Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium.
OBJECTIVE
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.


METHODS
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 [(3) H]-ACh overflow experiments.


RESULTS
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 [(3) H]-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
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.
Laboratório de Farmacologia e Neurobiologia/UMIB, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto (ICBAS-UP), Portugal.
Inês
I
Carneiro
M Alexandrina
MA
Timóteo
Isabel
I
Silva
Cátia
C
Vieira
Catarina
C
Baldaia
Fátima
F
Ferreirinha
Miguel
M
Silva-Ramos
Paulo
P
Correia-de-Sá
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism
C000597001:3-(2-oxo-2-phenylethyl)uridine-5'-diphosphate; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D000255:Adenosine Triphosphate
ATP release; P2Y6 receptor; UDP; acetylcholine release; anaesthetized rat; micturition reflex; urinary bladder; urothelium