Impairment of the extrusion transporter for asymmetric dimethyl-L-arginine: a novel mechanism underlying vasospastic angina.

Abstract

A 37-year old male patient presented with frequent angina attacks (up to 40/day) largely resistant to classical vasodilator therapy. The patient showed severe coronary and peripheral endothelial dysfunction, increased platelet aggregation and increased platelet-derived superoxide production. The endothelial nitric oxide synthase (eNOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced superoxide formation in platelets identifying "uncoupled" eNOS as a superoxide source. Oral L-arginine normalized coronary and peripheral endothelial dysfunction and reduced platelet aggregation and eNOS-derived superoxide production. Plasma concentrations of the endogenous NOS inhibitor asymmetric dimethyl-L-arginine (ADMA), representing an independent risk factor for cardiovascular disease, were normal in the patient. However, immediately after oral administration of cationic amino acid (CAA), plasma ADMA levels rose markedly, demonstrating increased ADMA efflux from intracellular stores. ADMA efflux from mononuclear cells of the patient was accelerated by CAA, but not neutral amino acids (NAA) demonstrating impairment of y(+)LAT (whose expression was found reduced in these cells). These data suggest that impairment of y(+)LAT may cause intracellular (endothelial) ADMA accumulation leading to systemic endothelial dysfunction. This may represent a novel mechanism underlying vasospastic angina and vascular dysfunction in general. Moreover, these new findings contribute to the understanding of the l-arginine paradox, the improvement of eNOS activity by oral L-arginine despite sufficient cellular l-arginine levels to ensure proper function of this enzyme.

• Authors: Ellen I Closs, Mir A Ostad, Alexandra Simon, Ascan Warnholtz, Alexander Jabs, Alice Habermeier, Andreas Daiber, Ulrich Förstermann, Thomas Münzel
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 423 Issue 2 Pg. 218-23 (Jun 29 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22609206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Superoxides
• N,N-dimethylarginine
• Arginine
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• NG-Nitroarginine Methyl Ester

Topics

• Adult
• Angina Pectoris (blood, drug therapy, metabolism)
• Arginine (administration & dosage, analogs & derivatives, blood, metabolism)
• Blood Platelets (drug effects, metabolism)
• Coronary Vasospasm (blood, drug therapy, metabolism)
• Endothelium, Vascular (enzymology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• Superoxides (metabolism)