Transport of extracellular l-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production.
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.
Zani
Brett G
BG
Department of Cellular and Integrative Physiology, Indiana University Medical School, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Bohlen
H Glenn
HG
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001120:Arginine / Q000493:pharmacokinetics*; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism*; D002412:Cations / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007583:Jejunum / Q000098:blood supply; D008239:Lysine / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009994:Osmolar Concentration; D010100:Oxygen / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012965:Sodium Chloride / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D027201:Cationic Amino Acid Transporter 1; D002412:Cations; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D012965:Sodium Chloride; D001120:Arginine; D013890:Thiourea; D008239:Lysine; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester