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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01085

Metabolomics-driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-induced Inactivation of Xanthine Oxidase

  • 1Oregon State University, United States
  • 2Jackson Laboratory, United States

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy.

Keywords: Nitrate tolerance, Nitroglycerin, Xanthine Oxidase, Ascorbic Acid, Nitric Oxide, Metabolomics

Received: 04 Jul 2018; Accepted: 06 Sep 2018.

Edited by:

Pedro D'Orléans-Juste, Université de Sherbrooke, Canada

Reviewed by:

InKyeom Kim, Kyungpook National University, South Korea
Carlos F. Sánchez-Ferrer, Universidad Autónoma de Madrid, Spain  

Copyright: © 2018 Stevens, Axton, Cristobal, Choi and Miranda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jan F. Stevens, Oregon State University, Corvallis, United States,