L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat.
OBJECTIVE
We previously reported that L-arginine infusion increased pial vessel diameter by nitric oxide-dependent mechanisms, improved regional cerebral blood flow (rCBF) distal to middle cerebral artery (MCA) occlusion, and reduced infarction volume in spontaneously hypertensive rats when administered intraperitoneally before and after MCA occlusion. In this report we extend our findings (1) by examining the time course of L-arginine on rCBF and pial vessel diameter under basal conditions and on rCBF after MCA occlusion and (2) by reproducing the protective effect of L-arginine on infarct volume when given intravenously immediately after the onset of MCA occlusion in both normotensive and hypertensive models of focal cerebral ischemia.


METHODS
Changes in pial vessel diameter (closed cranial window) and rCBF (laser-Doppler flowmetry) were measured over time after L-arginine infusion into anesthetized Sprague-Dawley rats. rCBF was also measured distal to MCA occlusion in a brain region showing rCBF reductions in the range of 80% of baseline. The effects of infusing L-arginine (300 mg/kg for 10 minutes beginning 5 minutes after occlusion) were assessed on infarction volume in Sprague-Dawley rats after proximal MCA occlusion and in spontaneously hypertensive rats after common carotid artery plus distal MCA occlusion.


RESULTS
L-Arginine (300 mg/kg IV) elevated rCBF by 20% when measured in the dorsolateral cortex of Sprague-Dawley rats and caused L-nitroarginine-methyl ester-inhibitable increases in pial vessel diameter. L-Arginine (> or = 30 mg/kg IV) increased blood flow distal to MCA occlusion by 50%. These effects were sustained throughout the observation period (70 to 105 minutes). Changes in mean arterial blood pressure were not observed. L-Arginine (300 mg/kg IV) reduced infarction volume by 35% and 28% in Sprague-Dawley and spontaneously hypertensive rats, respectively, when examined 24 hours after vessel occlusion.


CONCLUSIONS
These studies extend our previous findings by demonstrating that exogenous L-arginine induces sustained rCBF increases in normal brain as well as in a marginally perfused brain region distal to MCA occlusion. Our data in Sprague-Dawley rats support the conclusion that L-arginine-induced increases in rCBF can decrease infarction volume. We conclude that nitric oxide-mediated mechanisms increase rCBF and decrease infarction volume after MCA occlusion in both normotensive and hypertensive animals.
Morikawa
E
E
Neurosurgery Service, Massachusetts General Hospital, Boston 02114.
Moskowitz
M A
MA
Huang
Z
Z
Yoshida
T
T
Irikura
K
K
Dalkara
T
T
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002245:Carbon Dioxide / Q000097:blood; D002544:Cerebral Infarction / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010841:Pia Mater / Q000098:blood supply*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects
D002245:Carbon Dioxide; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester