Adenosine Receptor Mechanisms Underlying Bladder Dysfunction in Male Rats With Bladder Outlet Obstruction

Ei-Ichiro Takaoka; Masahiro Kurobe; Kanako Matsuoka; Tadanobu Kamijo; Shingo Kimura; Paul N Watton; Anne M Robertson; Naoki Yoshimura

doi:10.1002/nau.70080

Adenosine Receptor Mechanisms Underlying Bladder Dysfunction in Male Rats With Bladder Outlet Obstruction

Neurourol Urodyn. 2025 May 22. doi: 10.1002/nau.70080. Online ahead of print.

Authors

Ei-Ichiro Takaoka^{1

2}, Masahiro Kurobe¹, Kanako Matsuoka¹, Tadanobu Kamijo¹, Shingo Kimura¹, Paul N Watton³, Anne M Robertson⁴, Naoki Yoshimura¹

Affiliations

¹ Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
² Department of Urology, Jichi Medical University, Tochigi, Japan.
³ Department of Computer Science, Insigneo Institute for in silico Medicine, University of Sheffield, Sheffield, UK.
⁴ Department of Mechanical Engineering and Materials Science, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA.

PMID: 40401426
DOI: 10.1002/nau.70080

Abstract

Aims: We examined the role of subtypes of adenosine receptors in bladder dysfunction and changes in the adenosine receptor expression in the bladder using male rats with partial bladder outlet obstruction (BOO).

Methods: In Sprague-Dawley rats (male 8-weeks old), BOO was produced by a partial ligation of the urethra along a metal rod of a 1.2 mm outer diameter. Control rats underwent sham operation. Awake cystometrograms (CMG) were first recorded during saline instillation, and then an adenosine A1 receptor agonist (CCPA, 4.1 μM), an adenosine A2A antagonist (ZM241385, 15 μM), or inosine (1 mM) were applied intravesically in sham and BOO rats. In addition, mRNA levels of adenosine receptor subtypes in the bladder wall were measured using RT-PCR. Histological studies of bladder specimen were also performed.

Results: Weights of BOO bladders were significantly (p < 0.0001) larger compared with sham bladders. In CMG, a number of non-voiding contractions (NVCs), bladder contraction amplitudes during voiding, bladder capacity, and post-void residual (PVR) were significantly (p < 0.001) increased compared with sham rats. Voiding efficiency (VE) was significantly (p < 0.001) reduced in BOO versus sham rats. Intravesical application of CCPA or inosine did not induce statistically significant effects on CMG parameters in BOO rats. Yet, ZM241385 induced a significant (p = 0.040) reduction in NVCs of BOO rats. mRNA levels of adenosine A2A and A3 receptors were significantly (p < 0.0001 and p = 0.0145, respectively) upregulated in the BOO bladder mucosa, whereas adenosine A2B receptors showed a significant (p < 0.0001) reduction in the BOO bladder mucosa compared with sham bladders. Histologically, we found the thickened detrusor muscle layer in BOO versus sham rats.

Conclusions: The male rat model of BOO seems to be suitable for exploring urethral obstruction-related bladder dysfunction at the compensated phase. In addition, the adenosine A2A receptor subtype would be a potential target for the treatment of male BOO patients with bladder overactivity.

Clinical trial registration: A clinical trial registration is not required as this study reported the basic research data using animal models.

Grants and funding

This study was supported by an NIH grant (NIH R01 DK133434).