EP2 and EP3 receptors as therapeutic targets for underactive bladder/detrusor underactivity due to diabetic cystopathy in a type 1 diabetic rat model.

OBJECTIVES: Diabetic cystopathy (DC) is recognized as one of the major etiologies of underactive bladder (UAB)/detrusor underactivity (DU). Although DC was first reported about three decades ago, there is a distinct lack of effective pharmacological management methods for UAB/DU due to DC with a robust certainty of evidence. In this study, we investigated whether EP2 and EP3 receptors are promising targets of pharmacological management of UAB/DU due to DC. METHODS: We used streptozotocin (STZ)-induced diabetic Sprague-Dawley rats with postvoid residual urine (PVR) greater than 0.1 mL. Sixteen weeks after induction of diabetes, we performed awake single cystometry after oral administration of the vehicle, an α-blocker (tamsulosin [TAM], 0.1 and 0.3 mg/kg), a cholinesterase inhibitor (distigmine [DIS], 0.3 and 1.0 mg/kg), or an EP2/3 dual agonist (ONO-8055, 0.01 and 0.03 mg/kg). We compared cystometric parameters after administration of the vehicle and drugs using a paired t test. P < .05 was considered to be statistically significant. RESULTS: Compared with the vehicle, TAM significantly decreased maximum intravesical pressure during voiding (Pmax), while DIS significantly increased it. However, neither drug significantly affected PVR or the residual urine rate (RUR). On the other hand, ONO-8055 significantly decreased PVR and tended to decrease RUR, although it did not significantly affect Pmax. CONCLUSION: The present study was unable to demonstrate that stimulation of EP2 and EP3 receptors caused major improvements in UAB/DU due to DC. However, this equivocal result could arise from inherent limitations of the STZ-induced diabetic rat as a UAB/DU model.

Further characterization of a novel EP2 and EP3 receptor dual agonist, ONO-8055, on lower urinary tract function in normal and lumbar canal stenosis rats.

AIMS: To further explore the effects of a novel EP2 and EP3 dual agonist, ONO-8055, on detrusor contractility, we investigated the responses of bladder strips from sham and lumbar canal stenosis (LCS) rats to this agonist, its effects on lower urinary tract function in normal rats, and mRNA expression of EP2 and EP3 receptors in the sham and LCS rats. METHODS: The responses of bladder strips from sham and LCS rats to ONO-8055 were measured. The effects of ONO-8055 on LUT function of normal rats were investigated with awake cystometry and intraurethral perfusion pressure (Pura) measurements. The relative mRNA of bladder and urethral tissue of the sham and LCS rats was quantified using specific probes for EP1, EP2, EP3, and EP4 genes. RESULTS: Compared with the vehicle, the muscle tensions of both the sham and LCS rats were significantly increased after adding this agonist. On awake cystometry of normal rats, bladder capacity and Pura were decreased in the ONO-8055 groups, but a statistically significant difference in mean changes was demonstrated only between the vehicle group and the group receiving the highest dose. Compared with the sham rats, mRNA expressions of the four EP receptors in the lower urinary tract of the LCS rats did not show a statistically significant difference. CONCLUSIONS: This agonist did not augment bladder contractility or urethral relaxation in normal rats.

Effects of an EP2 and EP3 Receptor Dual Agonist, ONO-8055, on a Radical Hysterectomy-Induced Underactive Bladder Model in Monkeys.

OBJECTIVES: The objective was to develop an underactive bladder (UAB) model in primates and to evaluate the potential of prostanoid EP2 and EP3 receptor dual agonist ONO-8055 to become a therapeutic agent for UAB. METHODS: A surgical procedure resembling radical hysterectomy was performed on female cynomolgus monkeys. Subsequently, in vitro muscle strip studies were performed using bladder muscle strips from normal monkeys and monkeys that underwent surgery. In addition, uroflowmetric data were obtained at specified days after the surgery. To evaluate the effects of ONO-8055 and distigmine (DIS) on voiding function in the UAB monkey model, uroflowmetry was performed approximately 1 week after the surgery, before and after the cumulative intravenous administration of the compounds at 2 h intervals. RESULTS: In the bladder muscle strip studies, the responses to potassium chloride at 2 months, and carbachol and electrical field stimulation from 2 weeks decreased significantly. Voided volume (VV), maximum flow rate (Qmax), and average flow rate (Qave) decreased after surgery, while voiding time (VT) increased. In this model, ONO-8055 and DIS significantly increased VV and Qmax. DIS prolonged VT, while ONO-8055 had no effect. The results also showed that ONO-8055 increased Qave. CONCLUSIONS: We developed a neurogenic UAB model in primates. As ONO-8055 improved voiding function in this model to at least the same degree as DIS, this EP2 and EP3 receptor dual agonist has the potential to be a candidate for neurogenic UAB pharmacotherapy.

Promising Effects of a Novel EP2 and EP3 Receptor Dual Agonist, ONO-8055, on Neurogenic Underactive Bladder in a Rat Lumbar Canal Stenosis Model.

PURPOSE: We investigated whether the novel EP (prostaglandin E2) receptor agonist ONO-8055 would improve the lower urinary tract dysfunction of neurogenic underactive bladder in a rat lumbar spinal canal stenosis model. MATERIALS AND METHODS: First, we studied the agonistic effect of ONO-8055 on EP receptors in EP receptor expressing CHO (Chinese hamster ovary) cells using the increase in the intracellular calcium level and intracellular cAMP (cyclic adenosine monophosphate) production as indicators of receptor activation. The effects of ONO-8055 on bladder and urethral strips from normal rats were then investigated. Finally, the effects of ONO-8055 on bladder and urethral function in rats with lumbar spinal canal stenosis were evaluated by awake cystometry and intraurethral perfusion pressure, respectively. The effects of tamsulosin and distigmine on urethral pressure were also evaluated. RESULTS: ONO-8055 is a highly potent and selective agonist for EP2 and EP3 receptors on CHO cells. While this compound contracted bladder strips, it relaxed urethral strips. Awake cystometry showed that ONO-8055 significantly decreased bladder capacity, post-void residual urine and voiding pressure. Compared with vehicle, tamsulosin and ONO-8055 significantly decreased urethral pressure. CONCLUSIONS: ONO-8055 decreased post-void residual urine, probably by decreasing bladder capacity. The decrease in voiding pressure probably resulted from the lowered urethral pressure due to relaxation of the urethra. Thus, the novel EP2 and EP3 receptor dual agonist ONO-8055 has the potential to improve neurogenic underactive bladder.