Time Dependence of Effect of Nitric Oxide Synthase Inhibition on Cerebral Ischemic Damage

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Abstract
Nitric oxide, a potent vasodilator and an inhibitor of platelet aggregation, may be beneficial in the early stages of focal cerebral ischemia as it may facilitate collateral blood flow to the ischemic territory. Accordingly, the effect of inhibition of nitric oxide synthesis on cerebral ischemic damage may vary depending on the timing of the inhibition relative to the induction of ischemia. We therefore studied the time course of the effect of nitric oxide synthesis inhibition on focal cerebral ischemic damage. The middle cerebral artery was permanently occluded in spontaneously hypertensive rats and the nitric oxide synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) was administered systemically (3 mg/kg) 3H]arginine to l-[3H]citrulline. Administration of l-NAME 0.05). l-NAME administration 3 h after induction of ischemia reduced neocortical infarct size by 14 ± 11% (p < 0.05). l-NAME decreased cerebellar NOS activity comparably in all groups (range 16–25%). We conclude that the effects of inhibition of nitric oxide synthesis on focal cerebral ischemic damage are time dependent. Thus, inhibition of nitric oxide synthesis worsens ischemic damage when instituted shortly after induction of ischemia and does not affect or reduces damage at later times. The results support the hypothesis that the vascular actions of nitric oxide are beneficial only in the early stages of permanent focal cerebral ischemia.