Phosphodiesterase Type 5 Expression in Human and Rat Lower Urinary Tract Tissues and the Effect of Tadalafil on Prostate Gland Oxygenation in Spontaneously Hypertensive Rats

Abstract

Introduction In humans, prostate phosphodiesterase type 5 inhibitors (PDE5) expression was prominently localized in the endothelial and smooth muscle cells of the vascular bed, suggesting a possible action of PDE5 inhibitors (PDE5i) on prostate blood flow. Aim To investigate PDE5 expression in human and rat lower urinary tract (LUT) tissues, including vasculature, and determine the effects of PDE5 inhibition with tadalafil on prostatic blood perfusion. Main Outcome Measures Human vesicular-deferential arteries (which originate from the inferior vesical artery, the main arterial source of blood supply to the bladder and prostate) were analyzed for PDE5 expression and activity. The effects of tadalafil on prostate oxygenation were studied in spontaneously hypertensive rats (SHR), characterized by ischemia/hypoxia of the genitourinary tract. Methods PDE5 expression was evaluated by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. SHR were treated with tadalafil (2 mg/kg/day) for 1, 7, or 28 days and compared with untreated SHR and the unaffected counterpart Wistar-Kyoto (WKY) rats. Prostate oxygenation was detected by Hypoxyprobe-1 and hypoxia markers (hypoxia-inducible factor-1α[HIF-1α] and endothelin-1 type B [ETB]) immunostaining. Results Human vesicular-deferential artery expressed high levels of PDE5, similar to corpora cavernosa, immunolocalized in the endothelial and smooth muscle layer. In these arteries, tadalafil inhibited cyclic guanosine monophosphate breakdown (half maximal inhibitory concentration (IC50) in the low nanomolar range, as in corpora cavernosa) and increased the relaxant response to sodium nitroprusside. SHR prostate resulted markedly hypoxic (hypoxyprobe immunopositivity) and positive for HIF-1α and ETB, while tadalafil treatment restored oxygenation to WKY level at each time point. The mRNA expression of the HIF-1α target gene, BCL2/adenovirus E1B 19 kDa interacting protein 3, was significantly increased in SHR prostate and partially restored to WKY level by tadalafil. Conclusion Human vesicular-deferential artery is characterized by a high expression and activity of PDE5, which was inhibited by tadalafil in vitro. In SHR, tadalafil increases prostate tissue oxygenation, thus suggesting a possible mechanism through which PDE5i exert beneficial effects on LUT symptoms.

Comparative Study of Tadalafil and Tamsulosin as on therapy For Lower Urinary Tract Symptoms Due To Benign Hyperplasia of Prostate.

“…[10][11][12] PDE5 inhibitors acts by upregulation of the NO/cGMP activity. Preclinical studies reported partial reversal of nor-epinephrine-and endothelin-1-reduced prostatic tissue contraction 13 and an anti-proliferative effect on cultured prostate and bladder smooth muscle cells 14 . These mechanisms may decrease smooth muscle tension in the prostatic stroma and capsule and attenuate cellular proliferation associated with prostate/bladder hypertrophy respectively.…”

Singapore Urological Association Clinical Guidelines for Male Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia

“…Some of the possible mechanisms include relaxation of smooth muscle tones in the lower urinary tract caused by increased cyclic guanosine monophosphate, inhibition of local inflammatory processes, and improvement in blood flow and oxygenation to the lower urinary tract. (36)(37)(38) • Efficacy: Most studies demonstrate improvements in IPSS and QOL, but no significant improvement in Qmax. (39) Only tadalafil 5 mg daily has been approved for use in male LUTS by the US Food and Drug Administration and Health Sciences Authority, Singapore.…”

Comparative Study of Tadalafil And Tamsulosin in Benign Hyperplasia of Prostate For Lower Urinary Tract Symptoms (LUTS)

“…Preclinical studies reported partial reversal of nor-epinephrine-and endothelin-1-reduced prostatic tissue contraction 13 and an anti-proliferative effect on cultured prostate and bladder smooth muscle cells 14 . As a result there is decrease in smooth muscle tension in the prostatic stroma and capsule and also attenuate cellular proliferation associated with prostate/bladder neck hypertrophy respectively.…”