Functional Roles of Adenosine A 2B and A 3 Receptor Subtypes in the Bladder of Male Rats With A 2B Receptor Deletion or Bladder Outlet Obstruction

Purpose To investigate the adenosine receptor (AR) mechanism underlying bladder outlet obstruction (BOO)‐related bladder dysfunction, we examined the expression level of AR subtypes in bladder tissues, and the effects of AR subtypes A2B & A3 modulation on bladder activity using male BOO rats, and Dahl rats with A2B receptor deletion. Materials and Methods BOO was induced by partial ligation of the proximal urethra in male Sprague‐Dawley rats. At 4 weeks after BOO, conscious cystometrograms (CMG) were performed with the urethral ligature being intact. The effects of AR A3 agonist (2CL‐IB‐MECA) and AR A3 antagonist (MRS3777) were examined by intravesical administration. Furthermore, we examined the difference of bladder function of AR subtypes between AR A2B knockout (A2B‐KO) and wild‐type groups of male Dahl rats. mRNA levels of AR subtypes in bladder tissues were also analyzed. Results BOO versus sham rats showed heavier bladder weights, higher contraction amplitudes, and increased numbers of non‐voiding contractions (NVCs) during the filling phase. In the bladder mucosa – but not the detrusor ‐ of BOO versus sham rats, mRNA expression levels of A2A and A3 AR were significantly increased, while A2B levels were significantly decreased. In BOO rats, an A3 antagonist (MRS 3777; 10 and 100 μM) had no effect on CMG parameters. However, a high dose of an A3 agonist (2CL‐IB‐MECA; 100 μM) significantly increased NVCs ( p = 0.0034), an effect that was blocked by the A3 antagonist. Additionally, compared to wild‐type rats, A2B‐KO rats showed a significant increase in the number of NVCs ( p = 0.0039). Conclusions A2B AR down‐regulation in BOO rats and A2B deletion in Dahl rats could contribute to the development of bladder overactivity. Moreover, a high‐level of exogenous activation of A3 ARs might exacerbate bladder overactivity in BOO.