| 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.
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