Transformation of subcutaneous nitric oxide into nitrate in the rat

Following its addition to arterialized blood in vitro, nitric oxide (NO) is transformed into nitrate in the erythrocytes. Inhaled NO is similarly transformed into nitrate in the blood in vivo. These observations suggest that nitrate is a universal end-metabolite of NO, i.e. of endogenously formed NO as well. However, endogenous NO may also be inactivated in tissues, i.e. outside the vascular lumen. To study the fate of NO metabolized with delayed access to the blood, rats were given subcutaneous injections of (NO)-N-15 or (KNO3)-N-15, and the plasma concentrations of (NO3)-N-15- were followed for 450 min after injection. The values for the distribution volume and plasma decay (t1/2) of (NO3-)-N-15 did not differ between rats given N-15-labelled NO and NO3-. The area under the plasma decay curve for rats given (NO)-N-15 amounted to 89 % of the corresponding area for animals given (KNO3)-N-15. This demonstrates that (NO)-N-15, when given extravascularly in millimolar concentrations, is mainly transformed into N-15-labelled nitrate. Other rats were kept in an atmosphere containing a mixture of O-16(2) and O-18(2). Nitrate residues containing either one or two O-18 atoms were isolated from the blood, indicating that inhaled oxygen was incorporated during both the formation of NO and the subsequent transformation of NO into nitrate. The fraction of nitrate residues containing two O-18 atoms was larger than that containing one O-18 atom. We propose that nitrate is a major stable metabolite of endogenous NO that does not primarily diffuse into the vascular lumen following formation. Hence nitrate seems to be the quantitatively most important end-product of the metabolism of endogenous NO. The transformation of endogenous NO into nitrate involves the incorporation of inhaled oxygen.