多沙唑嗪对映体对兔四种血管α受体的作用

Effects of doxazosin enantiomers on α-adrenoceptors of isolated rabbit blood vessels

多沙唑嗪（doxazosin，DOX）作为高选择性α1受体阻断药，是临床上治疗良性前列腺增生（benign prostatic hyperplasia，BPH）的一线药物，但同时引起心血管系统的不良反应。本研究采用兔离体动脉环张力实验及电场刺激兔离体隐动脉诱发交感嘌呤能血管收缩实验观察R-多沙唑嗪（R-doxazosin，R-DOX）和S-多沙唑嗪（S-doxazosin，S-DOX）对兔耳动脉、肠系膜动脉和肺动脉血管平滑肌α1受体的作用，以及较高浓度R-DOX和S-DOX对兔隐动脉交感神经突触前膜α2受体的作用。结果表明，在兔耳动脉、肠系膜动脉和肺动脉，R-DOX和S-DOX竞争性拮抗去甲肾上腺素（noradrenaline，NA）诱发的血管收缩反应；其pA2值分别为7．91±0．03和7．53±0．05，7．80±0．05和7．29±0．07以及8．32±0．06和7．97±0．07；且S-DOX的pA2值均明显小于R-DOX的pA2值（P〈0．01）。R-DOX和S-DOX（0．1—10μmol·L^-1）对电刺激诱发的血管收缩反应无明显影响；R-DOX或S-DOX（100μmol·L^-1）显著抑制电刺激诱发的血管收缩反应，完全抑制外源性NA诱发的血管收缩反应，但对1mmol·L^-1腺苷三磷酸诱发的血管收缩反应无明显影响。上述结果提示，R-DOX和S-DOX对NA诱发兔耳动脉、肠系膜动脉和肺动脉收缩反应具有竞争性拮抗作用，对上述三种血管S-DOX拮抗NA的pA2值均明显小于R-DOX。此外，R-DOX和S-DOX的浓度升至10μmol·L^-1时，对血管交感神经末梢突触前膜α2受体仍无明显影响。

Doxazosin, a high selective α1-adrenoceptor antagonist, is considered as the first-line therapy for the patients with benign prostatic hyperplasia （BPH） and also produce several side effects in cardiovascular system. In this study, we observed the isometric vasoconstrictive responses of the rabbit isolated arterial rings to electric field stimulation and noradrenaline （NA） to study the effects of Rdoxazosin （R-DOX） and S-doxazosin （S-DOX） on the α1-adrenoceptor-regulated vasoconstrictive responses in the rabbit isolated ear artery, mesenteric artery and pulmonary artery, and the effects of higher concentration of S-DOX and R-DOX on presynaptic α2-adrenoceptor-regulated purinergic vasoconstriction in the rabbit isolated saphenous artery. We found that R-DOX and S-DOX competitively inhibited the vasoconstriction induced by NA in the rabbit isolated ear artery, mesenteric artery and pulmonary artery. The pA2 values of R-DOX and S-DOX against NA in the rabbit isolated ear artery, mesenteric artery and pulmonary artery were 7.91±0. 03 and 7.53 ± 0. 05, 7.80 ± 0. 05 and 7.29 ± 0.07, 8.32 ± 0. 06 and 7.97 ± 0.07, respectively. The pA2 values of R-DOX in the three arterial preparations were significantly higher than those of S-DOX （P 〈 0. 01 ）. R-DOX and S-DOX at the concentrations of 0. 1 -10 μmol·L^-1 did not affect the vasoconstriction induced by electric stimulation in the rabbit isolated saphenous artery. R-DOX and S-DOX at 100μmol·L^-1 in the rabbit isolated saphenous artery completely inhibited the vascular responses to exogenous NA, but did not affect the vascular responses to exogenous adenosine triphosphate （ 1 mmol·L^-1 ）. It is reasonable to suggest that R- DOX and S-DOX competitively inhibit the vasoconstriction induced by NA in the rabbit ear artery, mesenteric artery and pulmonary artery, and the pA2 values of S-DOX are significandy lower than those of R-DOX. The higher concentration （10 μmol·L^-1） of R-DOX and S-DOX does not affect the presynaptic α2-adrenoceptors at sympathetic nerve terminals of the rabbit saphenous artery.