Pharmacological management of underactive bladder (UAB) needs more effective drugs.  In a diabetic rat model that has been considered the most representative animal model of UAB, it was reported that EP3 receptors could be potential pharmacological targets [1].  We have reported that a novel EP2 and EP3 dual agonist, ONO-8055, improved lower urinary tract function in animal models of UAB, such as a rat lumbar canal stenosis model [2] and a primate post-radical hysterectomy model [3].  In this study, we investigated the effects of ONO-8055 on lower urinary tract function in a diabetic rat model.  Our hypothesis was that ONO-8055 would decrease post-void residual urine volume (PVR) and bladder capacity (BC) in the diabetic rat model.

We used streptozotocin-induced diabetic Sprague Dawley rats with PVR greater than 0.1 mL (mean ± SE; 0.24 ± 0.03 mL).  An average of sixteen weeks after the induction of diabetes, we performed awake single cystometry after the oral administration of the vehicle, tamsulosin (TAM, 0.1 and 0.3 mg/kg), distigmine (DIS, 0.3 and 1.0 mg/kg), or ONO-8055 (0.01 and 0.03 mg/kg).  We compared PVR (mL), residual urine rate (RUR, %), maximum intravesical pressure during voiding (Pmax, mmHg), and BC (mL) after administration of vehicle and drugs, using a paired t-test.  P<0.05 was considered to be statistically significant.

TAM significantly decreased Pmax, while DIS significantly increased it (Figure).  However, neither drug significantly affected PVR or RUR.  On the other hand, ONO-8055 significantly decreased PVR and tended to decrease RUR (Figure), although this drug did not significantly affect Pmax.  Moreover, no tested drugs had a significant effect on BC.

TAM decreased Pmax by lowering urethral pressure, while DIS increased Pmax by augmenting detrusor contractility in the diabetic rat model.  However, neither drug decreased PVR.  A proposed reason is that TAM did not augment detrusor contractility and DIS did not lower urethral pressure, which was suggested in a neuropathic UAB model [2].  On the other hand, ONO-8055 has been reported to augment detrusor contractility as well as lower urethral pressure [2], which probably results in a decrease in PVR without a significant change in Pmax in the diabetic rat model.  Although we expected ONO-8055 to reduce BC according to the previous report [1], this drug did not cause any significant changes in BC.  This suggests that a mechanism of action of ONO-8055 could be different in neuropathic UAB models [2,3] and the diabetic UAB model; further studies are needed to elucidate this difference.

A novel EP2 and EP3 receptor dual agonist showed promising effects on lower urinary tract function in a diabetic rat model of UAB.

PLoS ONE 9:e102644. Doi:10.1371/journal.pone.0102644
Urol 2016;196:609-16
Low Urin Tract Symptoms 2017 Apr 25. doi: 10.1111/luts. 12166