Studies on inhibitory modulation of urinary tract motility

Overactive Bladder (OAB) is a symptom syndrome characterized by urgency and frequency, with or without urge incontinence. Research concerning the mechanisms underlying OAB and finding new inhibitory factor(s) is intensive.

By using a cascade superfusion system, we confirmed the existence of urothelium- derived inhibitory activity in the guinea pig urinary bladder. The unknown inhibitory activity was transmissible over a significant distance, thus allowing attempts at isolation. The unknown factor(s) was found unlikely to be nitric oxide, an adenosine receptor agonist or cyclo-oxygenase products.

During isolation of the unknown transmissible inhibitory factor(s) using HPLC and bioassay technologies, we observed considerable amounts of PGE2 and PGD2 being released from guinea pig urinary bladder urothelium, in the resting state. PGE2 and PGD2 were not only released from the bladder but also exerted modulatory effects regulating the lower urinary tract motility.

Organ bath experiments using pharmacological tools in guinea pig urothelium-denuded bladder strips showed that PGE2 increased basal tone and spontaneous contractions. Exogenous PGE2 potentiated contractile responses to EFS, ACh and ATP, while PGD2 caused inhibition of EFS, ACh and ATP induced contractions. The inhibitory effect of PGD2 was exerted via DP1 receptors as judged from agonist and antagonist experiments. PGD2 also had a low affinity excitatory effect via TP receptors.

The bladder trigone and urethra have different innervations compared with the bladder dome. Both trigone and proximal urethra are important in continence. The effects of PGE2 and PGD2 were investigated also in these regions in the guinea pig. PGE2 and PGD2 in a dose-dependent manner inhibited trigone contractions induced by EFS and spontaneous contractions of the proximal urethra.

Immunohistochemical studies of DP1 and DP2 receptor proteins indicated that DP1 and DP2 receptors were localized in the guinea pig bladder dome, trigone and urethra. Both urothelium/sub-urothelium and smooth muscle cells were immunolabelled with DP1 and DP2 receptor antibodies. Hematopoietic prostaglandin D synthase was abundant in the immediate sub-urothelium.

These findings will be of importance in understanding normal function and pathophysiology of the lower urinary tract, hopefully opening up new future treatment modalities.

List of scientific papers

I. Guan NN, Thor A, Hallén K, Wiklund NP, Gustafsson LE (2014). Cascade bioassay evidence for the existence of urothelium-derived inhibitory factor in Guinea pig urinary bladder. PLoS One. 2014 Aug 1;9(8):e103932.
https://doi.org/10.1371/journal.pone.0103932

II. Guan NN, Nilsson KF, Wiklund NP, Gustafsson LE (2014). Release and inhibitory effects of prostaglandin D2 in guinea pig urinary bladder and the role of urothelium. Biochim Biophys Acta. 2014 Sep 16;1840(12):3443- 3451.
https://doi.org/10.1016/j.bbagen.2014.09.010

III. Guan NN, Svennersten K, de Verdier PJ, Wiklund NP, Gustafsson LE. Receptors involved in Prostaglandin D2 modulation of guinea pig urinary bladder motility. [Manuscript]

IV. Guan NN, Svennersten K, de Verdier PJ, Wiklund NP, Gustafsson LE. Prostaglandin D2 effects and DP1/DP2 receptor distribution in guinea pig urinary bladder outflow region. [Manuscript]