We examined the effect of modulating endogenous nitric oxide (NO) production on the recovery of neuronal function from temporary ischemia using a preparation in which blood flow is not a factor. Inhibition of nitric oxide synthase (NOS) during ischemia with L-NA (100 mumol-1) resulted in worse functional recovery compared to D-NA (100 mumol-1)-treated in control retinas (p < 0.01). In contrast, addition of L-Arg (1000 mumol-1) during ischemia, resulted in a concentration-dependent functional improvement (p < 0.05). These results show that inhibition of constitutive NOS is detrimental, whilst the enhancement of endogenous NO production improves the recovery of neuronal function during a period of temporary ischemia in the isolated retina, (an in vitro avascular model of the CNS). Thus, independent of its effects on the vasculature, NO production during temporary ischemia protects neurons from irreversible function damage.