Stereospecific pharmacodynamics and chiral inversion of NG-nitro-arginine in the beagle dogs.
In the present study, we analyzed the stereospecific pharmacodynamics and inversion of N(G)-nitro-arginine by an intravenous blous injection of L-N(G)-nitro-arginine (L-NNA) or D-N(G)-nitro-arginine (D-NNA) (10 mg/kg) in beagle dogs. Significant pressor responses were observed for both substances, though a similar maximum response induced by L-NNA was reached at 120 min slower as compared with D-NNA. The rise in mean arterial pressure (MAP) of D-NNA dogs was also shown to be slower than the L-NNA group. Our data showed that D-NNA had no impact on MAP within 60 min after its injection. Plasma L-NNA started to appear after 45 min posterior to the i.v. bolus injection of D-NNA. This chiral inversion is unidirectional because no D-NNA was not produced from L-NNA. The pressor response in the D-NNA-injected dogs was well parallel to the plasma L-NNA concentration. Similar disposition of N(G)-nitro-arginine enantiomers and 4% of chiral inversion ratio from D-NNA to L-NNA was found in the beagle dogs. Given that D-amino acid oxidase (DAAO) is the essential enzyme in chiral inversion of D-NNA, we further compared the enzymatic activity of the renal DAAO between dogs and rats. Our data showed that dogs had a significantly lower enzymatic activity than rats, thus supported a lower inversion ratio of D-NNA in dogs.
Xin
Yan-Fei
YF
State Key Laboratory of Safety Evaluation for New Drug, Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, China. xinyanfei@gmail.com
Gu
Li-Qiang
LQ
Zhang
Sheng
S
Bai
Yun-Sheng
YS
Zhou
Guo-Liang
GL
You
Zhen-Qiang
ZQ
Xuan
Yao-Xian
YX
D000465:Algorithms; D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D007668:Kidney / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases