Chirally Selective Effects Of Enantiomers Of Alfuzosin And Doxazosin On Blood Pressure And Urethral Perfusion Pressure In The Anesthetized Mice

α₁-Adrenoceptor antagonists are now used as first-line medical treatment for patients with benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS). ?α₁-Adrenoceptor antagonists relax the smooth muscle of the bladder neck, prostate gland 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, rhinitis and sexual dysfunction. Therefore, uroselectivity has become a very important issue of theα-adrenergic treatment option of BPH/LUTS.Objective: To investigate the chirally selective effects of enantiomers of alfuzosin and doxazosin administered intravenously on the blood pressure and urethral perfusion pressure in the anesthetized mice.Methods:1. After the male KM mouse was anaesthetized with urethane, a venoclysis needle 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 using a PowerLab/8sp and software PowerLab Chart 5.0. The tail vein was cannulated for drug administration.2. After the male KM mouse was anaesthetized with urethane, a catheter was inserted through the bladder dome into the urethra, and the catheter was fixed and secured at the bladder neck. A perfusion apparatus of BP Monitoring Kit (Becton Dickinson Infusion Inc USA) was connected to the catheter, and the perfusion rate was controlled at 1.8 mL/h. The urethral perfusion pressure (UPP) was recorded using a PowerLab/8sp and software PowerLab Chart 5.0. Results:1. Effects of (±)ALF, (±)DOX and their enantiomers on the blood pressure in the anesthetized miceThe SBP, DBP and MBP were significantly decreased by (±)ALF, (±)DOX and their enantiomers (0.2²000 nmol·kg^-1, iv) in a dose-dependent manner (P<0.05 and P<0.01). The hypotensive effect induced by (-)ALF was more potent than that by (+)ALF (P<0.01). On the contrary, the decrease in the SBP, DBP and MBP induced by (+)DOX was significantly larger than that by (-)DOX (P<0.05 and P<0.01).2 Effects of (±)ALF, (±)DOX and their enantiomers on the spontaneous urethral contraction of the perfused urethra in the anesthetized miceThe highest UPP and lowest UPP were significantly decreased by (-)ALF and (+)ALF at 200²000 nmol·kg^-1 (P<0.05 and P<0.01), and the decrease in the highest UPP and lowest UPP induced by (-)ALF was significantly larger than that by either (+)ALF or (±)ALF (P<0.05 and P<0.01). However, (-)DOX, (+)DOX and (±)DOX only at 2000 nmol·kg^-1 significantly decreased the highest UPP and lowest UPP (P<0.01), and there was no statistically significant difference in the extent of UPP change among the 3 agents (P>0.05).3 Effects of (±)ALF, (±)DOX and their enantiomers on the dose-responses curve of the increased UPP by phenylephrine in the anesthetized micePhenylephrine (0.1¹.6μmol·kg^-1, iv) increased the UPP in a dose-dependent manner in the anesthetized control animals. Accumulative administration of (-)ALF, (+)ALF or (±)ALF (2000 nmol·kg^-1, iv) significantly inhibited the increases in UPP induced by phenylephrine at 400⁸00 nmol·kg^-1 in the anesthetized mice (P<0.01), and there was no statistically significant difference in the extent of the inhibitory effect among the 3 agents (P>0.05). Accumulative administration of (+)DOX and (±)DOX (2000 nmol·kg^-1, iv) significantly inhibited the increase in UPP induced by phenylephrine at 0.2¹.6 nmol·kg^-1 (P<0.01), however same dose of (-)DOX produced a weak but significant inhibition in the anesthetized mice (P<0.01). (+)DOX and (±)DOX inhibited the increase in UPP induced by phenylephrine in the anesthetized mice to a greater extent than (-)DOX (P<0.01).4. Effects of (±)ALF, (±)DOX and their enantiomers on the increased UPP by single dose of phenylephrine in the anesthetized miceAfter administration of (±)ALF, (±)DOX and their enantiomers (1000 nmol·kg^-1, iv), only (-)ALF and (+)DOX significantly inhibited the increase in UPP induced by phenylephrine at 1.6μmol·kg^-1 (P<0.05). At a dose of 2000 nmol·kg^-1 (±)ALF, (±)DOX and their enantiomers significantly inhibited the increase in UPP induced by 1.6μmol·kg^-1 phenylephrine in the anesthetized mice (P<0.01), except for (-)DOX.5. Time-related effects of (±)ALF and (±)DOX on the increase in UPP induced by phenylephrine in the anesthetized micePhenylephrine (1.6μmol·kg^-1, iv) repeatedly administered at 5, 30, 60 and 90 min after solvent injection, increased the UPP to the same extent in the anesthetized control animals (P>0.05). (±)DOX at 2000 nmol·kg^-1 significantly inhibited phenylephrine-induced increases in UPP at 5, 30, 60 and 90 min after administration of (±)DOX in the anesthetized mice (P<0.05 and P<0.01). However, the inhibition effect of (±)ALF at the same dose on the phenylephrine-induced increases in UPP was gradually decreased during the time course (5⁹0 min). (±)ALF at 2000 nmol·kg^-1 did not significantly inhibit phenylephrine-induced increase in UPP at 90 min after administration of (±)ALF (P>0.05).6. Effects of terazosin and prazosin on the increased UPP by single dose of phenylephrine in the anesthetized miceAfter administration of terazosin, prazosin, (±)ALF and (±)DOX (1000 nmol·kg^-1, iv), terazosin, prazosin, (±)ALF but not (±)DOX significantly inhibited the increase in UPP induced by phenylephrine at 1.6μmol·kg^-1 in the anesthetized mice (P<0.05 and P<0.01). At a dose of 2000 nmol·kg^-1 terazosin, prazosin and (±)ALF further inhibited the increase in UPP induced by phenylephrine to a greater extent, and their inhibitory effects were more potent than the effect of (-)DOX (P<0.01). The percentage inhibition of (±)DOX, (±)ALF, terazosin and prazosin at 2000 nmol·kg^-1 on the increase in UPP induced by phenylephrine was 45.40%, 88.36%, 94.01% and 96.12%.Conclusion: Chiral structures of ALF and DOX influence their hypotensive effects obviously in the anesthetized mice. Inhibitory effects on spontaneous urethral contraction induced by urethral perfusion in the mouse treated with (±)ALF and its enantiomers are more potent than that in the mouse treated with (±)DOX and its enantiomers, and (-)ALF has a greater inhibitory effect than (+)ALF. On the other hand, (±)ALF and its enantiomers inhibit the increases in UPP induced by phenylephrine to the same extent, however (+)DOX and (±)DOX have much greater inhibitory effects than (-)DOX. These results suggest that mechanism underlying the inhibitory effect ofα₁-adrenoceptor antagonist on the spontaneous urethral contraction may be different from that on the urethral contraction induced by phenylephrine. The rank order of inhibitory potency ofα₁-adrenoceptor antagonists, quinazoline derivative, is prazosin > terazosin > (±)ALF > (±)DOX.