Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Abstract

Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α1A-adrenoceptors (in the prostate), α1D-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 (α1D-adrenoceptors) and rabbit prostate (α1A-adrenoceptors), we examined pA2 and pKB 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 pA2 value of (–)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pKB 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 α1A-adrenoceptors in the prostate, but significantly changes its blocking activity against α1D-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α1-adrenoceptor-independent mechanism.