Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine.
Infarct size and vascular hemodynamics were measured 24 h after middle cerebral artery (MCA) occlusion in mice genetically deficient in the endothelial nitric oxide synthase (eNOS) isoform. eNOS mutant mice developed larger infarcts (21%) than the wild-type strain when assessed 24 h after intraluminal filament occlusion. Moreover, regional CBF values recorded in the MCA territory by laser-Doppler flowmetry were more severely reduced after occlusion and were disproportionately reduced during controlled hemorrhagic hypotension in autoregulation experiments. Unlike the situation in wild-type mice, nitro-L-arginine superfusion (1 mM) dilated pial arterioles of eNOS knockout mice in a closed cranial window preparation. As noted previously, eNOS mutant mice were hypertensive. However, infarct size remained increased despite lowering blood pressure to normotensive levels by hydralazine treatment. Systemic administration of nitro-L-arginine decreased infarct size in eNOS mutant mice (24%) but not in the wild-type strain. This finding complements published data showing that nitro-L-arginine increases infarct size in knockout mice expressing the eNOS but not the neuronal NOS isoform (i.e., neuronal NOS knockout mice). We conclude that NO production within endothelium may protect brain tissue, perhaps by hemodynamic mechanisms, whereas neuronal NO overproduction may lead to neurotoxicity.
Huang
Z
Z
Laboratory of Stroke and Neurovascular Regulation, Neurosurgery, and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Huang
P L
PL
Ma
J
J
Meng
W
W
Ayata
C
C
Fishman
M C
MC
Moskowitz
M A
MA
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001794:Blood Pressure; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019335:Nitroarginine; D014655:Vascular Resistance
D019335:Nitroarginine; D001120:Arginine; D019001:Nitric Oxide Synthase