Glycosaminoglycan(GAG) layer destruction of the urothelium and chronic inflammatory cells infiltration in the bladder interstitium are common pathologic findings of the interstitial cystitis(IC).  Most of the IC bladder also show significant fibrosis at the advanced stage of the disease. Severe chronic inflammatory cell infiltration and fibrosis also contribute to clinical symptoms of pain, frequency, and decreased bladder cacpacity. There are some evidences that chronic inflammation of the tissue is associated with chronic ischemia resulting in fibrosis and increased tissue blood flow helped by phosphodiesterase -5(PDE-5) inhibitor is beneficial for prevention of tissue fibrosis. 
In this study, we aimed to investigate the action of PDE-5 inhibitor as a supplementary factor of pentosan polysulfate(PPS) for IC treatment in rat IC model as a preliminary research to find the clinical usefulness of PDE5 inhibitor(PDE5i) in IC treatment.

Fifty-four female Sprague-Dawley rats were used for this study (control group 18, IC-PPS group 18, IC-PPS+PDE5 inhibitor group 18). We followed the method previously reported techniques using 0.4M HCl for establishing animal model of IC. Establishment of IC bladder were pathologically confirmed by hematoxylin-eosin(H-E) stain. In control group, sesame oil was administered daily per oral, and in IC-PPS group, pentosan polysulfate was daily administered per oral (0.8mg BID, 1.6mg/day), in IC-PPS+PDE5 inhibitor group, PPS(0.8mg BID, 1.6mg/day) and PDE5 inhibitor (tadalafil, 0.6mg/day) were administered per oral daily for 8 weeks started from 4 weeks after IC bladder establishment. Bladder tissue was harvested after 8 weeks of treatment and immunohistochemical stains for TGF-beta were analyzed by image analyzer with p value as significant if p<0.05 in Kruskal-Wallis test. This study has been approved by the hospital animal research adversary board.

H-E stain of IC model bladder tissue proved to have chronic inflammatory cell infiltration, mucosal denudation and edema. In both IC-PPS group and IC-PPS+PDE5 inhibitor group showed decreased chronic inflammatory cell infiltration and mucosal denudation after 8 weeks of treatment in H-E stain (p<0.05).
In IC-PPS group, expression of TGF-beta in the rat bladder tissue was significantly lowered compared with control group in submucosal layer and interstitium (p<0.05) (Figure). In IC-PPS+PDE5 inhibitor group, expression of TGF-beta in the bladder tissue was also significantly lowered compared with control group in submucosal layer and interstitium (p<0.05). There was a tendency of more decreased TGF-beta expression in the bladder tissue in IC-PPS+PDE5 inhibitor group when compared with IC-PPS group with p value of 0.0531, however, it was not statistically significant.

Based on both H-E stain and immunohistochemical stain, both pentosan polysulfate or combination of pentosan polysulfate with PDE5 inhibitor helps to decrease or prevent inflammatory changes of the bladder in rat IC model. Although we could not find significant difference between pentosan polysulfate treatment group and combination of pentosan polysulfate and PDE5 inhibitor, tendency of more decreasing TGF-beta expression in pentosan polysulfate+PDE5 inhibitor group than pentosan polysulfate alone group suggest the possible usefulness of PDE5 inhibitor for vascular improvement in chronic inflammatory changes of the IC model. More qualified study design and more data analysis including additional staining for other chronic inflammatory markers would be necessary. This study has some limitations such as lack of comparing solid effect of PDE5 inhibitor and pentosan polysulfate.

Pentosan polysulfate has already been well proved to be effective to restore GAG layer defect and to prevent inflammatory reaction. In this study, not only pentosan polysulfate, but also additional PDE5 inhibitor showed decreased expression of TGF-beta, supporting its inflammation suppressive effect. Although we need more study to differentiate the solid effect of PDE5 inhibitor in IC tissue, in our IC rat model, pentosan polysulfate with PDE5 inhibitor suggest the possible benefit of PDE5 inhibitor in IC.

M Clyne. Can PDE5 inhibitors boost brain function? Nature Reviews Urology 2014;11:65
AT Hanna-Mitchell, LA Birder. New insights into the pharmacology of the bladder. Curr Opin Urol. 2008; 18(4): 347–352.
H Chen, F Wang, W Chen, et al. Efficacy of Daily Low-Dose Sildenafil for Treating Interstitial Cystitis: Results of a Randomized, Double-Blind, Placebo-Controlled Trial—Treatment of Interstitial Cystitis/Painful Bladder Syndrome With Low-Dose Sildenafil. Urology 2014;84(1)51-56.