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

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% N 2O/30% O 2. 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.