PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. MATERIALS AND METHODS: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. RESULTS: 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. CONCLUSIONS: 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.