) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROK␤ mRNA, whereas it increased eNOS plus ␣ 1a and ␣1b adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH. benign prostatic hyperplasia; contraction; lower urinary tract symptoms; phosphodiesterase 5; phosphodiesterase 5 inhibitors; smooth muscle myosin; nitric oxide BENIGN PROSTATIC HYPERPLASIA (BPH), a cause of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in aging men, is a common pathological process with a histological prevalence of ϳ50 -60% for men in their 60s and 80 -90% for men in their 70s and 80s (54). Although the etiology of prostatic hyperplasia is not well understood, androgens and aging are necessary for the development of BPH (55) containing two physiological components, static (increased prostate size) (40) and dynamic [increased prostatic smooth muscle (SM) tone] (11).The dynamic tone of prostatic SM is regulated mainly by the ␣ 1 -adrenoreceptor (72), with up to 50% of the total urethral pressure in BPH patients being attributed to ␣-adrenoreceptormediated muscle tone (18), and ␣ 1 -blockers are the first-line therapy for BPH. Three major subtypes of adrenoreceptors have been identified to exist in the prostate at the molecular level (␣ 1a , ␣ 1b , and ␣ 1d ) (15). Eckert et al. (14), using a patch clamp combined with the fura-2 fluorescence calcium labelin...

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