EP3 antagnoist alleviate detrusor overactivity in complete spinal cord injury rats

Lv L1, Shi B1, Li Y1

Research Type

Pure and Applied Science / Translational

Abstract Category

Pharmacology

Abstract 92
Physiology and Pharmacology
Scientific Podium Short Oral Session 12
Wednesday 27th September 2023
18:42 - 18:50
Room 104CD
Spinal Cord Injury Voiding Dysfunction Detrusor Overactivity
1. Qilu hospital of Shandong University
Presenter
Links

Abstract

Hypothesis / aims of study
Spinal cord injury (SCI) is a serious disease that poses huge burden on the economy and society. According to statistics, almost all SCI patients have neurogenic lower urinary tract dysfunction, manifested as detusor overactivity, detrusor-sphincter dyssynergia, and detrusor acontractility. Renal failure secondary to neurogenic lower urinary tract dysfunction is one of the main causes of late death in SCI patients. Currently, oral medication for detrusor overactivity after spinal cord injury has limited efficacy and may cause side effects such as dry mouth and constipation . Therefore, it is important to explore new therapeutic targets to expand relevant treatment methods. PGE2/EP3 pathway has been demonstrated to play an important role in the occurrence and development of various bladder dysfunction, and a large number of animal experimental studies have shown that EP3 can be a potential target for intervention in detrusor overactivity. This study explored the therapeutic effect of intervention with EP3 on detrusor overactivity secondary to SCI, providing a new potential target for the prevention and treatment of bladder detrusor overactivity after SCI.
Study design, materials and methods
Female 8-week-old Spauge Dawley rats underwent T9-10 spinal cord transection to establish a complete SCI model.  After 4 weeks of surgery, cystometry was conducted to evluate the urodynamic changes in SCI rats. Different concentrations of EP3 antagonist L-826266 were given to the SCI rats intravenously and the bladder pressure was recorded during the whole process. Maximum pressure, baseline pressure, bladder capacity and frequency of non-voiding contractions (NVCs) were collected for statistic analysis. Then, different concentrations of EP3 receptor agonist Sulprostone or antagonist L-826266 were injected into the tail vein of rats under physiological conditions to explore the physiological contribution of EP3 on bladder function.
Results
Administration of L-826266 increased the capacity (p<0.05), and decreased the NVC frequency (0.1mg/kg L-826266 group, p<0.05; 1.0mg/kg group, p<0.01) in SCI rats. To further investigate the physiological contribution of EP3 receptor to the bladder function, Sulprostone and L-826266 was administered to sham rats. Administration of Sulprostone decreased  bladder capacity (0.1mg/kg group, p<0.01; 1.0mg/kg group, p<0.001) and increased NVC frequency (1.0mg/kg group, p<0.05). Administration of 1.0 mg/kg L-826266 increased the bladder capacity in sham rats (p<0.05).
Interpretation of results
Among the EP receptor subtypes, EP3 has been proven to play an important role in smooth muscle contraction and development of bladder hyperactivity (1). Upon activation by PGE2, the G protein complexes associated with EP3 dissociate into Gαi, Gα12/13, Gαs, and Gβγ components and further activate various signaling molecules to achieve its biological function such as smooth muscle contraction (2). McCafferty et al. (3) reported that EP3 knock-out mice demonstrated an increased bladder capacity compared to wild-type mice, while the infusion of the EP3 receptor agonist GR63799X reduced bladder capacity, implicating that EP3 contributes to bladder function. In this present study, we demonstrated that intravenous administration of EP3 antagonist L-826266 significantly increased bladder capacity and decreased frequency of NVCs in SCI rats, which suggests that inhibition of EP3 alleviates SCI-induced detrusor overacitivity.
Concluding message
Inhibition of EP3 significantly relived detrusor overactivity in complete SCI rats. In physiologycal condition, activation of EP3 leads to decreased bladder capacity and increased frequency of NVCs, while inhibition of EP3 leads to increased bladder capacity. Overall, inhibition of EP3 is a possible target for treatment of detrusor overactivity caused by SCI.
Figure 1 EP3 antagonist L-826266 alleviated detrusor overactivity in complete SCI rats
Figure 2 The role of EP3 on bladder function in sham rats
References
  1. Hou R, Yu Y, Jiang J. PGE2 receptors in detrusor muscle: Drugging the undruggable for urgency. Biochem Pharmacol. 2021;184:114363.
  2. Yu Y, Nguyen D, Jiang J. G protein-coupled receptors in acquired epilepsy: Druggability and translatability. Progress in neurobiology. 2019;183:101682.
  3. McCafferty GP, Misajet BA, Laping NJ, Edwards RM, Thorneloe KS. Enhanced bladder capacity and reduced prostaglandin E2-mediated bladder hyperactivity in EP3 receptor knockout mice. Am J Physiol Renal Physiol. 2008;295(2):F507-14.
Disclosures
Funding Tai Shan Scholar Foundation and Clinical Research Project of Shandong University (Grant nos. 2021SDUCRCC001) to Benkang Shi; the National Natural Science Foundation of China (Grant nos.81900637) to Yan Li Clinical Trial No Subjects Animal Species Rat Ethics Committee Laboratory Animal Ethical and Welfare Committee of Shandong University Cheeloo College of Medicine
Citation

Continence 7S1 (2023) 100810
DOI: 10.1016/j.cont.2023.100810

13/11/2024 22:37:12