nitroarginine and ammonium-acetate

Elevated activities of nitric oxide synthase (NOS) have been reported previously in the brains of portacaval-shunted (PCS) rats, a model of chronic hepatic encephalopathy (HE). As L-arginine availability for nitric oxide synthesis depends on a specific uptake mechanism in neurons, we studied the kinetics of L-[3H]-arginine uptake into synaptosomes prepared from the brains of PCS rats. Results demonstrate that L-arginine uptake is significantly increased in cerebellum (60%; p < 0.01), cerebral cortex (42%; p < 0.01), hippocampus (56%; p < 0.01), and striatum (51%; p < 0.01) of PCS rats compared with sham-operated controls. Hyperammonemia in the absence of portacaval shunting also stimulated the transport of L-[3H]arginine; kinetic analysis revealed that the elevated uptake was due to increased uptake capacity (Vmax) without any change in affinity (Km). Incubation of cerebellar synaptosomes with ammonium acetate for 10 min caused a dose-dependent stimulation of L-[3H]arginine uptake. Neither portacaval shunting nor hyperammonemia had any significant effect on the synaptosomal uptake of NG-nitro-L-[3H]arginine. These studies demonstrate that increased NOS activity observed in experimental HE may result from increased availability of L-arginine resulting from a direct stimulatory effect of ammonia on L-arginine transport.

Topics: Acetates; Ammonia; Animals; Arginine; Biological Transport; Brain; Cerebellum; Enzyme Inhibitors; Male; Nitric Oxide Synthase; Nitroarginine; Portacaval Shunt, Surgical; Rats; Rats, Sprague-Dawley; Synaptosomes; Tritium

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.

Topics: Acetates; Amino Acid Oxidoreductases; Animals; Arginine; Encephalomyelitis, Autoimmune, Experimental; Female; Guanidines; Mice; Mice, Inbred Strains; Myelin Basic Protein; Neuritis, Autoimmune, Experimental; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Rats, Inbred Lew