We have demonstrated that both ATP and PGE2 Can induce ACh release from the bladder urothelium. Therefore, the stretch-induced ACh release, previously described in the bladder, might be a part of the result of a more complex series of signaling interactions within the urothelium. This complexity is increased because ACh can also modulate PGE2 release. This complex mechanism might provide a rapid ampliﬁcation of urothelial signal output. NO partially inhibits ACh-induced PGE2 release and therefore might play a role in downregulating the urothelial-derived signal release. This could be another part of a mechanism to ﬁne tune urothelial signal output. The ACh-induced PGE2 release in the bladder urothelium has been demonstrated to be mediated by the M2 receptor. A schematic of the bladder wall detailing the proposed location for the production of urothelial signals and their proposed interactions is shown in Figure1.
Figure 1 Summary of structural and functional complexity of urothelial signaling systems in guinea pig bladder. (A) Immunohistochemical staining. (a) Basal and intermediate cells expressing enzyme COX I (red), and umbrella cells express marker for exocytotic vesicles SV2 (green; Nile and Gillespie, unpublished observation): presumptive ACh- and ATP-producing cells. (b) Basal cell layer expresses neuronal NO synthase (green), and enzyme-producing ACh (choline-acetyl transferase [ChAT]; Nile and Gillespie, unpublished observation) found in SV2-positive umbrella cells (red). (c) Relationship between layers expressing neuronal NO synthase (green) and COX I (red). (d) Basal layer expressing neuronal NO synthase (red) and cells that respond to NO with increase in cyclic guanosine monophosphate (green): umbrella cells and suburothelial interstitial cells. (e) Cells of intermediate urothelium express COX I (blue) and suggest they are also positive for M2 receptors (red/colocalization seen as purple). Calibration bars = 15 μM. (B) Cartoon showing different cell layers of urothelium and different signals they can generate or respond to. (C) Interactions observed between urothelial signals reported previously. Reciprocal positive interactions found between ACh and PGE2, and ATP promotes PGE2 and ACh output. ATP stimulation of COX I occurs by way of P2X- and P2Y-mediated mechanisms. Potential inhibitory action of NO on PGE2 production also demonstrated.
The proposed schematic highlights the complexity of signal interactions that occur within the bladder wall. An understanding of these mechanisms and their interactions might reveal novel aspects of the control of bladder function. It could also lead to a better understanding of the nature of bladder pathologic features and facilitate the development of new pharmacologic approaches to manipulate and treat bladder disease.
UROLOGY 79: 240.e17–240.e23, 2012. © 2012 Elsevier Inc.