Changes in the expression and function of the PDE5 pathway in the obstructed urinary bladder

Abstract

Our study aims to explore changes in bladder contractility and the phosphodiesterase type 5 (PDE5) signalling pathway in response to partial bladder outlet obstruction (PBOO). A surgically induced male rat PBOO model and human obstructed bladder tissues were used. Histological changes were examined by H&E and Masson's trichrome staining. Bladder strip contractility was measured via organ bath. The expressions of nitric oxide synthase (NOS) isoforms, PDE5, muscarinic cholinergic receptor (CHRM) isoforms and PDE4 isoforms in bladder were detected by RT‐PCR and Western blotting. The immunolocalization of the PDE5 protein and its functional activity were also determined. PBOO bladder tissue exhibited significant SM hypertrophy and elevated responsiveness to KCl depolarization and the muscarinic receptor agonist carbachol. NOS isoforms, PDE5, CHRM2, CHRM3 and PDE4A were up‐regulated in obstructed bladder tissue, whereas no change in PDE4B and PDE4D isoform expression was observed. With regard to PDE5, it was expressed in the SM bundles of bladder. Interestingly, obstructed bladder exhibited less relaxation responsiveness to sodium nitroprusside (SNP), but an exaggerated PDE5 inhibition effect. The up‐regulation of PDE5 could contribute to the lack of effect on Qmax for benign prostatic hyperplasia/lower urinary tract symptom (BPH/LUTS) patients treated with PDE5 inhibitors. Moreover, PDE5 (with presence of NO) and PDE4 may serve as new therapeutic targets for bladder diseases such as BPH‐induced LUTS and overactive bladder (OAB).

Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction

“…There was a high correlation between increasing obstructed bladder weight and decreased contractile responses (22). Contrary to our findings, the contractility to carbachol stimulation of PBOO bladder was increased in both rats and human bladder (9). After obstruction, the bladder undergoes a 'compensated stage' or 'decompensated stage', and the contractile response changes accordingly.…”

“…In this study, eNOS and nNOS protein expression were greater in PBOO bladders than in controls. Numerous previous animal studies have demonstrated that the NOS expression increased in the rat obstructed bladder (9,27), which is responsible for bladder dysfunction. In our study, this increase in nNOS and eNOS expression was further normalized by the combined treatment.…”

“…However, in the decompensated stage, the bladder becomes unable to properly compensate with decreasing bladder contraction (24). The difference between these results could be associated with the obstructed bladders being obtained in different stages of compensation/decompensation (9). A reduction in detrusor contractility in isolated bladders is a characteristic feature of bladder decompensation (25).…”

“…Previous data suggest that obstruction leads to structural and functional changes, including urodynamic parameters (8). Furthermore, numerous studies assessed the effects of PBOO on morphologic changes and physiologic mechanisms in the bladder without in vivo urodynamic data (9,10).…”