Transport of extracellular L-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production

• Published in: American journal of physiology. Heart and circulatory physiology 2005-10, Vol.289 (4), p.H1381-H1390
• Main Authors: Zani, Brett G, Bohlen, H. Glenn
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Arginine - pharmacokinetics; Cationic Amino Acid Transporter 1 - metabolism; Cations - pharmacokinetics; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; Extracellular Space - metabolism; Jejunum - blood supply; Lysine - pharmacology; Male; Microcirculation - physiology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Osmolar Concentration; Oxygen - pharmacology; Perfusion; Rats; Rats, Sprague-Dawley; Regional Blood Flow - drug effects; Regional Blood Flow - physiology; Sodium Chloride - pharmacology; Thiourea - analogs & derivatives; Thiourea - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01231.2004

Department of Cellular and Integrative Physiology, Indiana University Medical School, Indianapolis, Indiana Submitted 7 December 2004 ; accepted in final form 8 April 2005 In cultured endothelial cells, 70–95% of extracellular L -arginine uptake has been attributed to the cationic amino acid transporter-1 protein (CAT-1). We tested the hypothesis that extracellular L -arginine entry into endothelial cells via CAT-1 plays a crucial role in endothelial nitric oxide (NO) production during in vivo conditions. Using L -lysine, the preferred amino acid transported by CAT-1, we competitively inhibited extracellular L -arginine transport into endothelial cells during conditions of NaCl hyperosmolarity, low oxygen, and flow increase. Our prior studies indicate that each of these perturbations causes NO-dependent vasodilation. The perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature. Suppression of extracellular L -arginine transport significantly and strongly inhibited increases in vascular [NO] and intestinal blood flow during NaCl hyperosmolarity, lowered oxygen tension, and increased flow. These results suggest that L -arginine from the extracellular space is accumulated by CAT-1. When CAT-1-mediated transport of extracellular L -arginine into endothelial cells was suppressed, the endothelial cell NO response to a wide range of physiological stimuli was strongly depressed. intestine; blood flow; arterioles; L -lysine; oxygen; hyperosmolarity; shear Address for reprint requests and other correspondence: H. G. Bohlen, Dept. of Cellular and Integrative Physiology, Indiana Univ. Medical School, 635 Barnhill Drive, Indianapolis, IN 46202 (e-mail: gbohlen{at}iupui.edu )