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Ann Thorac Surg 1996;62:1313-1320
© 1996 The Society of Thoracic Surgeons

Original Article: Cardiovascular

Induction of Neuronal Nitric Oxide After Hypothermic Circulatory Arrest

Malcolm V. Brock, MD, Mary E. Blue, PhD, Charles J. Lowenstein, MD, Frances A. Northington, MD, Mary S. Lange, MA, Michael V. Johnston, MD, William A. Baumgartner, MD

Division of Cardiothoracic Surgery and the Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland

Background. Although hypothermic circulatory arrest (HCA) has become routine practice in cardiac surgery, it is associated with substantial neurotoxicity. We tested the hypothesis that increased nitric oxide production during HCA participates in neuronal death. We previously described a canine survival model of HCA that produces a consistent neurologic deficit and histopathologic pattern of selective neuronal death.

Methods. Adult male hound dogs (n = 17) were subjected to 2 hours of HCA at a brain temperature of 18°C and reperfused to normothermia; they were sacrificed at various intervals up to 74 hours. Using in vivo cerebral microdialysis, dogs (n = 5) were given a simultaneous infusion of artificial cerebrospinal fluid containing L-[14C]arginine or L-[14C]arginine and L-nitroarginine methyl ester (a nitric oxide synthase inhibitor) in contralateral hemispheres while undergoing 2 hours of HCA and reperfusion to normothermia.

Results. L-[14C]citrulline recovery, a coproduct of nitric oxide, significantly increased during HCA in the hemisphere without the inhibitor (at 300 minutes: control, 236 ± 94 fmol/min versus L-nitroarginine methyl ester, 6 ± 6 fmol/min; p < 0.05). Citrulline production in vitro from canine cortical homogenates in the presence of calcium (n = 12) was significantly greater 8 and 20 hours after reperfusion (5.11 ± 0.54 x 10-7 mmol • mg-1• min-1 and 7.52 ± 0.59 x 10-7 mmol • mg-1 • min-1, respectively) than before HCA (1.51 ± 0.09 x 10-7 mmol • mg-1 • min-1; p < 0.05). Nitric oxide metabolites in the serum were also increased significantly early after reperfusion (baseline, 6.72 ± 0.95 mmol/L; at 4 hours, 17.58 ± 1.46 mmol/L; p < 0.05). Immunocytochemical staining of the cortex with neuronal nitric oxide synthase-specific monoclonal antibodies (Transduction Labs) revealed increased neuronal nitric oxide synthase expression 6 to 18 hours after HCA. Darkfield analysis demonstrated neuronal nitric oxide synthase localization to neuronal processes with widespread formation of dense plexi of nitric oxide synthase fibers.

Conclusions. We conclude that neurotoxicity after HCA involves a significant, early induction in neuronal nitric oxide synthase expression in neuronal processes leading to widespread augmented nitric oxide production in the brain.


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Discussion
Ann. Thorac. Surg. 1996 62: 1320. [Extract] [Full Text]



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