α₁-Adrenoceptor Antagonist Profil Of Doxazosin Enantiomers In The Rabbit Isolated Blood Vessels

Objective: To study the effects of α1-adrenoceptor antagonist, doxazosin enantiomers, on the vasoconstrictive responses to noradrenaline (NA) in the rabbit isolated ear artery, mesenteric artery and pulmonary artery and their effects on the sympathetic nerve stimulation-induced vascular responses in the rabbit isolated saphenous artery. Method: Vasoconstrictive responses of the rabbit isolated arterial rings to electric field stimulation and NA were recorded. Results: The cumulative concentration-response curves (CCRC) for NA were contructed for 6 times in the ear artery and mesenteric artery as time-control experiments. The values of Emax or EC50 obtained from the third to the sixth CCRC for NA were reproducible without significant differences (P＞0.05, n=6). The CCRC for NA were contructed for 5 times in the pulmonary artery as time-control experiments and the values of Emax or EC50 obtained from the second to the fifth CCRC for NA were also reproducible without significant differences (P＞0.05, n=6). The values of Emax or EC50 obtained from CCRC ( the third CCRC in the ear or mesenteric arteries and the second CCRCin the pulmonary artery) for NA before the treatment by prazosin, R-doxazosin or S-doxazosin were not significantly different in the ear artery, mesenteric artery or pulmonary artery (P＞0.05, n=6). Prazosin at 1nM, 10nM and 100nM noncompetitively (the slope of Schild plot was significantly different from unity) inhibited the CCRC for NA in the ear artery and pulmonary artery, and competitively inhibited the CCRC for NA without significant decrease in the Emax values in the mesenteric artery. R-doxazosin or S-doxazosin at 0.03, 0.1 and 0.3μM produced parallel shift to the right of the CCRC for NA without significant decrease in the Emax values in the ear artery, mesenteric artery and pulmonary artery, and the slope of Schild plot was not significantly different from unity (P＞0.05, n=6). The pA2 values of R-doxazosin were significantly higher than those of S-doxazosin in three arteries (P＜0.01, n=6). R-doxazosin or S-doxazosin (0.1~10μM) did not affect the vasoconstriction induced by electric stimulation, but significantly inhibited that at 100μM in the rabbit isolated saphenous artery (P＜0.01, n=5). R-doxazosin or S-doxazosin at 100μM signifi- cantly inhibited the vasoconstriction induced by exogenous NA (P＜0.01, n=5), but did not affect the vascular responses to exogenous adenosine triphosphate (1mM) (P＞0.05, n=5). Conclusion: R-doxazosin and S-doxazosin competitively inhibit the CCRC for NA in the rabbit earartery, mesenteric artery and pulmonary artery, and the pA2 values of S-doxazosin were significantly lower than those of R-doxazosin. The higher concentration (10μM) of R-doxazosin or S-doxazosin did not affect the prejunctional α2-adrenoceptor of the sympathetic nerve terminals in the rabbit isolated saphenous artery.