Role of cyclooxygenase-2 in the development of bladder overactivity after cerebral infarction in the rat.
OBJECTIVE
We investigated the role of cyclooxygenase (COX) isoforms in bladder overactivity induced by cerebral infarction (CI) in rats.


METHODS
CI was induced by left middle cerebral artery occlusion (MCAO) in female Sprague-Dawley rats. Bladder activity was monitored with continuous infusion cystometrography of conscious rats. Specimens were obtained from the pontine tegmental area (PTA) 1, 3, 5, 12 and 24 hours after CI or sham operation (SO). The effects of MK-801 (0.1 mg/kg intravenously), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, on bladder activity, and on COX-1 and 2 mRNA expression following MCAO were examined. Real-time quantitative reverse transcriptase-polymerase chain reaction was performed to evaluate the effects of CI on gene expression in the PTA. The effects of the COX-2 inhibitor NS398 (0.01 to 10 mg/kg intravenously) on bladder activity were examined.


RESULTS
The bladder capacity of CI rats was significantly decreased 1 to 24 hours after MCAO compared with that of SO rats (p <0.05 or 0.01). One and 3 hours after MCAO mean COX-2 mRNA expression +/- SE had increased significantly to 22.4 +/- 3.5 in terms of its expression relative to the outer control in a sample obtained immediately after MCAO, in contrast to that in SO rats (p <0.01). The expression level returned to the control level within 12 hours after MCAO. COX-1 expression was not influenced by MCAO. Pretreatment with MK-801 inhibited the development of bladder overactivity and significantly decreased the expression of COX-2 mRNA in the PTA (p <0.01). Treatment with NS398 before MCAO prevented the development of bladder overactivity in a dose dependent manner and did not influence infarct volume.


CONCLUSIONS
These results indicate that the development of bladder overactivity following MCAO is accompanied by an increase in COX-2 mRNA expression in the PTA and is mediated by NMDA receptor activity. COX-2 in the brain may be a new target for the treatment of neurogenic voiding dysfunction after cerebral infarction.
Yotsuyanagi
Satoshi
S
Departments of Urology, Kanazawa University School of Medicine, Kanazawa and University of Fukui, Fukui, Japan.
Yokoyama
Osamu
O
Komatsu
Kazuto
K
Kodama
Koichi
K
Nagasaka
Yasuhiro
Y
Namiki
Mikio
M
D000818:Animals; D002544:Cerebral Infarction / Q000150:complications / Q000201:enzymology*; D051546:Cyclooxygenase 2; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014549:Urinary Incontinence / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D016291:Dizocilpine Maleate; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases