NITRIC-OXIDE (NO) IS AN ENDOGENOUS ANTICONVULSANT BUT NOT A MEDIATOR OF THE INCREASE IN CEREBRAL BLOOD-FLOW ACCOMPANYING BICUCULLINE-INDUCED SEIZURES IN RATS

Neurons synthesize NO, which may act as a retrograde messenger, involv ed in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased ne uronal activity (i.e., seizures). In this study, two questions were as ked: (1) is NO an endogenous anticonvulsant or proconvulsant substance ? and (2) is the cerebral blood flow (CBF) increase accompanying bicuc ulline (BC)-induced seizures mediated by NO? The experiments were perf ormed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70 % N2O/30% O-2. CBF was measured using the intracarotid Xe-133 clearanc e method or laser-Doppler flowmetry. EEG activity was recorded. Chroni c treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthas e (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 sustaine d as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inact ive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS a ctivity, ranging from 87 to 100%. The duration of seizures in this gro up (average 8 +/- 2 min) corresponded directly to the magnitude of red uction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA re sults indicated that NOS inhibition had to exceed 95% before any effec t on seizure duration could be seen. Additional results demonstrated t hat only a total dose of 400 mg/kg of L-NA, given chronically was capa ble of prolonging the BC-induced CBF increase. With acute doses of 5 a nd 30 mg/kg L-NA, the time course of CBF changes after BC administrati on was not different from the control. These findings suggest that end ogenous NO acts as an anticonvulsant perhaps via a negative feedback m echanism at the NMDA receptor. NO, however, does not appear to couple neuronal activation to increased CBF in this model.