Nitric oxide mediates neurologic injury after hypothermic circulatory arrest

Elaine E. Tseng, Malcolm V. Brock, Mary S. Lange, Juan C. Troncoso, Charles J. Lowenstein, Mary E. Blue, Michael V. Johnston, William A. Baumgartner

Research output: Contribution to journalArticle

Abstract

Background. Prolonged hypothermic circulatory arrest (HCA) causes neurologic injury. However, the mechanism of this injury is unknown. We hypothesized that HCA causes nitric oxide production to result in neuronal necrosis. This study was undertaken to determine whether the neuronal nitric oxide synthase inhibitor 17477AR reduces necrosis after HCA. Methods. Thirty- two dogs underwent 2 hours of HCA at 18°C. Nitric oxide synthase catalytic assay and intracerebral microdialysis for nitric oxide production were performed in acute nonsurvival experiments (n = 16). Sixteen animals survived for 72 hours after HCA: Group 1 (n = 9) was treated with 17477AR (Astra Arcus), and group 2 (n = 7) received vehicle only. Animals were scored from 0 (normal) to 500 (coma) for neurologic function and from 0 (normal) to 100 (severe) for neuronal necrosis. Results. Administration of 17477AR reduced nitric oxide production in the striatum by 94% (HCA alone), 3.65 ± 2.42 μmol/L; HCA and 17477AR, 0.20 ± 0.14 μmol/L citrulline). Dogs treated with 17477AR after HCA had superior neurologic function (62.22 ± 29.82 for group 1 versus 141.86 ± 61.53 for group 2, p = 0.019) and significantly reduced neuronal necrosis (9.33 ± 4.67 for group 1 versus 38.14 ± 2.23 for group 2, p < 0.00001) compared with untreated HCA dogs. Conclusions. Our results provide evidence that neuronal nitric oxide synthase mediates neuronal necrosis after HCA and plays a significant role in HCA-induced neurotoxicity. Pharmacologic strategies to inhibit neuronal nitric oxide synthase after the ischemic period of HCA may be clinically beneficial.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalAnnals of Thoracic Surgery
Volume67
Issue number1
DOIs
StatePublished - Jan 1 1999

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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