Modulation of bladder function by luminal adenosine turnover and A1 receptor activation

Area of Science:

• Urology
• Pharmacology
• Physiology

Background:

• The bladder uroepithelium interacts with nervous and muscular systems and is exposed to strain.
• It expresses all four adenosine receptors (A1, A2A, A2B, A3) and produces adenosine.
• Adenosine's protective roles are known in other organs, but its function in the bladder urothelium is unclear.

Purpose of the Study:

• To investigate adenosine turnover in the bladder uroepithelium.
• To determine if altering luminal adenosine impacts bladder function or overactivity.
• To explore the role of adenosine A1 receptors in bladder activity.

Main Methods:

• Measured extracellular adenosine concentrations at mucosal and serosal surfaces.
• Investigated the role of ecto-adenosine deaminase, equilibrative nucleoside transporters, and adenosine kinase.
• Administered a selective A1 receptor agonist (CCPA) to stimulate mucosal receptors.
• Evaluated CCPA's effect on bladder activity and in a cyclophosphamide-induced cystitis model.

Main Results:

• Extracellular adenosine levels were regulated by ecto-adenosine deaminase and equilibrative nucleoside transporters (mucosal) and adenosine kinase and equilibrative nucleoside transporters (serosal).
• Enriching endogenous adenosine or activating mucosal A1 receptors with CCPA stimulated bladder activity by lowering voiding threshold pressure.
• CCPA exacerbated bladder hyperactivity in animals with cyclophosphamide-induced cystitis.

Conclusions:

• Adenosine levels at both urothelial surfaces are modulated by metabolic turnover.
• Blocking adenosine metabolism or directly stimulating luminal A1 receptors promotes bladder contractions.
• Adenosine further stimulates voiding in cystitis, indicating a pro-voiding role in this condition.