Cerebral metabolic recovery from deep hypothermic circulatory arrest after treatment with arginine and nitro-arginine methyl ester.
BACKGROUND
Recent studies suggest that nitric oxide is important in the pathogenesis of ischemic brain injury and also has a role in controlling cerebrovascular tone. This study examines the net effects of nitric oxide on cerebral metabolic recovery after deep hypothermic circulatory arrest.


METHODS
Two-week-old piglets were supported by cardiopulmonary bypass and cooled to 15 degrees C followed by 1 hour of deep hypothermic circulatory arrest, 45 minutes of reperfusion and rewarming, and then 3 hours of normothermic perfusion. Groups of 10 piglets received one of four treatments before bypass; L-nitro-arginine methyl ester, inhibitor of nitric oxide synthesis, 10 mg/kg intravenously; L-arginine, to enhance nitric oxide synthesis, 30 mg/kg intravenously before bypass and then 10 mg/kg per minute during the first hour of reperfusion; a combination of L-nitro-arginine methyl ester plus L-arginine at these same doses; and no pretreatment (controls). Cerebral high-energy phosphates and pH were measured by magnetic resonance spectroscopy in half the animals. Cerebral blood flow, metabolic rates for oxygen and glucose, and the oxidation/reduction state of cytochrome aa3 and oxygenated and deoxygenated hemoglobin measured by near-infrared spectroscopy were assessed in the other half of the piglets.


RESULTS
L-nitro-arginine methyl ester significantly increased cerebral vascular resistance and markedly reduced recovery of high-energy phosphates, pH, and oxidation state of cytochrome aa3, L-arginine increased cerebral blood flow, cerebral glucose and oxygen consumption, and recovery of cytochrome aa3 oxidation and high-energy phosphates. L-Arginine did not reverse completely the effects of L-nitro-arginine methyl ester on cerebral metabolic recovery.


CONCLUSIONS
In a piglet model of deep hypothermic circulatory arrest, L-nitro-arginine methyl ester has a deleterious effect and L-arginine has a beneficial effect on cerebral metabolic recovery. The deleterious metabolic effects of L-nitro-arginine methyl ester are only partially reversed by L-arginine. This fact suggests that there may be mechanisms in addition to inhibition of nitric oxide synthesis contributing to the neurotoxicity of L-nitro-arginine methyl ester in this model.
Hiramatsu
T
T
Department of Cardiac Surgery, Children's Hospital, Boston MA 02115, USA.
Jonas
R A
RA
Miura
T
T
duPlessis
A
A
Tanji
M
M
Forbess
J M
JM
Holtzman
D
D
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D006324:Heart Arrest, Induced; D006454:Hemoglobins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007036:Hypothermia, Induced; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010108:Oxyhemoglobins / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D015424:Reperfusion; D017694:Rewarming; D013055:Spectrophotometry, Infrared; D013552:Swine
D004791:Enzyme Inhibitors; D006454:Hemoglobins; D010108:Oxyhemoglobins; D010710:Phosphates; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D001120:Arginine; D019001:Nitric Oxide Synthase; D003576:Electron Transport Complex IV; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester