Nitric oxide-mediated suppression of detrusor overactivity by arginase inhibitor in rats with chronic spinal cord injury

Abstract

Objectives: We investigated the effects of an arginase inhibitor on bladder overactivity and measured bladder arginase I and II mRNA levels in rats with chronic spinal cord injury (SCI).

Methods: We performed awake cystometrograms 3 to 4 weeks after spinal cord transection in female rats. Cystometric parameters such as mean amplitudes and number of non-voiding contractions (NVCs), voided volume, voiding efficiency, and micturition pressure were evaluated before and after intravenous (i.v.) injection of an arginase inhibitor (nor-NOHA: N(omega)-hydroxy-nor-L-arginine) in SCI rats. We also examined the effects of an NOS inhibitor (L-NAME: N(omega)-nitro-L-arginine methyl ester hydrochloride) to determine whether suppression of bladder overactivity by arginase inhibition is mediated by increased production of NO. In addition, we measured mRNA levels of arginase I and II in SCI bladders using quantitative real-time polymerase chain reaction (qRT-PCR).

Results: We found that nor-NOHA (10 mg/kg, i.v.) significantly decreased the amplitude and number of NVCs. There were no significant changes in other parameters before and after administration of vehicle or nor-NOHA at any dose. When we administered L-NAME (20 mg/kg, i.v.) before nor-NOHA injection (10 mg/kg, i.v.), nor-NOHA-induced inhibition of NVCs was prevented. The relative levels of both arginase I and II mRNA in the bladder were significantly higher in SCI rats compared with spinal cord-intact rats.

Conclusions: These results suggest that arginase inhibition can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, arginase inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.

Figure 1

Effects of i.v. administration of nor-NOHA (A) alone and nor-NOHA after i.v. injection of L-NAME (B) on NVCs in SCI rats. Arrows indicate the timing of drug administration.

Figure 2

Amplitudes (A) and the number of NVCs (B) in SCI rats before (Pre) and after (Post) i.v. administration of vehicle (dH₂O), nor-NOHA (1.0–10.0 mg/kg) alone, and nor-NOHA after i.v. injection of L-NAME. Note that the highest dose of nor-NOHA significantly suppressed the number and amplitude of NVCs. Each histogram represents mean ± S.E. **P <0.01, *P <0.05 compared with pre-drug values.

Figure 3

Relative expression of arginase I (A) and arginase II (B) mRNAs in the bladder of normal rats (n=7) and SCI rats (n=7). Relative expression of arginase mRNAs was normalized against β-actin mRNA. Each bar represents mean ± S.E.