Determination of the Flux Control Coefficient of Nitric Oxide Synthase for Nitric Oxide Synthesis in Discrete Brain Regionsin vivo

The flux control coefficient of nitric oxide synthase (NOS), for thein vivosynthesis of the key biological mediator nitric oxide (NO), was determined in four rat brain regions with varying NOS activities (cerebral cortex, hippocampus, amygdala and cerebellum) using metabolic control theory. Flux control coefficients were calculated from the ratio of the initial slopes of the fractional effect of the NOS inhibitorNw-nitro-L-arginine (L-NA) on NO pathway flux and NOS activity. Under conditions of normal behaviour in the rat, NOS had a flux control coefficient not significantly different from one in all regions examined. These data demonstrate that the large majority of flux control for the synthesis of NO in the brain resides in NOS itself and not in the transport of its amino acid precursor, L-arginine, across the blood-brain or neuronal cell membranes. This paper describes the first example in which the control of metabolic flux has been quantified in a mammalian systemin vivoand demonstrates the power of metabolic control theory to elucidate the distribution of control within a metabolic pathwayin vivo.