Nitric oxide formation during cortical spreading depression is critical for rapid subsequent recovery of ionic homeostasis

Tihomir P. Obrenovitch*, Jutta Urenjak, Minyan Wang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Cortical spreading depression (CSD) is a temporary disruption of local ionic homeostasis that propagates slowly across the cerebral cortex. Cortical spreading depression promotes lesion progression in experimental stroke, and may contribute to the initiation of migraine attacks. The purpose of this study was to investigate the roles of the marked increase of nitric oxide (NO) formation that occurs with CSD. Microdialysis electrodes were implanted in the cortex of anesthetized rats to perform the following operations within the same region: (1) elicitation of CSD by perfusion of high K+ medium; (2) recording of CSD elicitation; (3) application of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME); and (4) recording of dialysate pH changes. The primary effect of L-NAME (0.3 to 3.0 mmol/L in the perfusion medium) was a marked widening of individual CSD wave, resulting essentially from a delayed initiation of the repolarization phase. This change was due to NO synthase inhibition because it was not observed with the inactive isomer D-NAME, and was reversed by L-arginine. This effect did not appear to be linked to the suppression of a sustained, NO-mediated vascular change associated with the superposition of NO synthase inhibition on high levels of extracellular K+. The delayed initiation of repolarization with local NO synthase inhibition may reflect the suppression of NO-mediated negative feedback mechanisms acting on neuronal or glial processes involved in CSD genesis. However, the possible abrogation of a very brief, NO-mediated vascular change associated with the early phase of CSD cannot be ruled out.

Original languageEnglish
Pages (from-to)680-688
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number6
Publication statusPublished - 2002
Externally publishedYes


  • L-NAME
  • Migraine
  • N-methyl-D-aspartate
  • Nitric oxide
  • Nitric oxide synthase
  • Spreading depression
  • Stroke

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