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, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
Q
Q
Department of Anesthesiology Research Laboratory, College of Pharmacy, University of Illinois at Chicago 60616.
Theard
M A
MA
Pelligrino
D A
DA
Baughman
V L
VL
Hoffman
W E
WE
Albrecht
R F
RF
Cwik
M
M
Paulson
O B
OB
Lassen
N A
NA
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001640:Bicuculline; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013237:Stereoisomerism
D000927:Anticonvulsants; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D001640:Bicuculline