Nitric oxide-mediated suppression of detrusor overactivity by arginase inhibitor in rats with chronic spinal cord injury.
OBJECTIVE
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.
Sasatomi
Kurumi
K
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Hiragata
Shiro
S
Miyazato
Minoru
M
Chancellor
Michael B
MB
Morris
Sidney M
SM
Yoshimura
Naoki
N
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002908:Chronic Disease; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D009569:Nitric Oxide / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000150:complications / Q000628:therapy*; D013131:Spine / Q000473:pathology; D001743:Urinary Bladder / Q000187:drug effects; D001750:Urinary Bladder, Neurogenic / Q000150:complications / Q000188:drug therapy*
D012333:RNA, Messenger; D009569:Nitric Oxide; D001119:Arginase