Introduction

Overactivity bladder syndrome has classically been treated with antimuscarinics. Frequent adverse systemic effects have led to the search for new therapeutic options. β3-adrenoceptor (β3-AR) agonists relax the detrusor smooth muscle (DSM) by the adenylyl cyclase pathway, increasing cAMP. Rolipram, a selective type 4 phosphodiesterase inhibitor (PDE4i), elevates cAMP levels by supressing hydrolysis. Phosphodiesterase type 5 inhibitors (PDE5i), such as tadalafil, relax DSM by the nitric oxide (NO)/cGMP pathway. It has been hypothesized that the inhibition of phophodiesterases could potentiate the relaxing effect of β3-AR agonists. The main objective of this study is to evaluate in vitro the effects of the combination of a β3-AR agonist with two different phophodiesterase (PDE) inhibitors (PDE4i and PDE5i) in an experimental model of detrusor overactivity.

Methods

The experiments were performed on bladder strips of mice treated with L-NAME for 30 days. Chronic L-NAME administration leads to detrusor overactivity by NO deprivation. The following drugs were used: BRL 37344 (β3-AR agonist), tadalafil (PDE5i) and rolipram (PDE4i). After potassium-induced contraction, strips isolated from mice were exposed to increasing concentrations of each drug. In another series of experiments, prior to contraction, strips were incubated with either tadalafil or rolipram and then increasing concentrations of BRL 37344 were added.

Results

Cumulative concentration-response curves were constructed. Rolipram showed the best relaxation when compared to the other drugs (Figure 1). Rolipram increased the relaxing response of BRL 37344 in almost all concentrations, but no synergistic effect with tadalafil was observed (Figure 2).

Conclusions

PDE inhibitors associated with the already proven effective β3-AR agonists may represent a new approach for patients with storage symptons. The relaxing effect of the β3-AR agonist was potentiated by PDE4i but not by PDE5i, suggesting cAMP plays an important role in DSM relaxation.

Funding

none