391 Upregulation of Phosphodiesterase Type 4 in the Hyperplastic Prostate

Abstract

Both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in the aging male. Numerous clinical trials have demonstrated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5-Is) for treating LUTS/BPH with/without ED. However, the influence of BPH on prostatic PDE5 expression has never been studied. A testosterone-induced rat model of BPH was developed and human hyperplastic prostate specimens were harvested during cystoprostatectomy. PDE5, nNOS, eNOS and α 1 -adrenoreceptor subtypes (α 1a ARs, α 1b ARs and α 1d ARs) were determined with real-time RT-PCR for rat tissues whilst PDE5 and α 1 -adrenoreceptor subtypes were determined in human samples. PDE5 was further analyzed with Western-blot and histological examination. Serum testosterone was measured with ELISA. The rat BPH model was validated as having a significantly enlarged prostate. PDE5 localized mainly in fibromuscular stroma in prostate. Our data showed a significant and previously undocumented upregulation of PDE5 in both rat and human BPH, along with increased expression of nNOS and α 1d ARs for rat tissues and α 1a ARs for human BPH. The upregulation of PDE5 in the hyperplastic prostate could explain the mechanism and contribute to the high effectiveness of PDE5-Is for treating LUTS/BPH. Fibromuscular stroma could be the main target for PDE5-Is within prostate.Lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in aging male. The prevalence of BPH is approximately 40% for men in their fifties and reaches to 90% for men in their eighties or above 1 and the incidence of LUTS is around 25% for men in their 50 s or older 2 . This disorder is typically characterized by enlargement of the prostate gland, constriction of the urethra, and the emergence of LUTS. Besides prostatectomy, present pharmaceutical treatments for LUTS/BPH are aimed at relieving symptoms and slowing the progression of the disease. Current oral medical treatment options are 1) α -adrenoceptor antagonists (α -blockers, ABs) which reduce urethral resistance by attenuating the tension of smooth muscle (SM) fibers located in the prostate 2) 5α -reductase inhibitors (5ARIs) which are involved in the hormonal control of prostate growth 3) muscarinic receptor antagonists (MRAs) and 4) a "new emerging treatment" phosphodiesterase type 5 inhibitors (PDE5-Is) 3,4 . Several clinical studies have demonstrated the efficacy and safety of PDE5-Is in treating LUTS/BPH. We recently performed a systematic review and network meta-analysis including 64 RCTs with 28196 participants comparing the effectiveness of different oral drug therapies for LUTS/BPH 5 . This data showed that among all the drug treatments, PDE5-Is combined with ABs ranked highest in efficacy for decreasing the international prostate symptom score (IPSS) including total score, storage subscore and voiding subscore. PDE5-Is used alone also showed promising efficacy, with the exception of not improving maximum flow rate (Q max ). However...