PLASMA NITRATE CLEARANCE IN MICE - MODELING OF THE SYSTEMIC PRODUCTION OF NITRATE FOLLOWING THE INDUCTION OF NITRIC-OXIDE SYNTHESIS

Nitric oxide (NO) is produced in mammals by the enzyme NO synthase (NO S) in response to a number of agents, including the experimental antit umour agent flavone acetic acid (FAA) and the cytokine tumour necrosis factor-alpha (TNF). NO is converted rapidly in the presence of oxygen , water and haemoglobin to oxidation products, largely nitrate. To qua ntitate the production of nitric oxide it is necessary to know the cle arance of nitrate. The concentration of nitrite and nitrate ion in the plasma of C3H and BDF1 (C(57)BL6 x DBA(2)) mice was assessed before a nd after injection of sodium nitrate and sodium nitrite. Nitrite was c onverted rapidly to nitrate and the kinetics of elimination of nitrate were determined. There was no significant difference between results obtained with different mouse strains, between levels of nitrite and n itrate, or between i.p. and i.v. administration, and the observations were therefore combined. The volume of distribution of nitrate was 0.7 1 +/- 0.04 l/kg and the clearance was 0.32 +/- 0.02 l/h(-1)/kg(-1) (pl asma half-life, 1.54 h). Using previously published data, we developed a pharmacokinetic-pharmacodynamic model that relates the production o f TNF in response to administration of FAA, the enhancement of NOS act ivity in response to TNF, and the elevation of plasma nitrate in respo nse to NO production. This information permits the prediction from obs erved plasma nitrate values of the amount of NOS induced in vivo.