Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation

Okt 13, 2017 | Medical research, Pharmaceutical research, References and publications

Place of publication

Redox Biology, Volume 13, October 2017, Pages 163-169

Field

Medical research; pharmaceutical research

Keywords

Nitric oxide; Organic nitrates; Xanthine oxidoreductase; Tolerance; Nitrite; Nitrate

Instrument

ECO PHYSICS CLD 77
i

Abstract

In this report, we describe the synthesis and characterization of 1,3-bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries.

DOI

https://doi.org/10.1016/j.redox.2017.05.014

Link

http://www.sciencedirect.com/science/article/pii/S2213231717302057

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