NITRIC-OXIDE INHIBITION AGGRAVATES ISCHEMIC DAMAGE OF HIPPOCAMPAL BUTNOT OF NADPH NEURONS IN GERBILS

Background and Purpose Nitric oxide may influence pathophysiology of b rain ischemia in a complex way depending on the sources of its product ion either from neurons or endothelial cells. We investigated whether inhibition of nitric oxide synthesis affects postischemic neuronal dea th in hippocampus. Moreover, we evaluated whether the presence of nitr ic oxide synthase activity in specific neurons protects these against ischemia in the hippocampus, striatum, and sensorimotor cortex. Method s To inhibit nitric oxide synthase, several dosing regimens of N-G-nit ro-L-arginine methyl ester (L-NAME) were used (5 or 50 mg/kg IP, twice a day for 4 days, or 30 mg/kg IV) in gerbils. Control animals receive d either the isomer N-G-nitro-D-arginine methyl ester or the vehicle. The gerbils underwent 10-minute occlusion of carotid arteries under et her anesthesia and controlled body temperature while physiological par ameters were monitored. Neuronal damage was assessed 5 days after isch emia using Nissl-stained sections of hippocampus. Nitric oxide synthas e neurons were histochemically stained for reduced nicotinamide adenin e dinucleotide phosphate (NADPH) diaphorase activity. Results L-NAME t reatments, but not the chronic one at 5 mg/kg, induced elevation of bl ood pressure (30% to 80% greater than the control level, P<.01), as ob served shortly before and after bilateral carotid occlusion. Postische mic neuronal loss in the CA1 through CA4 sectors was worsened by chron ic pretreatment with L-NAME at 50 mg/kg leg, CA1 neuronal counts per 1 00-mu m length: 3.2+/-2.74, mean+/-SD; n=19; P<.01). After the acute ( 30 mg/kg) or chronic pretreatment at lower dosage (5 mg/kg) with L-NAM E, neuronal loss was comparable to that of animals treated with the D- isomer or the vehicle (CA1 counts in vehicle-treated animals: 7.65+/-6 .51, mean+/-SD; n=14). None of the L-NAME treatments affected postisch emic survival of NADPH diaphorase-positive neurons in hippocampus, str iatum, and sensorimotor cortex. Conclusions These observations demonst rate that inhibition of endothelial and neuronal nitric oxide synthase activity does not modify resistance of nitric oxide-producing neurons to transient ischemia. The severe inhibition of nitric oxide producti on aggravates postischemic neuronal death in the hippocampus, whereas the mild inhibition is ineffective.