Tadalafil, a phosphodiesterase type 5 inhibitor is widely used for patients with benign prostatic hyperplasia related to lower urinary tract dysfunction [1]. Previous study showed treatment with tadalafil suppressed ventral prostate enlargement in the rat model with chronic pelvic ischemia induced by local atherosclerosis [1]. However, the molecular mechanisms are not well clarified. There are some lines of evidence that prostatic ischemia induces prostatic hyperplasia and prostatic enlargement in human and animal models [1-3]. Spontaneously hypertensive rat (SHR) has hypertension, prostatic ischemia and hyperplastic morphological abnormalities [3]. In this study, we investigated the effect of tadalafil on the prostate weight,  prostatic blood flow and hyperplasia in the ventral prostate of the SHR.

Twelve-week-old male SHRs were orally administered with tadalafil (2 or 10 mg/kg/day) for 6 weeks (n = 8). Wistar Kyoto (WKY) rats were used as normotensive controls treated with vehicle (n = 8). At 18 weeks of age, blood pressure was measured by the tail cuff method without anaesthesia. Blood flow in the ventral prostate was measured by the hydrogen clearance method under the urethane (1.0 g/kg i.p.) anaesthesia. Then, the rats were euthanized with overdose of sodium pentobarbital (100 mg/kg i.p.). The prostates were removed and weighted. The tissue levels of oxidative stress marker, malondialdehyde (MDA), pro-inflammatory cytokine, interleukin-6 (IL-6), and growth factors, transforming growth factor beta 1 (TGF-β1) and basic fibroblast growth factor (bFGF) in the ventral prostate were measured by using colorimetric assay or ELISA. The histological evaluation was performed by haematoxylin and eosin staining. Epithelial growth ratio was calculated by Image J software.

There was no significant difference on body weight between vehicle treated-WKY rats and vehicle treated-SHRs. On the other hand, the SHRs demonstrated a significant increase in prostate weight, prostate weigh/body weight ratio (PBR), mean blood pressure, and ventral prostatic tissue levels of MDA, IL-6, TGF-β1, and bFGF when compared with the WKY rats (Figures 1 and 2). There was a significant decrease in blood flow in ventral prostate of SHRs compared with WKY rats (Figures 1 and 2). Histological examination of the ventral prostate showed the epithelial overgrowth in the SHRs compared with the WKY rats (data not shown). Treatment with tadalafil failed to affect the body weight and mean blood pressure in the SHRs. However, treatment with tadalafil significantly and dose-dependently improved the decreased prostatic blood flow, and increased PBR and tissue levels of MDA, IL-6, TGF-β1, and bFGF in the ventral prostate of SHRs (Figures 1 and 2). Moreover, tadalafil decreased epithelial growth ratio in the ventral prostate of SHRs (data not shown).

Present data reveal that tadalafil reduced prostate weight, PBR, oxidative stress, pro-inflammatory cytokine, growth factors, and prostatic morphological abnormalities in the ventral prostate of SHR without affecting blood pressure. Prostatic ischemia induces oxidative stress and inflammation, subsequently causes the growth factor in the prostate [1-3]. The previous report showed that treatment with alpha1 adrenoceptor antagonist silodosin decreased the PBR, prostatic tissue levels of MDA, IL-6, TGF-β1 and bFGF and ameliorated prostatic blood flow in the SHR. Treatment with silodosin may decrease the prostate weight via a recovery of prostatic blood flow in the rat [3]. These data suggested that treatment with tadalafil could also suppress the prostatic enlargement through a recovery of prostatic blood flow.

Treatment with tadalafil improved the decreased the prostatic blood flow and increased prostate weight, and tissue levels of oxidative stress, inflammation and growth factors in the SHR. Tadalafil could suppress the development of prostatic enlargement in the SHR.

Fujii S, Yamashita S, Hayashi N, et al. Phosphodiesterase type 5 inhibitor attenuates chronic ischemia-induced prostatic hyperplasia in a rat model. Prostate. 2019;79(5):536-543.
Haga N, Akaihata H, Hata J, et al. The association between local atherosclerosis of the prostatic artery and benign prostatic enlargement in humans: Putative mechanism of chronic ischemia for prostatic enlargement. Prostate. 2018;78(13):1001-1012.
Shimizu S, Shimizu T, Tsounapi P, et al. Effect of Silodosin, an Alpha1A-Adrenoceptor Antagonist, on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat. PLoS One. 2015;10(8):e0133798.