The alpha-adrenoceptor antagonist properties of the enantiomers of doxazosin in the human prostate.

The alpha-adrenoceptor antagonist properties of doxazosin and its enantiomers were characterized using human prostate tissue and cell membranes isolated from rat-1 fibroblast expressing each of the cloned human alpha 1-adrenoceptor subtypes. In the alpha 1-adrenoceptor-binding studies on the human prostate with [3H]doxazosin and 2-{[beta-(3-[125I],4-hydroxyphenyl)ethyl]aminomethyl}-l-tetralone ([125I]HEAT), no significant differences were observed between racemic doxazosin, R-doxazosin and S-doxazosin (mean -log Ki (pKi) values were 8.60-8.63, 8.47-8.55 and 8.61-8.65, respectively), whereas the alpha 2-adrenoceptor-binding studies with [3H]rauwolscine and [3H]clonidine revealed that the alpha 2-adrenoceptor-binding affinity of S-doxazosin (pKi = 5.91-5.94) was slightly (3- or 4-fold), but significantly lower than that of R-doxazosin (pKi = 6.47-6.54). Studies in phenylephrine-contracted prostatic tissue showed no significant difference in alpha 1-adrenoceptor antagonist potency between racemic doxazosin, R-doxazosin and S-doxazosin (pA2 values were 8.43 +/- 0.28, 8.64 +/- 0.56 and 8.75 +/- 0.38, respectively). In the binding studies with cloned alpha 1-adrenoceptor subtypes using [3H]prazosin and [125I]HEAT, racemic doxazosin, R-doxazosin and S-doxazosin showed no selectivity for the alpha 1-adrenoceptor subtypes. The present study demonstrated that doxazosin and its enantiomers are highly selective alpha 1-adrenoceptor antagonists and that there is no evidence suggesting differential alpha 1-adrenoceptor antagonist effects of doxazosin and its enantiomers in the human prostate. Doxazosin, therefore, could be described as displaying balanced activity across all three alpha 1-adrenoceptor subtypes.