Effects of chronic administration of doxazosin on alpha1-adrenoceptors in the rat prostate.

Abstract

Although the clinical efficacy of alpha1-adrenoceptor (alpha1-AR) antagonists for the treatment of benign prostatic hyperplasia is not disputed, their mechanism of action and ability to maintain long-term effectiveness have only recently been investigated. Since it is known that chronic administration of receptor antagonists causes up-regulation in the targeted receptor, we examined the effects of chronic administration of doxazosin, a nonspecific long acting alpha1-AR antagonist, on the properties of alpha1-AR subtypes in the rat prostate. Rats were treated with doxazosin (2 or 4 mg/kg daily subcutaneously, supplemented with 4 mg/kg daily orally) for 8 or 12 weeks. Prostatic alpha1-AR properties at the protein and gene transcript levels were quantified by radioligand receptor binding and real-time reverse transcriptase-polymerase chain reaction, respectively. Treated rats that received the highest levels of doxazosin had significantly heavier prostates compared with age matched controls. After 12 weeks of treatment radioligand binding studies with radiolabeled alpha1-AR antagonist demonstrated no significant differences in the density of total alpha1-ARs in the prostate, whereas the results of real-time reverse transcriptase-polymerase chain reaction showed up-regulation in the mRNA expression levels of all 3 alpha1-AR subtypes (alpha1A, alpha1B and alpha1D) in the ventral and dorsolateral regions of the rat prostate. These data demonstrate that chronic treatment with doxazosin causes an alteration in the properties of the alpha1-AR system in the rat prostate. These findings may provide insight into the long-term effectiveness of alpha1-AR antagonists in the treatment of benign prostatic hyperplasia.