Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.

译文

:多沙唑嗪用于前列腺增生症具有引起低血压和心力衰竭风险的副作用。 α(1A)-肾上腺素受体(在前列腺中),α(1D)-肾上腺素受体(在主动脉中)和未知机制(在心脏中)的3个靶点分别涉及。我们假设在3个靶标中有手性识别多沙唑嗪对映体。使用分离的大鼠主动脉(α(1D)-肾上腺素受体)和兔前列腺(α(1A)-肾上腺素受体),我们检查了多沙唑嗪对映体的pA(2)和pK(B)值​​。我们观察到了多沙唑嗪对映异构体在离体大鼠和兔心脏组织中的变时性和变力作用。 (-)多沙唑嗪和()多沙唑嗪使去甲肾上腺素(主动脉)和去氧肾上腺素(前列腺平滑肌)的浓度-收缩曲线向右移动。大鼠主动脉中(-)恶唑烷的pA(2)值(8.625±0.053)小于()恶唑烷(9.503±0.051),但它们在兔前列腺中的pK(B)值​​相同。在大鼠和兔子的心脏组织中,()多沙唑嗪(3-30 µmol·L(-1))显着降低心房率,并产生负性变力作用;然而,(-)doxazosin不会影响心房率,并在心房产生正性肌力作用。因此,多沙唑嗪的手性碳原子不影响其对前列腺中α(1A)-肾上腺素受体治疗靶点的活性,但会显着改变其对主动脉中α(1D)-肾上腺素受体的阻断活性,并产生相反的正性肌力作用通过独立于α(1)-肾上腺素受体机制的心房。

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