Aminoguanidine ameliorates and L-arginine worsens brain damage from intraluminal middle cerebral artery occlusion.
OBJECTIVE
We studied whether the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine reduces focal cerebral ischemic damage in a relatively noninvasive stroke model in which the rat middle cerebral artery (MCA) is occluded using an intravascular filament.


METHODS
In rats anesthetized with halothane, a nylon filament was advanced into the internal carotid artery until its tip occluded the origin of the MCA. The filament was left in place for 2 hours and then withdrawn. Twenty-four hours later, rats received intraperitoneal injections of aminoguanidine (100 mg/kg BID; n = 7), aminoguanidine+L-arginine (300 mg/kg QID; n = 7), L-arginine alone (n = 6), D-arginine alone (n = 6), or vehicle (n = 10). Drugs were administered for 3 consecutive days. Infarct volume was determined by image analysis in thionin-stained brain sections 4 days after ischemia. iNOS mRNA was detected with the use of reverse transcription polymerase chain reaction.


RESULTS
Cerebral ischemia led to iNOS mRNA expression in the affected brain 48 hours after induction of ischemia. Administration of aminoguanidine reduced neocortical infarct volume by 26% (P < .05 versus vehicle, ANOVA and Tukey's test), a reduction that was antagonized by coadministration of L-arginine (P > .05 versus vehicle). Administration of L-arginine alone, but not D-arginine, enlarged the infarct by 29% (P < .05). Aminoguanidine or L-arginine did not influence the increase in water content in the postischemic brain, indicating that the effect on infarct volume is not related to modulation of ischemic edema.


CONCLUSIONS
These results demonstrate that cerebral ischemia is also associated with iNOS expression in a minimally invasive model of transient MCA occlusion and that iNOS inhibition reduces focal ischemic damage. The findings support the hypothesis that nitric oxide produced by iNOS contributes to ischemic brain damage and that inhibition of iNOS may be a valuable tool in the management of cerebral ischemia.
Zhang
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F
Laboratory of Cerebrovascular Biology and Stroke, University of Minnesota Medical School, Minneapolis 55455, USA.
Casey
R M
RM
Ross
M E
ME
Iadecola
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C
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001157:Arterial Occlusive Diseases / Q000503:physiopathology*; D001483:Base Sequence; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D001925:Brain Damage, Chronic / Q000503:physiopathology* / Q000517:prevention & control; D002539:Cerebral Arterial Diseases / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000378:metabolism; D002544:Cerebral Infarction / Q000201:enzymology / Q000503:physiopathology; D017931:DNA Primers; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine