Hidekazu Matsuya

ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis.

&NA; Given the previous evidence for involvement of prostanoid EP1 receptors in facilitation of the bladder afferent nerve activity and micturition reflex, the present study investigated the effect of ONO‐8130, a selective EP1 receptor antagonist, on cystitis‐related bladder pain in mice. Cystitis in mice was produced by intraperitoneal administration of cyclophosphamide at 300 mg/kg. Bladder pain‐like nociceptive behavior and referred hyperalgesia were assessed in conscious mice. Phosphorylation of extracellular signal‐regulated kinase (ERK) in the L6 spinal cord was determined by immunohistochemistry in anesthetized mice. Cyclophosphamide treatment caused bladder pain‐like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms, including increased bladder weight and vascular permeability and upregulation of cyclooxygenase‐2 in the bladder tissue. Oral preadministration of ONO‐8130 at 0.3–30 mg/kg strongly prevented both the bladder pain‐like behavior and referred hyperalgesia in a dose‐dependent manner, but had slight effect on the increased bladder weight and vascular permeability. Oral ONO‐8130 at 30 mg/kg also reversed the established cystitis‐related bladder pain. Intravesical administration of prostaglandin E2 caused prompt phosphorylation of ERK in the L6 spinal cord, an effect blocked by ONO‐8130. Our findings strongly suggest that the prostaglandin E2/EP1 system participates in processing of cystitis‐related bladder pain, and that EP1 antagonists including ONO‐8130 are useful for treatment of bladder pain, particularly in interstitial cystitis. Prostaglandin E2 contributes to cystitis‐related bladder pain via EP1 receptors in mice, indicating possible therapeutic usefulness of selective EP1 antagonists.

A novel animal model of underactive bladder: Analysis of lower urinary tract function in a rat lumbar canal stenosis model†‡§

An animal model of neurogenic underactive bladder (UAB) has not been established. It was reported that a rat lumbar spinal canal stenosis (LCS) model created by cauda equina compression manifested intermittent claudication and allodynia. In this study, we examined the lower urinary tract function of the rat LCS model.

The potent inducible nitric oxide synthase inhibitor ONO-1714 inhibits neuronal NOS and exerts antinociception in rats

We evaluated if ONO-1714, known as an inducible nitric oxide synthase (iNOS) inhibitor, could inhibit neuronal NOS (nNOS) and exert antinociception. ONO-1714 potently inhibited both crude rat cerebellar NOS and recombinant human nNOS in vitro. Systemic ONO-1714 at 1-10 mg/kg suppressed carrageenan-induced thermal hyperalgesia in rats, an effect being equivalent to the antinociception caused by L-NAME or 7-nitroindazole at 25 mg/kg. The same doses of ONO-1714 also caused hypertension. Intrathecal (i.t.) ONO-1714 potently reduced the hyperalgesia, the effective dose range (0.2-0.6 microg/rat) being much lower than the antinociceptive dose (150 microg/rat) of i.t. L-NAME. Thus, ONO-1714 is considered a potent inhibitor of nNOS in addition to iNOS. The distinct relative antinociceptive activities of systemic and i.t. ONO-1714 are attributable to its possible poor blood-brain barrier permeability.

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.

Inhibitory effects of retigabine, a Kv7 channel activator, on mechanosensitive primary bladder afferent activities and nociceptive behaviors in rats.

Kv7 voltage‐gated potassium channels have been suggested to modulate mechano‐afferent transduction and nociception in the bladder. We investigated the effects of retigabine, a Kv7 channel activator, on rhythmic bladder contractions (RBCs), and single‐unit afferent activities (SAAs) of the primary bladder mechanosensitive afferent nerve fibers in urethane‐anesthetized rats. In addition, the effects of pretreatment with retigabine on the nociceptive behaviors provoked by an intravesical instillation of resiniferatoxin (RTX) were evaluated in the conscious condition.

Effects of α1 Antagonist and Cholinesterase Inhibitor on Cystometric Parameters in Lumbar Canal Stenosis Rats With Underactive Bladder

OBJECTIVE To examine the lower urinary tract function of a rat lumbar canal stenosis (LCS) model by in vivo cystometry before and after α1 adrenoceptor antagonist or cholinesterase inhibitor administration. MATERIALS AND METHODS One small hole was drilled at the fifth lumbar vertebral arch, and a rectangular piece of silicone rubber was inserted into the L5-L6 epidural space. Two weeks after the surgery, awake cystometry was performed before and after the oral administration of the vehicle, tamsulosin (TAM, 0.03 and 0.1 mg/kg), or distigmine (DIS, 0.3 and 1 mg/kg). We compared the awake cystometry parameters before and after drug administration. RESULTS The LCS rats showed a large maximum cystometric capacity (MCC) and a high residual urine rate with a lower maximum bladder pressure during micturition (Pmax). TAM and DIS significantly decreased the pressure at the onset of voiding contraction, MCC, and postvoid residual urine volume. Residual urine rate was also significantly decreased by DIS at 0.3 and 1.0 mg/kg, and TAM at 0.03 mg/kg. DIS significantly increased the frequency of nonvoiding contractions per minute. Pmax was not significantly different even after administration of DIS. CONCLUSION The LCS rats had salient characteristics of severe infra-sacral neuropathic bladder dysfunction. TAM and DIS decreased postvoid residual urine volume, but this decrease was not accompanied by an increased Pmax or increased voided volume. Rather, decreased MCC was a possible contributing factor. Moreover, increased nonvoiding contractions after administration of DIS might participate in the decreased MCC. This novel model will be useful in studying the pharmacotherapy of the underactive bladder.

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

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.

MP8-01 THE ESTABLISHMENT OF AN UNDERACTIVE BLADDER MODEL FOLLOWING A HYSTERECTOMY IN MONKEY

INTRODUCTION AND OBJECTIVES: Underactive bladder (UAB) syndrome describes a dysfunctional condition of the bladder where patients are unable to produce an effective voiding contraction. To date a pathophysiological mechanisms are not fully understood. To address this issue, we established on underactive bladder model in monkeys after having a hysterectomy. METHODS: Female cynomolgus monkeys were anesthetized with ketamine chloride and pentobarbital sodium. The uterine corpus was then surgically removed while preserving the uterine cervix. Days after surgery, conscious animals were placed on chairs to monitor natural urination after oral administration of 150 mL water (uroflowmetry, UFM). In addition to this, in order to confirm the detrusor underactivity, pressure flow study (PFS) was conducted in the conscious animals. An in vitro muscle strip study was also performed. RESULTS: Monkeys showed typical detrusor underactivity in PFS. Maximum flow rate (Qmax), average flow rate (Qave) and voided volume per micturition were significantly decreased at 2, 4, 6, 8, 21, 60 days after surgery compared with before surgery. On the contrary, voiding time per micturition was significantly increased. Sham-operated group did not show any changes. In muscle strip studies, there was significant decrease in maximum response to potassium chloride (KCl) in the 2 months group but not in the 2 weeks group compared with the sham group. There was a significant decrease in the response to carbachol (CCh) and electric field stimulation (EFS) in both the 2 weeks and 2 months group. CONCLUSIONS: This is the first report on UAB model following a hysterectomy in monkeys. This model had an acutely neurogenic but chronically neurogenic and myogenic characteristics. It seems to be useful in the pathophysiological elucidation of UAB and have potential for assessment of pharmacotherapy of UAB. Source of Funding: none