Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats.
We investigated whether an angiotensin-converting enzyme (ACE) inhibitor could inhibit matrix metalloproteinase (MMP) activities in cerebral infarct lesions after middle cerebral artery occlusion (MCAO) in rats. After placebo or trandolapril (5 mg/kg per day) was administered orally for 7 days, we permanently occluded the right middle cerebral artery. ACE activity in extracts from the infarct side of placebo-treated rats was significantly higher than that in extracts from the non-infarct side from 5 days after MCAO, though they did not differ at 1 day. ACE activities in extracts from both hemispheric segments in the trandolapril-treated group were significantly decreased compared with those in the placebo-treated group before MCAO, and this significant reduction persisted even at 7 days after MCAO. In the placebo-treated group, MMP-9 and MMP-2 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO, respectively. Trandolapril treatment significantly reduced MMP-9 and MMP-2 activities to 68.5% and 53.2%, respectively. Seven days after MCAO, the ratios of infarct areas to the hemispheric sectional areas in placebo- and trandolapril-treated rats were 55.4+/-2.1% and 30.9+/-2.9%, respectively, and this difference was significant. Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril-treated rats. Cumulative survival in trandolapril-treated rats was significantly increased compared with that in placebo-treated rats. Thus, the inhibition of MMP-9 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia.
Tanaka
Hidekazu
H
Department of Neurosurgery, Osaka Medical College, Takatsuki, Japan.
Takai
Shinji
S
Jin
Denan
D
Furubayashi
Keiichi
K
Inoue
Nao
N
Kajimoto
Yoshinaga
Y
Miyatake
Shin-Ichi
S
Kuroiwa
Toshihiko
T
Miyazaki
Mizuo
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012720:Severity of Illness Index; D015996:Survival Rate
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; C052035:trandolapril; D007703:Peptidyl-Dipeptidase A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9