EFFECTS OF M274773, A NEUROKININ-2 RECEPTOR ANTAGONIST, ON BLADDER FUNCTION IN CHRONICALLY SPINALIZED RATS

Abstract

Increased afferent nerve activity may have an important role in the pathogenesis of neurogenic detrusor overactivity. We tested the efficacy of the neuokinin-2 receptor antagonist M274773 ((S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydro-pyrimidin-l-yl) piperidino]butyl]-N-methylbenzamide dihydrochloride) on neurogenic detrusor overactivity after spinal cord injury in rats. Included in this study were 48 adult Sprague-Dawley rats (Charles River, Montreal, Quebec, Canada). Six animals served as normal controls, while 32 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm neurogenic detrusor overactivity, while another 12 served as paraplegic controls. The remaining 24 paraplegic animals were used to test the drug and they were divided into 2 equal groups of 12. Group 1 received the drug at a dose of 0.3 mg/kg daily, while group 2 received a dose of 0.6 mg/kg daily. Each paraplegic control and treatment group was further subdivided into 2 subgroups of 6 rats each. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury. Three weeks after spinal cord injury neurogenic detrusor overactivity developed in all paraplegic control animals with a mean bladder capacity +/- SD of 0.7 +/- 0.2 ml and a mean voiding pressure of 59 +/- 14.2 cm H2O. Neurogenic detrusor overactivity resolved in 50% and 83% of the animals that received M274773 for 1 week at doses of 0.3 and 0.6 mg/kg daily, respectively. Mean cystometric bladder capacity was 1.2 +/- 0.5 vs 1.3 +/- 0.4 ml and mean voiding pressure was 46.1 +/- 10.8 vs 40 +/- 9.9 cm H2O in animals that received 0.3 vs 0.6 mg/kg daily, respectively. The drug produced better urodynamic results when given for 2 weeks rather than 1 week. M274773 is effective for neurogenic detrusor overactivity after spinal cord injury in the rat. It may provide an alternative clinical treatment option for neurogenic detrusor overactivity and urgency/frequency syndrome. This new neurokinin-2 selective antagonist has time and dose response effects, which further suggests the potential for clinical application.