A phosphodiesterase 5 inhibitor, tadalafil, suppresses stromal predominance and inflammation in a rat model of nonbacterial prostatitis

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is common in aging males worldwide. Because LUTS/BPH often interferes with activities of daily living, many patients seek definitive treatment to improve their quality of life [1‐3].

The etiology of LUTS is highly complex and is likely to be multifactorial, and several processes may contribute to the development of LUTS in BPH. Chronic inflammation in the prostate may contribute to prostate growth, tissue damage, and prostate enlargement [4]. The Medical Therapies of Prostate Symptoms (MTOPS) study, the largest study to examine chronic prostatic inflammation, suggests that the risk of serious BPH-related outcomes, including acute urinary retention and the need for BPH-related surgery, is increased. Therefore it is important to study the action of clinically used drugs on prostatic inflammation.

Phosphodiesterase type 5 inhibitors (PDE5-Is), such as tadalafil, are effective for the treatment of LUTS/BPH [5, 6], and have been acknowledged in the recent guidelines published by the Japanese Urological Association [7] and the European Association of Urology [8], with Level 1 evidence. Several LUT tissues—prostate, urethra, and bladder, as well as their vasculatures—are thought to be potential targets for tadalafil [9]. There are several reports focused on prostate inflammation regarding the mechanism of tadalafil in several animal models. Single or repeated dosing with tadalafil improves prostate hypoxia in spontaneously hypertensive rats [10]. In the prostate of rabbits fed a high-fat diet, chronic tadalafil treatment produces inhibition of inflammation, fibrosis, and hypoxia [11]. More recently, repeated treatment with tadalafil was found to suppress tactile allodynia in rat non-bacterial prostatitis induced by 17β-estradiol treatment combined with castration [12]. Although inflammatory changes, including histopathological changes and increases in several cytokine/chemokine levels, were demonstrated in this model in the absence of tadalafil treatment, whether tadalafil affects these kinds of pathological conditions in this hormone/castration-induced prostatitis model was not investigated [12].

This study aimed to elucidate the effect of the repeated administration of tadalafil on the inflammatory changes in a rat model of hormone/castration-induced prostatitis as a model of nonbacterial prostatitis (NBP) as indicated by changes in prostate histology and inflammatory factors.

Chronic inflammation (mostly nonbacterial and asymptomatic) is associated with symptom development in BPH [4]. To investigate the underlying mechanisms of chronic inflammation in the prostate that are responsible for symptomatic BPH, experimental animal models with inflammatory prostatitis are needed. Kamijo et al. [13] and our group [14‐16] used 10-month-old rats treated with 17β-estradiol for 30 days after castration to investigate the effects of therapeutic agents such as cernitin pollen extract and Eviprostat. Therefore, this was an appropriate model to use for evaluation of the effects of drugs on inflammatory changes in the prostate. Although this animal model does not match human BPH in prostate size or glandular hyperplasia, it demonstrates certain characteristics, including severe acinar gland atrophy and stromal predominance, in addition to inflammatory infiltrates, which mimic symptom progression in BPH.

Recently Yamaguchi et al. [12] found that an increase in pelvic pain is induced in this NBP model and that this pain is suppressed by repeated treatment with tadalafil. However, they did not investigate the effects of tadalafil on inflammatory changes. In the present study, we demonstrated for the first time that the administration of tadalafil showed a reduction in macrophage levels and the extent of T-cell infiltration in the same NBP model. Meanwhile, the increased concentrations of TNF-α, IL-8, and IL-1β in the prostate tissue of NBP rats were also suppressed in the tadalafil administration group. We assume that the attenuation of pelvic pain shown by Yamaguchi et al. [12] is partly due to these effects of tadalafil. IL-1β and TNF-α are both pro-inflammatory cytokines and reported to be up-regulated in prostatic sections of prostatitis, suggesting that these are the key markers in inflammatory prostate [17]. IL-8 also seems to be a key mediator in human BPH: its concentrations in prostatic secretions from patients with BPH accompanied by inflammation are higher than in patients with BPH alone [18].

This study is consistent with other available evidence that PDE5-Is reduce chronic inflammation in the prostate, because several investigators have reported their anti-inflammatory effects in different animal models such as metabolic syndrome-induced prostatitis in the rabbit [11] and spontaneously hypertensive rats [10], as well as in human BPH cells [19]. In addition, tadalafil has protective effects on prostatic structural and functional changes induced by chronic pelvic ischemia [20]. Moreover, in a rat model of experimental autoimmune prostatitis, tadalafil reduces prostatic inflammation [21].

The latest evidence on the pathophysiology of LUTS/BPH has provided the rationale for use of PDE5-Is, which bring about improvement of LUT oxygenation, smooth muscle relaxation, negative regulation of proliferation, transdifferentiation of LUT stroma, and reduction of bladder afferent nerve activity [22]. Besides protection of the prostate by tadalafil, several investigators have shown the effect of tadalafil on chronic ischemia-related bladder dysfunction in animal models, including a rat model of chronic pelvic ischemia [23] and bladder outlet obstruction [24]. It has been hypothesized that PDE5-Is could reduce inflammation and the associated fibrosis and improve oxygenation in the human prostate and bladder, with normalization of prostatic and bladder structural anatomy and physiologic activity. All of these effects of tadalafil may contribute to the amelioration of bladder dysfunction.

Previous studies have evaluated the pharmacological effects of tadalafil in animal models, almost all of which used oral administration of tadalafil at doses of 2 or 10 mg/kg. For example, Morelli et al. [10] demonstrated an improvement in prostate gland oxygenation by tadalafil at 2 mg/kg/day for 1, 7 or 28 days. Nomiya et al. [23] have described the protective effects of tadalafil on bladder function at 2 mg/kg/day for 8 weeks in a rat model of chronic bladder ischemia induced by iliac arterial endothelial injury. Kawai et al. [24] reported that the repeated administration of tadalafil at 10 mg/kg/day for 14 days ameliorated the bladder function in a rat model of bladder outlet obstruction. According to these reports, in this study we used tadalafil at 10 mg/kg/day for 30 days. Recently Yoshinaga et al. [25] reported that C_max values of 68.5 and 460 ng/ml in rats after single oral doses of tadalafil of 2 and 10 mg/kg, respectively are physiologically relevant with the clinical plasma concentration of tadalafil is 95.6 ng/ml when the drug is administered at 5 mg/person (for BPH patients) and 446 ng/ml when it is administered at 40 mg/person (for PAH patients). Since the doses of tadalafil used in current studies are similar to the plasma concentrations in humans being treated for BPH and PAH, the results we showed in the paper partly may explain the protective mechanisms of Tadalafil in BPH patients.

In the present study, the anti-inflammatory effect of tadalafil was demonstrated in the NBP rat model. However, this model is hormone-induced, and there is are anatomic differences between the rat and the human prostate. The effect of tadalafil on the relief of LUTS cannot therefore be assessed in this model. Despite this experimental limitation, the results obtained in the present study partially clarify the mechanism by which tadalafil prevents the development of BPH through the suppression of nonbacterial inflammation. To elucidate the mechanism of the effect of tadalafil in more detail, further study is needed.

The phosphodiesterase 5 inhibitor tadalafil suppressed the increase in inflammatory factors and stromal proliferation in a rat model of nonbacterial prostatitis, providing evidence for anti-inflammatory effects of tadalafil in this model.