的影响
与模型组相比,S-DOX各剂量组及rac-DOX组大鼠细胞增殖周期时相分布、增殖指数及细胞凋亡百分率均无明显改变(P>0.05)。
3 S-DOX对大鼠前叶前列腺细胞Bcl-2和Bax蛋白含量的影响
与假手术组相比,模型组大鼠Bcl-2蛋白FI值及Bcl-2/Bax值明显增高(P<0.05);与模型组相比,S-DOX各剂量组及rac-DOX组大鼠Bcl-2蛋白FI值、Bax蛋白FI值及Bcl-2/Bax值均无明显改变(P>0.05)。
4 S-DOX对大鼠后侧叶前列腺细胞Bcl-2和Bax蛋白含量的影响
与模型组相比,S-DOX各剂量组及rac-DOX组大鼠Bcl-2蛋白FI值、Bax蛋白FI值及Bcl-2/Bax值均无明显改变(P>0.05)。
综上所述,灌胃给予S-DOX和rac-DOX,可促进丙酸睾酮诱导前列腺增生大鼠前叶前列腺细胞凋亡,但对前列腺细胞的增殖周期无明显影响。S-DOX和rac-DOX促进前列腺增生大鼠前列腺细胞凋亡的作用可能与Bcl-2和Bax蛋白表达水平的改变无关。
结论
十二指肠给予S-DOX、R-DOX和rac-DOX,均可剂量依赖性降低麻醉大鼠和豚鼠的膀胱排尿压,S-DOX降低排尿压的作用强度与rac-DOX相同;与R-DOX和rac-DOX相比,S-DOX对排尿间隔和排尿量无不良影响,对血压和心率的抑制作用较弱。
S-DOX、R-DOX和rac-DOX可使膀胱出口梗阻大鼠离体膀胱体平滑肌对卡巴胆碱的过度收缩反应和异丙肾上腺素的过度舒张反应恢复正常,三者作用强度无显著差异。
组织病理学结果表明,S-DOX和rac-DOX对丙酸睾酮诱导去势大鼠前列腺增生均有抑制作用;S-DOX抗前列腺增生作用优于同等剂量的rac-DOX。促进前列腺细胞凋亡是S-DOX和rac-DOX抗前列腺增生的作用机制之一。
Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are the most common urogenital disorders in ageing male. Patients with BPH/LUTS are suffering serious troubles on the quality of life, and BPH/LUTS have become a public health problem in the world. Surgical therapy seems to be the best option to treat BPH/LUTS, but it might cause some impairment to patients, such as uroclepsia, erectile dysfunction, retrograde ejaculation or relapse. Accordingly, it is becoming a considerable issue to develop safe and effective therapeutic agents treating the mild and intermediate BPH/LUTS. At present, therapeutic drugs to treat BPH/LUTS includeα1-adrenoceptor antagonists, 5α-reductase inhibitors and phytotherapeutic agents.
Doxazosin (DOX), a quinazoline derivative, is a long acting selectiveα1-adrenoceptor antagonist, and racemic-doxazosin (rac-DOX) is the current medication of DOX for the clinical treatment of BPH/LUTS. Several clinical studies have demonstrated that rac-DOX produces a decrease in urethral resistance and an increase in maximal urinary flow rate with a corresponding improvement in lower urinary tract symptoms in BPH patients. However, rac-DOX is limited in the clinical application for BPH/LUTS due to its common adverse effects of dizziness, headache, adynamia and orthostatic hypotension. Therefore, the urinary tract selectivity should be necessarily considered whenα1-adrenoceptor antagonists are used for the BPH/LUTS patients. In chemical structure, rac-DOX has a chiral carbon with two optical isomers, i.e. R- and S-forms. It was reported that S-doxazosin (S-DOX) and R-doxazosin (R-DOX) were prepared using chiral mobile phase HPLC. In a pharmacological study using the human isolated prostate tissue, S-DOX, R-DOX and rac-DOX were showed to have higher affinity for α1-adrenoceptors thanα2-adrenoceptors, and no significant differences inα1-adrenoceptor affinity were found among the three compounds. Furthermore, S-DOX, R-DOX and rac-DOX all competitively antagonized the phenylephrine-induced constractile responses in the human isolated prostate with no significant differences in their pA2 values among S-DOX, R-DOX and rac-DOX. Recently, a study in our laboratory showed that S-DOX, R-DOX and rac-DOX all competitively inhibited the norepinephrine-induced constractile responses in the rabbit thoracic aorta and carotid artery, but the pA2 value of S-DOX was significantly lower than that of R-DOX or rac-DOX, indicating that the affinity of S-DOX againstα1-adrenoceptors was significantly lower than that of R-DOX or rac-DOX in the rabbit isolated blood vessels. Therefore, it is reasonable to suggest that S-DOX is a potentially therapeutic agent improving BPH/LUTS with minor cardiovascular adverse effects.
In the present experiments, the effects of intraduodenal administration of S-DOX, R-DOX and rac-DOX on the rat carotid blood pressure and urinary bladder function, and the effects of S-DOX, R-DOX and rac-DOX by different routes of administration on the guinea pig urinary bladder function were observed. A rat model of partial outlet obstruction of urinary bladder was established and the effects of S-DOX, R-DOX and rac-DOX on the detrusor smooth muscle in vitro were investigated. Furthermore, a prostatic hyperplasia model induced by testosterone propionate in the castrated rat was made, and the effects of S-DOX and rac-DOX on prostatic histomorphology, cell proliferation and apoptosis were investigated.
PartⅠEffects of intraduodenal administration of doxazosin enantiomers on blood pressure and urinary bladder function in rats
We observed the effects of intraduodenal administration of S-DOX, R-DOX and rac-DOX on the carotid blood pressure and urinary bladder function in anesthetized rats. The parameters of carotid blood pressure, heart rate, vesical micturition pressure and intercontraction interval in anesthetized rats were recorded with an ADInstruments PowerLab/8sp data recording and analysis system, and the vesical micturition volume was measured, in order to investigate the selective effects of S-DOX, R-DOX and rac-DOX on the carotid blood pressure and urinary bladder function in rats.
1 Effects of doxazosin enantiomers on the carotid blood pressure and heart rate in rats
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.1~3.0 mg·kg-1) decreased the systolic blood pressure, diastolic blood pressure and mean arterial blood pressure significantly in the anesthetized rats in a dose-dependent manner. The inhibition of mean arterial pressure by S-DOX, R-DOX and rac-DOX at 1.0 mg·kg-1 was 26.9±8.2 %, 40.5±8.8 % and 43.1±7.7 %, respectively. The ED30 values of decreasing mean arterial blood pressure by S-DOX, R-DOX and rac-DOX were 1.7±0.8, 0.5±0.6 and 0.5±0.4 mg·kg-1. S-DOX had a weaker inhibitory effect on the carotid blood pressure in comparison with R-DOX and rac-DOX (P<0.05), but no significantly different effects were observed between R-DOX and rac-DOX on the carotid blood pressure (P>0.05). rac-DOX produced a significant inhibition on the heart rate at 1.0 and 3.0 mg·kg-1, but S-DOX and R-DOX reduced the heart rate only at 3.0 mg·kg-1.
2 Effects of doxazosin enantiomers on the urinary bladder function in rats
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.1~3.0 mg·kg-1) decreased the vesical micturition pressure dose-dependently in the anesthetized rats. The maximal inhibition of vesical micturition pressure by S-DOX, R-DOX and rac-DOX was 13.4±5.7 %, 14.5±11.0 % and 10.9±7.6 %, and their inhibitory potency on the vesical micturition pressure was not significantly different from each other (P>0.05). However, R-DOX, not S-DOX and rac-DOX, decreased the intercontraction interval and vesical micturition volume significantly (P<0.05).
These results indicate that S-DOX administered intraduodenally retains the beneficial action on vesical micturition pressure and improves the adverse effects on blood pressure, heart rate and intercontraction interval in comparison with R-DOX and rac-DOX in the anesthetized rats.
PartⅡEffects of doxazosin enantiomers by different routes of administration on urinary bladder function in guinea pigs
We observed the effects of intraduodenal and intravenous administration of S-DOX, R-DOX and rac-DOX on the urinary bladder function in anesthetized guinea pigs. The vesical micturition pressure, micturition threshold pressure and intercontraction interval in the anesthetized guinea pigs were recorded using an ADInstruments PowerLab/8sp data recording and analysis system, and the vesical micturition volume was measured, in order to investigate the effects of S-DOX, R-DOX and rac-DOX on the urinary bladder function by different routes of administration.
1 Effects of intraduodenal administration of doxazosin enantiomers on the urinary bladder function in guinea pigs
S-DOX, R-DOX and rac-DOX administered intraduodenally (0.08~2.4 mg·kg-1) decreased the vesical micturition pressure dose-dependently in the anesthetized guinea pigs. No significantly different effects on the vesical micturition pressure were observed among S-DOX, R-DOX and rac-DOX at 0.8 and 2.4 mg·kg-1 (P>0.05). S-DOX administered intraduodenally did not affect the micturition threshold pressure, intercontraction interval and vesical micturition volume significantly (P>0.05), but R-DOX and rac-DOX significantly depressed the micturition threshold pressure (P<0.05). R-DOX and rac-DOX also markedly decreased the intercontraction interval at 2.4 mg·kg-1 (P<0.05), and reduced the vesical micturition volume at 0.8 and 2.4 mg·kg-1(P<0.05).
2 Effects of intravenous administration of doxazosin enantiomers on the urinary bladder function in guinea pigs
S-DOX, R-DOX and rac-DOX administered intravenously (0.008~0.8 mg·kg-1) decreased the vesical micturition pressure in a dose-dependent manner in the anesthetized guinea pigs. The maximal inhibition of vesical micturition pressure by S-DOX, R-DOX and rac-doxazosin administered intravenously was 14.9±7.8 %, 19.2±14.4 % and 19.3±9.8 %, and their inhibitory potency on the vesical micturition pressure was not significantly different from each other (P>0.05). S-DOX, R-DOX and rac-DOX administered intravenously increased the intercontraction interval significantly (P<0.05), and S-DOX and R-DOX also increased the vesical micturition volume markedly (P<0.05). None of the three agents administered intravenously affected the micturition threshold pressure significantly (P>0.05).
These results indicate that S-DOX, administered intraduodenally or intravenously, produces a decrease in the vesical micturition pressure with less adverse effects on the micturition threshold pressure, intercontraction interval and vesical micturition volume in comparison with R-DOX and rac-DOX in the anesthetized guinea pigs.
PartⅢEffects of doxazosin enantiomers on the bladder strips from rats of partial outlet obstruction of urinary bladder
We investigated the effects of S-DOX, R-DOX and rac-DOX on the detrusor smooth muscle preparations from the rats with partial outlet obstruction of urinary bladder. A rat model of partial outlet obstruction of urinary bladder was established and S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) were administered intragastrically to the respective groups for 2 weeks. After the rats were killed, the detrusor smooth muscle strips were prepared and the responses to carbachol (0.01~100μmol·L-1) and isoprenaline (0.01~300μmol·L-1) in the detrusor smooth muscle preparations were observed.
1 Bladder wet weight of rats treated with doxazosin enantiomers
The bladder wet weight (111±18 mg) of the obstructed model group was significantly increased in comparison with the sham-operated rats (89±8 mg, P<0.01). There were no significant changes in the bladder wet weight of the obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks in comparison with that of obstructed model group (P>0.05).
2 Contractile responses to carbachol in the detrusor smooth muscle preparations from rats treated with doxazosin enantiomers
In comparison with sham-operated rats, the contractile responses to carbachol in the detrusor smooth muscle preparations obtained from obstructed model rats were significantly enhanced (P<0.01), and the concentration-response curve for carbachol was shifted to the left in a parallel manner, with an increase in Emax value and a decrease in EC50 value of carbachol (P<0.01). Contractile responses to carbachol in the detrusor smooth muscle preparations obtained from obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks were significantly depressed (P<0.01). The Emax and EC50 values of carbachol in the three groups treated with doxazosin enantiomers were significantly different from that in obstructed model group (P<0.01), but not different from that in sham-operated group.
3 Relaxant responses to isoprenaline in the detrusor smooth muscle preparations from rats treated with doxazosin enantiomers
In comparison with sham-operated rats, the relaxant responses to isoprenaline in the detrusor smooth muscle preparations obtained from obstructed model rats were significantly enhanced (P<0.01), and the concentration-response curve for isoprenaline was shifted to the left in a parallel manner, with an increase in Emax value and a decrease in EC50 value of isoprenaline (P<0.01). Relaxant responses to isoprenaline in the detrusor smooth muscle preparations obtained from obstructed rats treated with S-DOX, R-DOX or rac-DOX (3.0 mg·kg-1) for 2 weeks were significantly depressed (P<0.01). The Emax and EC50 values of isoprenaline in the three groups treated with doxazosin enantiomers were significantly different from that in obstructed model group (P<0.01), but not different from that in sham-operated group.
These results indicate that S-DOX, R-DOX and rac-DOX are able to reverse abnormal increased responses to carbachol and isoprenaline to normal levels in the detrusor smooth muscle preparations obtained from the outlet obstructed bladder of rats, and the potencies of the three agents are not different from each other. PartⅣEffects of S-doxazosin on experimental prostatic hyperplasia in rats: quantitative evaluation of prostatic histomorphology
We observed the effects of S-DOX and rac-DOX on experimental prostatic hyperplasia in rats using a method of quantitative evaluation of prostatic histomorphology. A prostatic hyperplasia model was established in the castrated rat treated with testosterone propionate, and S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were administered intragastrically for 30 days. After the rats were killed, the prostate was dissected and weighed, and the prostate volume was measured. The morphological changes in the anterior lobe and posterolateral lobe of the rat prostate were observed under light microscope, and their quantitative measurements were done by an image analysis system.
1 Effects of S-DOX on the volume and wet weight of the rat prostate
In comparison with the sham-operated rats, the volume, volume index, wet weight and wet weight index of the prostate in the castrated model rats were significantly increased (P<0.01). In comparison with the castrated model rats, treatment with S-DOX (3.0 mg·kg-1) produced a significant decrease in volume index of the prostate in castrated rats (P<0.05), but S-DOX (0.3, 1.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not affect the volume, volume index, wet weight and wet weight index of the prostate (P>0.05).
2 Morphological changes in prostate induced by S-DOX in prostatic hyperplasia of the rat
Epithelial cells in the anterior lobe and posterolateral lobe of the prostate in castrated model rats proliferated markedly, and glandular cavities of the prostate became enlarged significantly. In comparison with the castrated model rats, the proliferation of epithelial cells and enlargement of glandular cavities of the anterior lobe of the prostate were inhibited in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1). The morphological changes in posterolateral lobe of the prostate in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were similar to those of the anterior lobe in prostatic hyperplasia of the rats treated with S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1).
3 Quantitative evaluation of prostatic histomorphology in the prostatic hyperplasia rat treated with S-DOX
In comparison with the sham-operated rats, the maximal diameter, perimeter and area of the glandular cavity as well as the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats were significantly increased (P<0.01). In comparison with the castrated model rats, S-DOX (1.0, 3.0 mg·kg-1) significantly decreased the maximal diameter, perimeter and area of the glandular cavity as well as the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats (P<0.05, P<0.01). rac-DOX (1.0 mg·kg-1) significantly decreased the perimeter of the glandular cavity of the prostate posterolateral lobe and the epithelial cell height of the prostate anterior and posterolateral lobes in prostatic hyperplasia of the rats (P<0.05, P<0.01) without effects on maximal diameter and area of the prostate glandular cavity (P>0.05).
Results of quantitative evaluation of prostatic histomorphology indicate that the inhibitory effects by S-DOX on prostatic hyperplasia of the prostate anterior and posterolateral lobes of the castrated rat treated with testosterone propionate are more potent than those by rac-DOX.
PartⅤEffects of S-doxazosin on cell proliferation and apoptosis of the prostate in prostatic hyperplasia of the rat
We studied the effects of S-DOX and rac-DOX on the cell proliferation and apoptosis of prostate in prostatic hyperplasia of the rat. A prostatic hyperplasia was induced by testosterone propionate in the castrated rat, and S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) were administered intragastrically for 30 days. After the rats were killed, the anterior and posterolateral lobes of prostate were dissected, and the cell cycle phase distribution, apoptotic rate and expression of Bcl-2 and Bax proteins of prostatic cells were detected by FCM.
1 Effects of S-DOX on proliferation and apoptosis of the prostate anterior lobe cells in prostatic hyperplasia of the rat
In comparison with the sham-operated rats, the prostatic cells in S- and G2/M-phase of the cell cycle and the proliferation index of the prostatic cells in the castrated model rats were significantly increased (P<0.05). S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) had no significant influence on the distribution of cell cycle and proliferation index of the prostatic cells in prostatic hyperplasia of the rats. S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1), however, produced a slight and significant increase in the apoptotic rates by 7.90±3.91 %, 8.26±4.21 %, 8.33±4.49 % and 8.29±1.59 % (P<0.05, P<0.01) in prostatic hyperplasia of the rats in comparison with the castrated model rats by 4.42±1.08 %.
2 Effects of S-DOX on proliferation and apoptosis of the prostate posterolateral lobe cells in prostatic hyperplasia of the rat
S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the distribution of cell cycle, proliferation index and the apoptotic rate of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
3 Effects of S-DOX on the expression of Bcl-2 and Bax proteins of the prostate anterior lobe cells in prostatic hyperplasia of the rat
In comparison with the sham-operated rats, the fluorescence index of Bcl-2 protein and the Bcl-2/Bax ratio of the prostatic cells in the castrated model rats were significantly increased (P<0.05). S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the fluorescence indexes of Bcl-2 and Bax proteins and the Bcl-2/Bax ratio of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
4 Effects of S-DOX on the expression of Bcl-2 and Bax proteins of the prostate posterolateral lobe cells in prostatic hyperplasia of the rat
S-DOX (0.3, 1.0, 3.0 mg·kg-1) and rac-DOX (1.0 mg·kg-1) did not significantly affect the fluorescence indexes of Bcl-2 and Bax proteins and the Bcl-2/Bax ratio of the prostatic cells in prostatic hyperplasia of the rats in comparison with the castrated model rats (P>0.05).
These results indicate that S-DOX and rac-DOX administered intragastrically produce a slight and significant increase in the apoptotic rate of the prostate anterior lobe cells in prostatic hyperplasia of the rat induced by testosterone propionate without effects on cell proliferation, and the apoptogenic role of S-DOX and rac-DOX may not be involved in a change in expression of Bcl-2 and Bax proteins.
Conclusion
S-DOX, R-DOX and rac-DOX administered intraduodenally decrease the vesical micturition pressure dose-dependently in the anesthetized rats and guinea pigs, and the inhibitory potencies on the vesical micturition pressure are not significantly different between S-DOX and rac-DOX. S-DOX has less adverse effects on intercontraction interval and vesical micturition volume, and weaker inhibitory effects on blood pressure and heart rate in comparison with R-DOX and rac-DOX.
S-DOX, R-DOX and rac-DOX are able to reverse abnormal increased responses to carbachol and isoprenaline to normal levels in the detrusor smooth muscle preparations obtained from the outlet obstructed bladder of rats, and the potencies of the three agents are not different from each other.
Histopathological examination findings indicate that S-DOX inhibits the prostatic hyperplasia induced by testosterone propionate in the castrated rat, and its effect is more potent than rac-DOX at the same dose. Promotion of prostatic cell apoptosis is one of the mechanisms of the inhibitory effect of S-DOX and rac-DOX on prostatic hyperplasia.
引文
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