The effects of blood pressure and urokinase on brain injuries after experimental cerebral infarction in rats.
OBJECTIVE
With the proposal of penumbra theory and development of intra-arterial thrombolysis (such as urokinase), the outcome of ischemic cerebrovascular disease is greatly improved. However, the incidence of hemorrhagic transformation (HT) increased concomitantly, and some studies showed a close relationship between blood pressure and HT. The mechanisms of blood pressure and urokinase effect on the incidence of HT are not clear. In this study, we investigated the effects of the different levels of blood pressure and urokinase on the ischemic lesions, the incidence of HT and the expression of matrix metalloproteinase 9 (MMP-9) in the rat ischemia-reperfusion models.


METHODS
Temporary focal ischemia was induced in male Sprague-Dawley rats using the intraluminal vascular occlusion method. The animals were assigned into four groups (n=11 in each group): low blood pressure group (LP), normal blood pressure group (NP), high blood pressure group (HP) and urokinase/high blood pressure group (UKHP). Adnephrin was applied to enhance the mean arterial blood pressure (MABP) at the beginning of reperfusion. MABP was maintained 20 mmHg higher than the baseline for 1 hour. Sodium nitroprusside was used to decrease MABP by 20 mmHg lower than the baseline for 1 hour. Both urokinase and adnephrin were used concomitantly in the UKHP group. Neurological deficit scores were evaluated at 2 hours (R2h) and 24 hours (R24h) after reperfusion. All rats were decapitated, their brains were sliced into 15-mum-thick slices, and the infarct volume and the visible HT were analysed. Three rats in each group were taken for immunohistochemistry and pathological analysis.


RESULTS
There was no significant difference in MABP among the groups at the baseline time points (p>0.05), but blood pressure are definitely increased and decreased in the HP, UKHP, and LP groups. Neurological deficit scores showed no significant difference at R2h among the groups (p=0.443). However, neurological deficit scores showed significant differences at R24h among the groups, the neurological deficits scores of rats in the LP group are significantly higher than that in the other groups. Compared with that of 2 hours after reperfusion, neurological deficit scores deteriorated in the LP group (p=0.047) but was improved in the NP, HP and UKHP groups (p=0.076, 0.002, 0.017, respectively) at 24 hours after reperfusion. The infarct volume in the HP group was apparently smaller than that in the LP group (p=0.006). There was indeed a tendency that HT occurred more frequently in the UKHP group (42.8%) than in the HP (25%) and LP (28.5%) groups. MMP-9 expression showed significant increase around the ischemic lesion areas of the UKHP group and significant decrease in the cortical areas of the LP and HP groups but no significant difference in the basal ganglia of rats of all groups.


CONCLUSIONS
Mild elevation of blood pressure during reperfusion is supposed to improve neurological outcomes in rats following ischemia/reperfusion. The incidence of HT tended to increase with the elevation of blood pressure and the administration of urokinase. Immunohistochemitry analysis indicated that incidence of HT may correlate with excessive expression of MMP-9.
Ji
Xunming
X
Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, Beijing, China.
Li
Ke
K
Li
Wenbin
W
Li
Shuting
S
Yan
Feng
F
Gong
Wei
W
Luo
Yumin
Y
D000634:Aminoquinolines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology; D002544:Cerebral Infarction / Q000150:complications*; D004195:Disease Models, Animal; D004837:Epinephrine / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009460:Neurologic Examination; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000379:methods; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000009:adverse effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000634:Aminoquinolines; D005343:Fibrinolytic Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; C012169:adepren; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D004837:Epinephrine