Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling.
Testosterone (T) 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 ROKβ mRNA, whereas it increased eNOS plus α(1a) and α(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.
Cooper University Hospital, Three Cooper Plaza, Camden, NJ 08103, USA.
Xinhua
X
Zhang
Ning
N
Zang
Yu
Y
Wei
Jin
J
Yin
Ruobing
R
Teng
Allen
A
Seftel
Michael E
ME
Disanto
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009919:Orchiectomy; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013739:Testosterone / Q000494:pharmacology*
D000728:Androgens; D058986:Phosphodiesterase 5 Inhibitors; D011688:Purinones; D018340:Receptors, Adrenergic, alpha-1; D013739:Testosterone; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; C011145:zaprinast