Induction of neuronal nitric oxide after hypothermic circulatory arrest

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1313-1320
Number of pages8
JournalAnnals of Thoracic Surgery
Volume62
Issue number5
DOIs
StatePublished - Nov 1996

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Nitric Oxide Synthase Type I
Nitric Oxide
Reperfusion
Citrulline
Nitroarginine
Nitric Oxide Synthase
Canidae
Dogs
Microdialysis
Brain
Neurologic Manifestations
Thoracic Surgery
Cerebrospinal Fluid
Arginine
Esters
Monoclonal Antibodies
Staining and Labeling
Calcium
Temperature
Serum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Induction of neuronal nitric oxide after hypothermic circulatory arrest. / Brock, Malcolm V; Blue, Mary E; Lowenstein, Charles J.; Northington, Frances; Lange, Mary S.; Johnston, Michael V; Baumgartner, William A.

In: Annals of Thoracic Surgery, Vol. 62, No. 5, 11.1996, p. 1313-1320.

Research output: Contribution to journalArticle

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abstract = "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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T1 - Induction of neuronal nitric oxide after hypothermic circulatory arrest

AU - Brock, Malcolm V

AU - Blue, Mary E

AU - Lowenstein, Charles J.

AU - Northington, Frances

AU - Lange, Mary S.

AU - Johnston, Michael V

AU - Baumgartner, William A

PY - 1996/11

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N2 - 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.

AB - 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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