Functional Roles of Adenosine A2B and A3 Receptor Subtypes in the Bladder of Male Rats With A2B 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.