Roles of adenosine A1 and A2A receptors in the control of micturition in rats

Abstract

Adenosine is a neurotransmitter that exerts numerous physiological effects in many organs. However, few studies have focused on the role of adenosine receptors in the control of micturition. Therefore, we examined the role of adenosine A1 and A2A receptors in the control of bladder activity in rats with normal or acetic acid (AA) irritated bladders. Cystometrograms during saline or 0.2% AA infusion were recorded under urethane anesthesia in female Sprague-Dawley rats. After a stabilization period, CCPA (A1 receptor agonist) and/or ZM24138 (A2A receptor antagonist) were administered intravenously (i.v.), intrathecally (i.t.), intracerebroventricularly (i.c.v.), or intravesically. Micturition parameters were recorded and compared before and after drug administration. I.v., i.t., or i.c.v. administration of CCPA or ZM24138 significantly increased intercontraction intervals (ICIs) in both saline and AA infusion groups. During AA infusion, the inhibitory effects induced by i.c.v. CCPA or i.t. ZM24138 were significantly greater than those by i.t. or i.c.v. administration, respectively. Intravesical administration of CCPA, but not ZM24138, significantly increased ICI. These results indicated that: (1) when nociceptive signals from the bladder increase, adenosine A1 receptor-mediated inhibition of micturition is enhanced in the brain, compared to the normal condition, (2) A1 receptor activation also exerts a peripheral inhibitory effect on micturition, and (3) adenosine A2A receptor-mediated excitatory mechanisms are enhanced in the spinal cord following C-fiber bladder afferent stimulation. Thus adenosine A1 receptor agonists and A2A receptor antagonists might be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders, in which C-fiber afferent function is enhanced.