These authors contributed equally to this work.
Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium
Article first published online: 25 JUN 2014
© 2014 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 14, pages 3404–3419, July 2014
How to Cite
Carneiro, I., Timóteo, M. A., Silva, I., Vieira, C., Baldaia, C., Ferreirinha, F., Silva-Ramos, M. and Correia-de-Sá, P. (2014), Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium. British Journal of Pharmacology, 171: 3404–3419. doi: 10.1111/bph.12711
- Issue published online: 25 JUN 2014
- Article first published online: 25 JUN 2014
- Accepted manuscript online: 4 APR 2014 01:55AM EST
- Manuscript Accepted: 2 MAR 2014
- Manuscript Revised: 13 JAN 2014
- Manuscript Received: 10 AUG 2013
- Fundação para a Ciência e a Tecnologia. Grant Numbers: PTDC/SAU-OSM/104369/2008, Pest/OE/UI0215/2011
- Associação Portuguesa de Urologia
- University of Porto/Caixa Geral de Depósitos
- urinary bladder;
- micturition reflex;
- P2Y6 receptor;
- ATP release;
- acetylcholine release;
- anaesthetized rat
Background and purpose
Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood.
We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [3H]-ACh overflow experiments.
Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [3H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid.
Conclusions and Implications
Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors.