Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest.
BACKGROUND
Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline.


METHODS
Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18 degrees C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury).


RESULTS
Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 +/- 5.67 at 8 hours and 30.63 +/- 14.96 at 20 hours after HCA.


CONCLUSIONS
Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.
Tseng
E E
EE
Division of Cardiac Surgery, Johns Hopkins Medical Institutions and Kennedy-Krieger Research Institute, Baltimore, Maryland, USA.
Brock
M V
MV
Kwon
C C
CC
Annanata
M
M
Lange
M S
MS
Troncoso
J C
JC
Johnston
M V
MV
Baumgartner
W A
WA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000378:metabolism; D004285:Dogs; D018846:Excitatory Amino Acids / Q000378:metabolism*; D006324:Heart Arrest, Induced; D007036:Hypothermia, Induced; D008297:Male; D009474:Neurons / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*
D018846:Excitatory Amino Acids; D002956:Citrulline; D009569:Nitric Oxide