Pharmacokinetics and pharmacodynamics of L-arginine in rats: a model of stimulated neuronal nitric oxide synthesis.
Nitric oxide (NO) is believed to be involved in a variety of central nervous system (CNS) functions, including opioid responsivity. Elucidation of the role of NO in the CNS requires the ability to elevate systematically neuronal NO concentrations in vivo. This study was conducted to assess the pharmacokinetics of L-arginine, a NO precursor, and to relate the disposition of this amino acid to the pharmacodynamic endpoint of neuronal NO production. L-Arginine (250-, 500-, or 1000-mg/kg/h) or saline was infused intravenously for 6 h to rats. L-Arginine was quantified in brain and blood (after in vivo microdialysis) with high-performance liquid chromatography. NO was quantified simultaneously with a sensitive and specific amperometric sensor placed in the hippocampus. The data were fit with a comprehensive pharmacokinetic-pharmacodynamic (PK/PD) model to obtain parameters governing the systemic disposition of L-arginine, the uptake of L-arginine into the brain, and subsequent NO production. Exogenous administration of L-arginine resulted in incremental elevations in hippocampal NO, with a approximately 33, 48, and approximately 50% increase from control for the 250-, 500-, and 1000-mg/kg/h L-arginine treated rats, respectively. The PK/PD model, which incorporated known characteristics of the system (saturable uptake of L-arginine into brain; NO production governed by circadian changes in enzyme activity) was capable of describing accurately the observed data. The model developed herein will be invaluable in characterizing the numerous roles of NO in the CNS.
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