Activation of P2Y(6) Receptors Facilitates Nonneuronal Adenosine Triphosphate and Acetylcholine Release from Urothelium with the Lamina Propria of Men with Bladder Outlet Obstruction

作者：Silva Isabel; Ferreirinha Fatima; Magalhaes Cardoso Maria Teresa; Silva Ramos Miguel; Correia de Sa Paulo^*

来源：Journal of Urology, 2015, 194(4): 1146-1154.

DOI：10.1016/j.juro.2015.05.080

• urinary bladder neck obstruction
• urothelium
• acetylcholine
• adenosine triphosphate
• purinoceptor P2Y6

Purpose: Deregulation of purinergic bladder signaling may contribute to persistent detrusor overactivity in patients with bladder outlet obstruction. Activation of uridine diphosphate sensitive P2Y(6) receptors increases voiding frequency in rats indirectly by releasing adenosine triphosphate from the urothelium. To our knowledge this mechanism has never been tested in the human bladder.
Materials and Methods: We examined the role of the uridine diphosphate sensitive P2Y(6) receptor on tetrodotoxin insensitive nonneuronal adenosine triphosphate and [H-3] acetylcholine release from the human urothelium with the lamina propria of control organ donors and patients with benign prostatic hyperplasia.
Results: The adenosine triphosphate-to-[H-3] acetylcholine ratio was fivefold higher in mucosal urothelium/lamina propria strips from benign prostatic hyperplasia patients than control men. The selective P2Y(6) receptor agonist PSB0474 (100 nM) augmented by a similar amount adenosine triphosphate and [H-3] acetylcholine release from mucosal urothelium/lamina propria strips from both groups of individuals. The facilitatory effect of PSB0474 was prevented by MRS2578 (50 nM) and by carbenoxolone (10 mu M), which block P2Y(6) receptor and pannexin-1 hemichannels, respectively. Blockade of P2X3 (and/or P2X2/3) receptors with A317491 (100 nM) also attenuated release facilitation by PSB0474 in control men but not in patients with benign prostatic hyperplasia. Immunolocalization studies showed that P2Y(6), P2X2 and P2X3 receptors were present in choline acetyltransferase positive urothelial cells. In contrast to P2Y(6) staining, choline acetyltransferase, P2X2 and P2X3 immunoreactivity decreased in the urothelium of benign prostatic hyperplasia patients.
Conclusions: Activation of P2Y(6) receptor amplifies mucosal adenosine triphosphate release underlying bladder overactivity in patients with benign prostatic hyperplasia. Therefore, we propose selective P2Y(6) receptor blockade as a novel therapeutic strategy to control persistent storage symptoms in obstructed patients.

• 出版日期2015-10