TY - JOUR
T1 - Nitric oxide mediates neurologic injury after hypothermic circulatory arrest
AU - Tseng, Elaine E.
AU - Brock, Malcolm V.
AU - Lange, Mary S.
AU - Troncoso, Juan C.
AU - Lowenstein, Charles J.
AU - Blue, Mary E.
AU - Johnston, Michael V.
AU - Baumgartner, William A.
N1 - Funding Information:
This work was supported by The Dana and Albert Broccoli Center for Aortic Diseases and grant 2RO1NS31238-05 from the National Institutes of Health. Elaine Tseng was supported by the Nina Braunwald Research Fellowship Award from the Thoracic Surgery Foundation for Research and Education. We thank Melissa Haggerty, Jeffrey Brawn, Chieh A. Lee, and Christopher Kwon for technical assistance. We also thank David Reif and Astra Arcus, USA for providing 17477AR and its pharmacokinetic data.
PY - 1999/1
Y1 - 1999/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0003-4975(98)01363-0
DO - 10.1016/S0003-4975(98)01363-0
M3 - Article
C2 - 10086526
AN - SCOPUS:0033052080
VL - 67
SP - 65
EP - 71
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
SN - 0003-4975
IS - 1
ER -