• Indu Dhar, Arti Dhar, Lingyun Wu, and Kaushik Desai.
• Department of Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
• J. Pharmacol. Exp. Ther. 2012 Jul 1; 342 (1): 196-204.

AbstractMethylglyoxal (MG), a reactive metabolite of glucose, has high affinity for arginine and is a precursor of advanced glycation endproducts (AGEs). We tested the hypothesis that L-arginine, and its inactive isomer D-arginine, can efficiently scavenge MG, administered exogenously or produced endogenously from high glucose, and attenuate its harmful effects including endothelial dysfunction and oxidative stress by an endothelial nitric-oxide synthase (eNOS)-independent mechanism. We used isolated aortic rings from 12-week-old male Sprague-Dawley rats and cultured human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs). Both D-arginine and L-arginine prevented the attenuation of acetylcholine-induced endothelium-dependent vasorelaxation by MG and high glucose. However, the inhibitory effect of the NOS inhibitor N(ω)-nitro-L-arginine methyl ester on vasorelaxation was prevented by L-arginine, but not D-arginine. MG and high glucose increased protein expression of arginase, a novel finding, NADPH oxidase 4, and nuclear factor κB and increased production of reactive oxygen species in HUVECs and VSMCs, which were attenuated by D-arginine and L-arginine. However, D-arginine and L-arginine did not attenuate MG- and high glucose-induced increased arginase activity in VSMCs and the aorta. D-arginine and L-arginine also attenuated the increased formation of the MG-specific AGE N(ε)-carboxyethyl lysine, caused by MG and high glucose in VSMCs. In conclusion, arginine attenuates the increased arginase expression, oxidative stress, endothelial dysfunction, and AGE formation induced by MG and high glucose by an eNOS-independent mechanism. The therapeutic potential of arginine against MG- and high glucose-induced pathology merits further investigation.

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