Effects Of Alfuzosin And Doxazosin Enantiomers On Blood Pressure And Vesical Micturition Pressure In Anesthetized Animals

Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are the most common urogenital disorders in the ageing male. Patients with BPH/LUTS are suffering from a serious decrease in the quality of life, and BPH/LUTS have become a major 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 erectile dysfunction, uroclepsia, retrograde ejaculation or relapse. Accordingly, medication is becoming a safe and effective therapeutic way to treat mild and intermediate BPH/LUTS.α₁-Adrenoceptor antagonists are now used as first-line medical treatment of the patients with BPH/LUTS.α₁-Adrenoceptor antagonists relax the smooth muscle of the bladder neck, prostatic smooth muscle and prostatic urethra, thereby reducing urethral tone and bladder outlet resistance, and improving obstructive symptoms in BPH patients. Nevertheless, these agents can produce adverse reactions including dizziness, headache, asthenia, postural hypotension and sexual dysfunction. Therefore, uroselectivity has become a very important issue of the treatment withα-adrenergic blockade for BPH/LUTS.Objective: To investigate the pharmacological effects of (-)alfuzosin [(-)ALF], (+)alfuzosin [(+)ALF], (-)doxazosin [(-)DOX] and (-)doxazosin [(+)DOX] administered intravenously on the blood pressure in the anesthetized rats and vesical micturition pressure in the anesthetized guinea pigs.Methods: 1. After the male Wistar rat was anesthetized with urethane, a polyethylene catheter was inserted into the left common carotid artery for blood pressure measurement. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) were recorded by using a PowerLab/8SP Chart 5 software (ADInstruments).2. After the male guinea pigs was anesthetized with urethane, a longitudinal midline incision (1.0 cm) was made in the skin just above the pubic symphysis, and the ureters were cut. The distal ends of the ureters were ligated, and a cotton wool ball was placed on the proximal ends to absorb urine. For bladder pressure measurements, an intravenous catheter (22GA×1.00) was inserted gently through the bladder apex into the lumen. The intravenous catheter was filled with physiologic saline and connected to a perfusion pump with perfusion rate of 18 ml·h-1. The vesical micturition pressure (VMP), micturition threshold pressure (MBP), intercontraction interval (ICI) and vesical micturition volume (VMV) were recorded by using a PowerLab/8SP Chart 5 software (ADInstruments).Results:1. Effects of (-)ALF, (+)ALF, (-)DOX and (+)DOX on blood pressure in anesthetized ratsIntravenous administration of physiological saline (solvent) in solvent control group of the anesthetized rats did not change the SBP, DBP and MBP significantly (P>0.05). There were no significant differences in the value of SBP, DBP or MBP among solvent control, (-)ALF, (+)ALF, (-)DOX and (+)DOX groups before administration (P>0.05).The SBP, DBP and MBP were significantly decreased by (-)ALF and (+)ALF (0.3³00 nmol·kg^-1, iv) in a dose-dependent manner in the anesthetized rats (P<0.01). Two-way ANOVA results showed that (-)ALF decreased the SBP, DBP and MBP more potently than (+)ALF (P<0.01). (-)ALF and (+)ALF at 300 nmol·kg^-1 decreased the MBP by 44.42±7.38% and 35.17±6.93%, and there was a significant difference between the two values (P<0.01). The SBP, DBP and MBP were also significantly decreased by (-)DOX and (+)DOX (0.3³00 nmol·kg^-1, iv) in a dose-dependent manner in the anesthetized rats (P<0.05 and P<0.01). Two-way ANOVA results showed that (+)DOX decreased the SBP, DBP and MBP more potently than (-)DOX (P<0.01). (-)DOX and (+)DOX at 300 nmol·kg^-1 decreased the MBP by 30.71±9.44% and 43.13±5.17%, and there was a significant difference between the two values (P<0.01).2. Effects of (-)ALF, (+)ALF, (-)DOX and (+)DOX on micturition function in anesthetized guinea pigsIntravenous administration of physiological saline (solvent) in solvent control group of the anesthetized guinea pigs did not change the VMP, MTP, ICI and VMV significantly (P>0.05). There were no significant differences in the value of VMP, MTP, ICI or VMV among solvent control, (-)ALF, (+)ALF, (-)DOX and (+)DOX groups before administration (P>0.05).The VMP was significantly decreased by (-)ALF and (+)ALF (15¹500 nmol·kg^-1, iv) in a dose-dependent manner in the anesthetized guinea pigs (P<0.01). Two-way ANOVA results showed that (-)ALF decreased the VMP to the same extent as (+)ALF (P>0.05), and maximal decreases in the VMP by (-)ALF and (+)ALF were 24.31±9.33% and 25.67±6.78%. The values of MTP, ICI and VMV were not affected by (-)ALF and (+)ALF significantly (P>0.05).The VMP was also significantly decreased by (-)DOX and (+)DOX (15¹500 nmol·kg^-1, iv) in a dose-dependent manner in the anesthetized guinea pigs (P<0.05 and P<0.01). Two-way ANOVA results showed that (-)DOX decreased the VMP to the same extent as (+)DOX (P>0.05), and maximal decreases in the VMP by (-)DOX and (+)DOX were 28.09±13.54% and 28.83±11.47%. The values of MTP, ICI and VMV were not affected by (-)DOX and (+)DOX significantly (P>0.05).Conclusion: Intravenously administered (-)ALF, (+)ALF, (-)DOX and (+)DOX significantly decrease the VMP in the anesthetized guinea pigs, and they decrease the VMP to the same extent. However, the hypotensive effects by (-)ALF and (+)DOX in the anesthetized rats are significantly bigger than those by (+)ALF and (-)DOX respectively. These results suggest that the chiral structure of ALF and DOX has an obvious influence on their hypotensive action, but not their action on micturition.