The role of the prostacyclin receptor antagonist RO3244019 in treating neurogenic detrusor overactivity after spinal cord injury in rats

Abstract

Objective: To determine the effects of the prostacyclin receptor (IP) antagonist RO3244019 on neurogenic detrusor overactivity (NDO) in spinal cord-injured (SCI) neurogenic bladder of the rat.

Materials and methods: Female Sprague-Dawley rats with SCI were divided into four treatment groups of eight each: vehicle (200 mm Tris base), indomethacin (3 mg/kg), RO3244019 (at 1 and 5 mg/kg). The conscious rats were assessed by cystometry, by slowly infusing the bladder with physiological normal saline at 0.04 mL/min. After 1 h of cystometry one of the four compounds was administered intravenously to the rats and changes in cystometrogram tracings recorded. Seven voiding variables were calculated before and after administering each compound: the intercontractile interval (ICI) for all contractions, voiding ICI, amplitude of all contractions, amplitude of voiding contractions, time to first void (TFV), voided volumes (VVs), and first VV. Data were analysed using a paired t-test for each of the experiments.

Results: At 1 mg/kg, the RO compound was associated with a statistically significant difference in the voiding ICI and VVs (both P < 0.05). The mean (sd) voiding ICI increased from 621 (140) to 889 (119) s (43% increase) and the VVs from 0.53 (0.13) to 0.72 (0.09) mL (36% increase). However, there was no statistically significant difference in the TFV or the first VVs. Increasing the dose to 5 mg/kg was more effective in improving the voiding ICI and the VVs (both P < 0.01). The voiding ICI increased from 716 (130) to 1346 (159) s (88% increase) and the VVs from 0.60 (0.11) to 1.05 (0.12) mL (75% increase). In addition, the higher dose had a statistically significant difference in the TFV (P < 0.05). There was more than a four-fold increase in the TFV, from 807 (138) to 3239 (883) s. At 5 mg/kg, the difference in the first VV before and after administering the compound was also almost statistically significant (P = 0.057); the first VV increased from 0.56 (0.14) to 1.01 (0.21) mL. There were no statistically significant differences in the amplitude of contractions or the ICI for all contractions for either of the dosages. Indomethacin at 3 mg/kg was the most effective compound for improving all of the voiding variables and was the only one to show a significant difference in the first VV. However, the IP antagonist at 5 mg/kg was almost as effective as indomethacin when comparing other variables, e.g. the voiding ICI and the VV. There was no statistically significant difference in any of the seven voiding variables before and after administering the vehicle.

Conclusion: The IP antagonist RO3244019 was effective in treating NDO in SCI bladders. While RO3244019 at 1 mg/kg significantly increased the voiding ICI and VVs, 5 mg/kg appeared to be more effective, suggesting a dose-dependent effect of the drug. The RO compound at 5 mg/kg was almost as effective as indomethacin in improving all of the voiding variables.