Renal D-amino acid oxidase mediates chiral inversion of N(G)-nitro-D-arginine.
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.
Xin
Yan-Fei
YF
Laboratory of Pharmacology, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, China. yxwang@sjtu.edu.cn
Zhou
Xiang-Jun
XJ
Cheng
Xi
X
Wang
Yong-Xiang
YX
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003605:D-Amino-Acid Oxidase / Q000502:physiology*; D007536:Isomerism; D007668:Kidney / Q000201:enzymology*; D008297:Male; D019335:Nitroarginine / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020160:Sodium Benzoate / Q000494:pharmacology
D019335:Nitroarginine; D003605:D-Amino-Acid Oxidase; D020160:Sodium Benzoate