Renal d-Amino Acid Oxidase Mediates Chiral Inversion of N^G-Nitro-d-arginine

Abstract

N^G-nitro-d-arginine (d-NNA), i.v. injected into rats, produced a pressor response, and was presumed to act via chiral inversion into N^G-nitro-l-arginine (l-NNA), an inhibitor of nitric oxide synthase. We examined the possible role of renal d-amino acid oxidase (DAAO) in the chiral inversion of d-NNA to l-NNA. In pentobarbital-anesthetized rats, l-NNA was detected via capillary electrochromatography in the blood immediately after i.v. injection of d-NNA. The time course of appearance of l-NNA paralleled the increase in blood pressure elicited by d-NNA. Unilateral renal ligation partially, and bilateral ligation completely, blocked the pressor response as well as the conversion of d-NNA to l-NNA. Furthermore, injection into conscious rats of sodium benzoate, a selective DAAO inhibitor, completely blocked the pressor response to naive d-NNA, but not pressor response to d-NNA preincubated with homogenates of the kidney. Homogenates of the kidneys, liver (lesser degree), and brain (much lesser degree) converted d-NNA to l-NNA, and the chiral inversion was blocked by the addition of benzoate. Moreover, d-NNA chiral inversion correlates with the activity of DAAO. Our results reveal a novel pathway of chiral inversion of d-amino acids where the renal DAAO plays an essential role that accounts for the biological activity of d-NNA.