Effects of the nitric oxide donor 3-morpholinosydnonimine (SIN-1) in focal cerebral ischemia dependent on intracellular brain pH

Bernard A. Coert, Robert E. Anderson, Fredric B. Meyer

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Object. A nitric oxide (NO) donor that has been successfully used in the treatment of myocardial infarction, 3-morpholinosydnonimine (SIN-1), may be a potential neuroprotective agent. Production of NO in brain microsomes is dependent on the pH. The purpose of this study was to determine the efficacy of SIN-1 and its dependence on pH in vivo during periods of focal cerebral ischemia. Methods. At 0.1 or 1 mg/kg, SIN-1 was administered to 54 Wistar rats 30 minutes before a 2-hour period of focal cerebral ischemia under moderate hypo-, normo-, and hyperglycemic conditions. Measurements of brain intracellular pH (pHi); regional cortical blood flow, and the redox state of nicotinamide adenine dinucleotide were obtained in three additional animals to confirm the effects of the serum glucose manipulations. The animals were killed at 72 hours after the ischemic period to obtain infarction volumes. Administration of SIN-1 significantly reduced infarction in normoglycemic animals and, to a lesser extent, in hyperglycemic animals, indicating that SIN-1 was less effective under hyperglycemic conditions. At either dose SIN-1 had no significant effect on infarction volume in moderately hypoglycemic animals because moderate hypoglycemia in itself significantly (p < 0.005) reduced infarction volume. Conclusions. The NO donor SIN-1 may be a useful intraoperative cerebral protective agent. Furthermore, it is hypothesized that a mechanism that could explain the published discrepancies regarding the effects of NO donors in vivo may be affected by differences in ischemic brain acidosis.

Original languageEnglish (US)
Pages (from-to)914-921
Number of pages8
JournalJournal of Neurosurgery
Volume97
Issue number4
StatePublished - Oct 1 2002

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Nitric Oxide Donors
Brain Ischemia
Infarction
Brain
Protective Agents
Regional Blood Flow
Neuroprotective Agents
Microsomes
Acidosis
Hypoglycemia
Hypoglycemic Agents
NAD
Oxidation-Reduction
Wistar Rats
Nitric Oxide
Myocardial Infarction
Glucose
Serum

Keywords

  • 3-Morpholinosydnonimine
  • Focal cerebral ischemia
  • Intracellular brain pH
  • Nitric oxide
  • Nitric oxide donor
  • Rat

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)
  • Clinical Neurology

Cite this

Effects of the nitric oxide donor 3-morpholinosydnonimine (SIN-1) in focal cerebral ischemia dependent on intracellular brain pH. / Coert, Bernard A.; Anderson, Robert E.; Meyer, Fredric B.

In: Journal of Neurosurgery, Vol. 97, No. 4, 01.10.2002, p. 914-921.

Research output: Contribution to journalArticle

Coert, Bernard A. ; Anderson, Robert E. ; Meyer, Fredric B. / Effects of the nitric oxide donor 3-morpholinosydnonimine (SIN-1) in focal cerebral ischemia dependent on intracellular brain pH. In: Journal of Neurosurgery. 2002 ; Vol. 97, No. 4. pp. 914-921.
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N2 - Object. A nitric oxide (NO) donor that has been successfully used in the treatment of myocardial infarction, 3-morpholinosydnonimine (SIN-1), may be a potential neuroprotective agent. Production of NO in brain microsomes is dependent on the pH. The purpose of this study was to determine the efficacy of SIN-1 and its dependence on pH in vivo during periods of focal cerebral ischemia. Methods. At 0.1 or 1 mg/kg, SIN-1 was administered to 54 Wistar rats 30 minutes before a 2-hour period of focal cerebral ischemia under moderate hypo-, normo-, and hyperglycemic conditions. Measurements of brain intracellular pH (pHi); regional cortical blood flow, and the redox state of nicotinamide adenine dinucleotide were obtained in three additional animals to confirm the effects of the serum glucose manipulations. The animals were killed at 72 hours after the ischemic period to obtain infarction volumes. Administration of SIN-1 significantly reduced infarction in normoglycemic animals and, to a lesser extent, in hyperglycemic animals, indicating that SIN-1 was less effective under hyperglycemic conditions. At either dose SIN-1 had no significant effect on infarction volume in moderately hypoglycemic animals because moderate hypoglycemia in itself significantly (p < 0.005) reduced infarction volume. Conclusions. The NO donor SIN-1 may be a useful intraoperative cerebral protective agent. Furthermore, it is hypothesized that a mechanism that could explain the published discrepancies regarding the effects of NO donors in vivo may be affected by differences in ischemic brain acidosis.

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