【作者】 吴志刚；

【导师】 任雷鸣；

【作者基本信息】 河北医科大学 ， 药理学， 2008， 硕士

【摘要】 良性前列腺增生(benign prostatic hyperplasia,BPH)可造成膀胱出口梗阻(bladder outlet obstruction,BOO),从而引起一系列的下尿路症状(lower urinary tract symptoms, LUTS)。α受体阻断药可阻断α受体,使膀胱颈部及前列腺平滑肌松弛,降低近段尿道压,已被广泛用于治疗BPH/LUTS。多沙唑嗪(racemic-doxazosin,rac-DOX)属选择性α1受体阻断药,是临床上治疗BPH的一线药物,但同时可引起心血管系统的不良反应。利用HPLC技术对rac-DOX进行手性拆分,可制备其单一光学异构体S-DOX和R-DOX。我们采用静脉给药法,观察rac-DOX及其光学异构体对麻醉兔颈总动脉血压和尿道压的影响,探讨rac-DOX及其光学异构体对下尿路药理作用的选择性。目的:建立可同步测定血压和尿道压的动物模型,观察S-DOX、R-DOX和rac-DOX静脉给药对苯肾上腺素升高麻醉兔颈总动脉血压和尿道压的影响,分析rac-DOX及其光学异构体对下尿路药理作用的立体选择性。方法:雄性新西兰白兔静脉注射乌拉坦(1.25g·kg-1)麻醉后,行气管插管,保持呼吸畅通;将聚乙烯导管插入左侧颈总动脉测定血压,导管另一端经压力换能器与八道生理记录仪相连,记录颈总动脉血压。于兔下腹部打开腹腔,剪开耻骨连合,暴露尿道。于膀胱顶部造一小口,将充满生理盐水的聚乙烯插管(外径1.3mm,内径0.8mm)经膀胱插入尿道,于膀胱颈部结扎固定,并于膀胱颈下方1cm处结扎尿道远端。聚乙烯管的另一端与压力换能器和八道生理记录仪相连,记录尿道压。手术完成后,经三通由聚乙烯管向尿道内注入一定量的生理盐水(0.2~0.4ml),使尿道压升至100cmH2O左右,平衡30min,待血压、尿道压稳定后开始实验。结果:1苯肾上腺素对麻醉兔颈总动脉血压的作用静脉给予苯肾上腺素(1~45μg·kg-1),剂量依赖性升高麻醉兔颈总动脉收缩压、舒张压和平均动脉压;45μg·kg-1时升高收缩压、舒张压和平均动脉压的最大值分别为57.29±6.63、51.68±7.27和52.62±7.13(mmHg,n=8)。2苯肾上腺素对麻醉兔尿道压的作用静脉给予苯肾上腺素(1~45μg·kg-1),剂量依赖性升高麻醉兔尿道压;45μg·kg-1时升高尿道压的最大值为51.75±9.72(cmH2O,n=8)。3 rac-DOX、S-DOX及R-DOX对麻醉兔血压的影响静脉注射S-DOX、R-DOX和rac-DOX(0.5~50μg·kg-1),剂量依赖性降低麻醉兔颈总动脉收缩压、舒张压和平均动脉压;在50μg·kg-1剂量时,三者对平均动脉压的降低幅度分别为19.73±4.83%、23.80±8.45%和22.21±6.43%。R-DOX降低舒张压和平均动脉压的作用显著强于S-DOX(P<0.05)。4 rac-DOX、S-DOX及R-DOX对苯肾上腺素升高麻醉兔血压和尿道压的影响静脉给予S-DOX、R-DOX和rac-DOX(0.5~50μg·kg-1),均剂量依赖性降低苯肾上腺素升高麻醉兔颈总动脉收缩压、舒张压和平均动脉压的作用。S-DOX、R-DOX和rac-DOX在50μg·kg-1剂量时,降低苯肾上腺素升高平均动脉压的幅度分别为10.45±18.36%、53.38±11.86%和47.88±12.88%。S-DOX降低苯肾上腺素升高血压各参数的作用强度均显著弱于R-DOX和rac-DOX(P<0.01)。R-DOX降低苯肾上腺素升高血压各参数的作用强度与rac-DOX相同(P>0.05)。在尿道压方面,S-DOX、R-DOX和rac-DOX均能显著降低苯肾上腺素升高麻醉兔尿道压的作用;在50μg·kg-1剂量时,三者降低苯肾上腺素升高尿道压的幅度分别为48.18±15.85%、71.47±9.23%和53.26±15.35%;S-DOX的作用强度与rac-DOX相同(P>0.05),R-DOX的作用明显强于S-DOX与rac-DOX(P<0.01)。采用尿道压抑制率与平均动脉压抑制率比值法计算药物抑制指数(IRIUP/IRMBP ratio),分析rac-DOX及其光学异构体在不同剂量下,降低苯肾上腺素升高麻醉兔平均动脉压和尿道压的选择性。S-DOX在各个剂量下IRIUP/IRMBP值均在2.5以上,而R-DOX和rac-DOX的IRIUP/IRMBP值均小于S-DOX。结果表明,S-DOX对下尿路的选择性高于R-DOX和rac-DOX。结论:S-DOX静脉给药降低麻醉兔颈总动脉舒张压和平均动脉压的作用弱于R-DOX。S-DOX降低苯肾上腺素升高血压的作用显著弱于R-DOX和rac-DOX,而其降低苯肾上腺素升高尿道压的作用与rac-DOX相同。研究结果表明,S-DOX降低苯肾上腺素升高尿道压的选择性高于R-DOX和rac-DOX。更多还原

【Abstract】 Benign prostatic hyperplasia (BPH) often leads to bladder outlet obstruction (BOO) and induces lower urinary tract symptoms (LUTS).α1-Adrenoceptor antagonists relax the smooth muscle of the bladder neck and prostate gland, and decrease the proximal urethral pressure by blockingα1-adrenoceptors. They were used most frequently for the treatment of BPH/LUTS. Racemic-doxazosin (rac-DOX), a highly selectiveα1-adrenoceptor antagonist, is considered as the first-line therapy for the patients with BPH and also produces several side effects in cardiovascular system. It was reported that S-doxazosin (S-DOX) and R-doxazosin (R-DOX) were prepared using chiral mobile phase HPLC. In the present experiments, we observed the effects of intravenous administration of S-DOX, R-DOX and rac-DOX on the carotid blood pressure and intra-urethral pressure (IUP) in the anesthetized rabbit to analyse the uroselectivity of doxazosin enantiomers.Aim: To establish an animal model observing blood pressure and IUP at the same time in the anesthetized rabbit for evaluating the stereoselective effects of intravenous administration of S-DOX, R-DOX and rac-DOX between the carotid blood pressure and IUP.Methods: New Zealand white male rabbit was anesthetized with an intravenous injection of urethane (1.25g·kg-1). Then, a catheter was inserted into trachea to allow drainage of bronchial secretion and to facilitate the breath. Polyethylene catheter was inserted into the left common carotid artery for blood pressure measurement. Blood pressure was monitored via the arterial catheter connected to a pressure transducer, and displayed on PowerLab/8sp through computer running the PowerLab Chart 5.0 software. The rabbit was opened through a midline incision over the lower abdomen. After resection of the pubic bone, the urethra was exposed. A small hole was made at the dome of the bladder in order to intubate a catheter (outer diameter 1.3mm, inner diameter 0.8mm) filled with physiological saline into the urethra from the bladder side. The catheter was fixed and secured at the bladder neck, and the distal end of urethra 1cm from the bladder neck was ligated. IUP was monitored via the catheter connected to a pressure transducer, and displayed on PowerLab/8sp through computer running the PowerLab Chart 5.0 software. After all the surgical preparations, the IUP was increased to approximately 100cmH2O by injection a small volume (0.2~0.4ml) of physiological saline into urethra via the catheter, then the blood pressure and IUP were equilibrated for 30min.Results: 1 Effects of phenylephrine on the carotid blood pressure in anesthetized rabbitsPhenylephrine administered intravenously(1~45μg·kg-1) increased the systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MBP) in the anesthetized rabbits in a dose-dependent manner. SBP, DBP and MBP were increased with phenylephrine at 45μg·kg-1 by 57.29±6.63, 51.68±7.27 and 52.62±7.13 (mmHg, n=8), respectively.2 Effects of phenylephrine on the intra-urethral pressure in anesthetized rabbitsPhenylephrine administered intravenously(1~45μg·kg-1) increased the IUP in the anesthetized rabbits in a dose-dependent manner. IUP was increased with phenylephrine at 45μg·kg-1 by 51.75±9.72 (cmH2O, n=8).3 Effects of doxazosin enantiomers on the boold pressure in anesthetized rabbitsS-DOX, R-DOX and rac-DOX administered intravenously (0.5~50μg·kg-1)decreased SBP, DBP and MBP in the anesthetized rabbits in a dose-dependent manner. The percentage inhibition of MBP by S-DOX, R-DOX and rac-DOX administered intravenously at 50μg·kg-1 was 19.73±4.83%, 23.80±8.45% and 22.21±6.43%, respectively. R-DOX had a stronger inhibitory effect on the DBP and MBP in comparison with S-DOX (P<0.05).4 Effects of doxazosin enantiomers on phenylephrine-induced increases in blood pressure and intra-urethral pressure in anesthetized rabbitsS-DOX, R-DOX and rac-DOX administered intravenously (0.5~50μg·kg-1) decreased the increases of SBP, DBP and MBP induced by phenylephrine in the anesthetized rabbits in a dose-dependent manner. The percentage inhibition by S-DOX, R-DOX and rac-DOX on the increase in MBP induced by phenylephrine was 10.45±18.36%, 53.38±11.86% and 47.88±12.88%, respectively. S-DOX had a weaker inhibitory effect on phenylephrine-induced increase in SBP, DBP and MBP in comparison with R-DOX and rac-DOX (P<0.01). R-DOX inhibited the increase in the blood pressure induced by phenylephrine to the same extent as rac-DOX (P>0.05). S-DOX, R-DOX and rac-DOX decreased the increases in IUP induced by phenylephrine significantly. The percentage inhibition of the increase in IUP induced by phenylephrine by S-DOX, R-DOX and rac-DOX administered intravenously at 50μg·kg-1 was 48.18±15.85%, 71.47±9.23% and 53.26±15.35%. S-DOX inhibited the increase in the IUP induced by phenylephrine to the same extent as rac-DOX (P>0.05). R-DOX had a stronger inhibitory effect on phenylephrine-induced increase in IUP in comparison with S-DOX and rac-DOX (P<0.01).The ratio of inhibition rate in IUP (IRIUP) to inhibition rate in MBP (IRMBP) by S-DOX, R-DOX and rac-DOX on the phenylephrine-induced responses was used to analyse the selectivity of an agent between blood pressure and bladder urinary system. The value (IRIUP/IRMBP ratio) of S-DOX at each concentration was larger than 2.5, but the values (IRIUP/IRMBP ratio) of R-DOX and rac-DOX were much smaller than S-DOX indicating that S-DOX had a higher uroselectivity than R-DOX and rac-DOX.Conclusion: S-DOX administered intravenously decreases DBP and MBP more weakly than R-DOX in anesthetized rabbits. The inhibitory effect by S-DOX on the increase in blood pressure induced by phenylephrine is much weaker than that by R-DOX and rac-DOX, but the inhibitory effec by S-DOX on the increase in IUP induced by phenylephrine is the same to rac-DOX. Results of the present study suggest that S-DOX has chiral selectivity between cardiovascular system and urethral tissue much highly than R-DOX and rac-DOX in anesthetized rabbits.更多还原