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.