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 Annamaria Morelli, PhD,* Erica Sarchielli, PhD, † Paolo Comeglio, PhD,* Sandra Filippi, PhD,* Rosa Mancina, PhD,* Mauro Gacci, MD, ‡ Linda Vignozzi, MD,* Marco Carini, MD, ‡ Gabriella B. Vannelli, MD, † and Mario Maggi, MD* *Department of Clinical Physiopathology, Sexual Medicine and Andrology Unit, University of Florence, Florence, Italy; † Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy; ‡ Department of Urology, University of Florence, Florence, Italy DOI: 10.1111/j.1743-6109.2011.02416.x 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-1a [HIF-1a] and endothelin-1 type B [ETB]) immunostaining. Results. Human vesicular-deferential artery expressed high levels of PDE5, similar to corpora cavernosa, immu- nolocalized 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-1a and ETB, while tadalafil treatment restored oxygenation to WKY level at each time point. The mRNA expression of the HIF-1a 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. Morelli A, Sarchielli E, Comeglio P, Filippi S, Mancina R, Gacci M, Vignozzi L, Carini M, Vannelli GB, and Maggi M. 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. J Sex Med 2011;8:2746–2760. Key Words. PDE5 Inhibition; Prostate Oxygenation; Human Vesicular-Deferential Artery; Hypoxyprobe 2746 J Sex Med 2011;8:2746–2760 © 2011 International Society for Sexual Medicine