@article {Kiemer421, author = {Alexandra K. Kiemer and Angelika M. Vollmar}, title = {Induction of l-Arginine Transport Is Inhibited by Atrial Natriuretic Peptide: A Peptide Hormone as a Novel Regulator of Inducible Nitric-Oxide Synthase Substrate Availability}, volume = {60}, number = {3}, pages = {421--426}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Background: The inducible nitric-oxide synthase (iNOS) synthesizes NO from l-arginine. Availability ofl-arginine is maintained by a lipopolysaccharide (LPS)-induced induction of the CAT-2B amino acids transporter. Recently, we could show that the cardiovascular hormone atrial natriuretic peptide (ANP) inhibits the induction of iNOS in LPS-stimulated macrophages via its guanylate cyclase-coupled A-receptor. Purpose: To investigate whether ANP exerts an effect on LPS-induced l-arginine uptake.Methods: Murine bone marrow derived macrophages were activated with LPS (1 μg/ml, 20 h) in the presence or absence of ANP or C-type natriuretic peptide (CNP). l-Arginine transport was determined by measuring the uptake ofl-[3H]arginine.l-[3H]Arginine influx was also determined in LPS-activated cells in the presence ofNG-monomethyl-l-arginine (l-NMMA), competitor amino acids, or ANP. Nitrite accumulation was determined in supernatants of LPS-activated cells cultured in the presence or absence ofl-ornithine. Results: ANP dose dependently (10-8{\textendash}10-6M) inhibited LPS-inducedl-[3H]arginine uptake when added simultaneously with LPS, whereas it showed no effect when added simultaneously withl-[3H]arginine. The effect was abrogated by the A-receptor antagonist HS-142{\textendash}1 (10 μg/ml). CNP (10-6 M) did not influencel-arginine transport. Competitor amino acids (10-2 M) inhibitedl-[3H]arginine uptake. An excess of unlabeled l-arginine (10-2 M) as well as its analogl-NMMA (10-3 M) also reduced l-[3H]arginine influx. l-Arginine uptake was critical for production of NO because l-ornithine significantly decreased LPS-induced nitrite accumulation.Conclusion: This work demonstrates that ANP inhibits LPS-induced l-arginine uptake via its guanylate cyclase-coupled A-receptor. Besides its influence on the induction of iNOS, this effect may represent an important and unique mechanism by which ANP regulates NO production in macrophages. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/60/3/421}, eprint = {https://molpharm.aspetjournals.org/content/60/3/421.full.pdf}, journal = {Molecular Pharmacology} }