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 cu adrenoceptor subtypes. In the a adrenoceptor-binding studies on the human prostate with [H-3]doxazosin and 2-{[beta-(3-[I-125],4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone ([I-125]HEAT), no significant differences were observed between racemic doxazosin, R-doxazosin and S-doxazosin (mean -log K-i (pK(i)) values were 8.60-8.63, 8.47-8.55 and 8.61-8.65, respectively), whereas the alpha(2)-adrenoceptor-binding studies with [H-3]rauwolscine and [H-3]clonidine revealed that the alpha(2)-adrenoceptor-binding affinity of S-doxazosin (pK(i) = 5.91-5.94) was slightly (3- or 4-fold), but significantly lower than that of R-doxazosin (pK(i) = 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 (pA(2) 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 [H-3]prazosin and [I-125]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 a 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.