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.