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

Redox Biology

Valdir A. Braga¹  Luciano L. Paulo¹  Petrônio F. Athayde-Filho²  Maria C.R. Brandão²  Jon O. Lundberg³  Arghavan Jahandideh³  Marcelo F. Montenegro³  Zhengbing Zhuge³  Mattias Carlström³ 

[1]Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil

[2]Department of Chemistry, Federal University of Paraíba, João Pessoa, PB, Brazil

[3]Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

关键词: Nitric oxide;    Organic nitrates;    Xanthine oxidoreductase;    Tolerance;    Nitrite;    Nitrate;   

DOI  :  10.1016/j.redox.2017.05.014

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown