Evaluation of purinergic mechanism for the treatment of voiding dysfunction: A study in conscious spinal cord-injured rats

Background: To investigate the effect of a selective P2X₃-P2X_2/3 purinergic receptor antagonist (A-317491) on detrusor hyperreflexia in conscious chronic spinal cord-injured female rats. Methods: Six chronic spinal cord-transected female Sprague-Dawley rats (290-336g) were used in this study. Spinal transection at the T8-T9 segmental level was performed using aseptic techniques under halothane anesthesia. Fourteen to 16 weeks after spinal transection, A-317491, a selective P2X₃ purinergic receptor antagonist, was administered intravenously in cystometry studies at increasing doses of 0.03, 0.1, 0.3, 1, 3, 10 and 30 μmol/kg at 40-50 minute intervals. Cystometrograms (CMGs) were performed before and after the administration of each dose of the drug. Results: The continuous filling of CMGs revealed a large number of small-amplitude (>8 cmH₂O), non-voiding contractions (NVCs) (average, 9.7 per voiding cycle) preceding voiding contractions (mean amplitude, 31 cmH₂O; duration, 2.5 minutes), which occurred at an interval of 539 seconds and at a pressure threshold of 5.7 cmH₂O. When tested in a range of doses (0.03-30 μmol/ kg, intravenous), A-317491 in doses between 1 and 30 μmol/kg significantly (p < 0.05) increased the interval between voids by 25%, reduced the number of NVCs by 42-62%, and increased the pressure threshold for voiding by 53-73%, but did not change the amplitude of the duration of the voiding contractions. The effects of the drug were apparent within 10 minutes following administration. Conclusion: These results indicate that purinergic mechanisms, presumably involving P2X₃ or P2X_2/3 receptors on bladder C-fiber afferent nerves, play an important role in the detrusor hyperreflexia that occurs after spinal cord injury in rats.