L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient mice.
Delayed administration of the nitric oxide precursor L-arginine increases brain injury in models of focal cerebral ischemia. We tested the hypothesis that L-arginine worsens the damage by acting as a substrate for inducible nitric oxide synthase (iNOS) and increasing the output of this enzyme. iNOS-null mice or wild-type littermates were treated with L-arginine (300 mg/kg; i.p, three times/day) starting 12 h after occlusion of the middle cerebral artery. Infarct volume was determined 96 h after ischemia. We found that L-arginine enlarges infarct volume in wild-type mice (+28+/-5% in neocortex) but not in iNOS-null mice. Thus, the worsening of ischemic damage produced by L-arginine depends on iNOS. The findings support the hypothesis that L-arginine worsens ischemic injury by increasing the catalytic output of iNOS and suggest that administration of L-arginine should be avoided in patients with acute stroke.
Zhao
Xueren
X
Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Ross
M Elizabeth
ME
Iadecola
Costantino
C
D000818:Animals; D001120:Arginine / Q000009:adverse effects* / Q000031:analogs & derivatives; D002545:Brain Ischemia / Q000201:enzymology / Q000503:physiopathology* / Q000517:prevention & control; D016022:Case-Control Studies; D002544:Cerebral Infarction / Q000201:enzymology / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II
D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse