Original ArticleImpaired L-Arginine Uptake But Not Arginase Contributes to Endothelial Dysfunction in Rats With Chronic Kidney DiseaseMartens, Christopher R. BS*; Kuczmarski, James M. MS*,†; Lennon-Edwards, Shannon PhD‡; Edwards, David G. PhD*,†Author Information Departments of *Kinesiology and Applied Physiology; †Biological Sciences; and ‡Behavioral Health and Nutrition, University of Delaware, Newark, DE. Reprints: David G. Edwards, PhD, Department of Kinesiology and Applied Physiology, University of Delaware, 541 South College Avenue, Newark, DE 19716 (e-mail: [email protected]). Supported by National Institutes of Health (grant P20 RR016472-11). The authors report no conflicts of interest. Received March 01, 2013 Accepted September 05, 2013 Journal of Cardiovascular Pharmacology: January 2014 - Volume 63 - Issue 1 - p 40-48 doi: 10.1097/FJC.0000000000000022 Buy Metrics Abstract Reduced nitric oxide bioavailability contributes to increased cardiovascular disease risk in patients with chronic kidney disease (CKD). Arginase has been implicated as a potential therapeutic target to treat vascular dysfunction by improving substrate availability for endothelial nitric oxide synthase. The purpose of this study was to determine if arginase contributes to endothelial dysfunction in the 5/6 ablation infarction (AI) rat model of CKD. Endothelium-dependent relaxation of aortic rings to acetylcholine was significantly impaired in AI animals versus sham after 8 weeks and was not improved by arginase inhibition (S-(2-Boronoethyl)-L-cysteine hydrochloride) alone or in combination with L-arginine. Additionally, scavenging of superoxide (Tempol, Tempol + L-arginine, Tempol + L-arginine + S-(2-Boronoethyl)-L-cysteine hydrochloride) was not effective, suggesting that a mechanism independent of oxidative stress contributes to endothelium-dependent relaxation in moderate to severe CKD. Aortic uptake of radiolabeled L-arginine was attenuated in AI animals and was associated with a reduced expression of the L-arginine transporter CAT-1. These data suggest that arginase does not contribute to endothelial dysfunction in CKD; however, impaired L-arginine transport may play an important role in diminishing substrate availability for nitric oxide production leading to endothelial dysfunction. © 2014 by Lippincott Williams & Wilkins.