Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells.
BACKGROUND
This study was to delineate the therapeutic efficacy and potential cellular and molecular mechanisms of aminoguanidine (AG), a relatively selective inhibitor of iNOS activity, in cerebral vasospasm after subarachnoid hemorrhage (SAH) in rabbits.


METHODS
SAH was induced by a single injection of autologous arterial blood into the cisterna magna of adult male rabbits. An intravenous bolus injection of AG (150 mg/kg) was administrated 1h after SAH, and this dosage was repeated on the following day. Vasospasm was verified by computed tomography angiography (CTA) day 2 after SAH. Rabbit basilar arteries were harvested for transmission electron microscopy (TEM), immunohistochemical examination, RT-PCR, and western blot analysis.


RESULTS
CTA data revealed that cerebral vasospasm of SAH rabbits was significantly prevented via AG treatment. TEM results demonstrated the ultrastructural morphological changes of endothelial cells of SAH rabbits were ameliorated by AG treatment. In parallel, AG treatment increased eNOS mRNA and protein levels along with the reduced immunoreactivity of nitrotyrosine in rabbit basilar arteries.


CONCLUSIONS
Our discovery suggested AG inhibition of iNOS activity could significantly reverse cerebral vasospasm after SAH via restoration of dysfunctional endothelial cells by the upregulation of eNOS, indicating a regulatory cross-talk between eNOS and iNOS in the pathogenesis of SAH.
Zheng
Bingjie
B
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Zheng
Tianhu
T
Wang
Ligang
L
Chen
Xiaofeng
X
Shi
Changbin
C
Zhao
Shiguang
S
D000704:Analysis of Variance; D000818:Animals; D001488:Basilar Artery / Q000473:pathology; D002533:Cerebral Angiography / Q000379:methods; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications; D014057:Tomography, X-Ray Computed / Q000379:methods; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*
D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine