Hypothesis / aims of study
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.
Study design, materials and methods
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.
Results
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.
Interpretation of results
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.