Benign prostatic hyperplasia (BPH) results in an age related and hormone dependent increase in prostate gland volume, which leads to voiding dysfunction caused by bladder outlet obstruction. The functional importance of α1-adrenoceptor (α1-AR) in the sympathetic nerve terminals of the prostate has been determined. α1-AR antagonists have been widely used to treat BPH relaxing the obstructed prostatic urethra. Currently, α1-ARs are subdivided into the 3 subtypes α1A, αB and α1D-AR. However, add-on therapy using different selective α1-AR antagonist has not yet been determined. The aim of this study was to investigate the efficacy of add-on therapy using selective α1-AR antagonists such as tamsulosin and naftopidil in a rat model of BPH.

Adult male Sprague-Dawley rats were used for this study. The animals were randomly divided into the following 5 groups (n=10 in each group): the sham operation group, the BPH-induced group, the BPH-induced and tamsulosin-treated group, the BPH-induced and naftopidil-treated group, and the BPH-induced and combination-treated group. To induce BPH, rats were castrated and testosterone (20 mg/kg) was injected subcutaneously once per day for 30 days. The recommended daily allowance of each drug was administered as follows: 0.2 mg/kg of tamsulosin, 75 mg/kg of naftopidil, and 0.2 mg/kg of tamsulosin+75 mg/kg of naftopidil in the combination group. Rats in the drug-treated groups were orally administered each drug once a day for 30 days after orchiectomy. The animals in the control and BPH-induced groups received the same amount of distilled water. Cystometry was conducted to measure voiding contraction pressure and the interval contraction time. Immunohistochemistry was performed to measure c-Fos and nerve growth factor (NGF) expression and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was used to measure nitric oxide synthase (NOS) expression in the neuronal voiding centers (medial preoptic area, ventrolateral periaqueductal gray, pontine micturition center, and spinal cord L4–L5).

On cystometry, voiding contraction pressure and the interval contraction time were significantly decreased by the induction of BPH. Monotherapy with tamsulosin or naftopidil did not exert a significant effect on voiding contraction pressure or the interval contraction time, whereas combination therapy (tamsulosin with naftopidil) significantly increased voiding contraction pressure and the interval contraction time. On immunohistochemical and histochemistry analysis, c-Fos, NGF, and NOS expression in the neuronal voiding centers was significantly increased by the induction of BPH. Monotherapy with tamsulosin or naftopidil showed an inhibitory effect on c-Fos, NGF, and NOS expression depending on the site in the neuronal voiding centers. However, combination therapy (tamsulosin with naftopidil) showed an even greater reduction in c-Fos, NGF, and NOS expression at all sites of the neuronal voiding centers than the case for tamsulosin monotherapy or naftopidil monotherapy.

Combination therapy of tamsulosin and naftopidil may inhibit neuronal activity in the neuronal voiding centers to a greater extent than monotherapy with tamsulosin or naftopidil, and the enhanced inhibitory signal may relax the urethral and prostate smooth muscle.

As combination therapy showed greater efficacy for the treatment of BPH than monotherapy, combination therapy can be considered as a novel therapeutic method for BPH.

J Urol. 2006;176(3):1236-41.