Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats

Qiong Wang, Mary A. Theard, Dale A. Pelligrino, Verna L. Baughman, William E. Hoffman, Ronald F. Albrecht, Michael Cwik, Olaf B. Paulson, Niels A. Lassen

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300–400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using the intracarotid 133Xe clearance method or laser-Doppler flowmetry. EEG activity was recorded. Chronic treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthase (NOS) inhibitor (400 mg/kg total), suppressed brain NOS by > 97% and prolonged seizure duration from 6±1 (saline-treated controls) to 12 ± 2 min. In the L-NA-treated group, the CBF increase was sustained as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inactive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS activity, ranging from 87 to 100%. The duration of seizures in this group (average 8 ± 2 min) corresponded directly to the magnitude of reduction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA results indicated that NOS inhibition had to exceed 95% before any effect on seizure duration could be seen. Additional results demonstrated that only a total dose of 400 mg/kg of L-NA, given chronically was capable of prolonging the BC-induced CBF increase. With acute doses of 5 and 30 mg/kg L-NA, the time course of CBF changes after BC administration was not different from the control. These findings suggest that endogenous NO acts as an anticonvulsant perhaps via a negative feedback mechanism at the NMDA receptor. NO, however, does not appear to couple neuronal activation to increased CBF in this model.

Original languageEnglish (US)
Pages (from-to)192-198
Number of pages7
JournalBrain research
Volume658
Issue number1-2
DOIs
StatePublished - 1994
Externally publishedYes

Keywords

  • Bicuculline
  • Cerebral blood flow
  • Nitric oxide (NO)
  • NMDA receptor
  • Seizure

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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