title: Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension.
abstract: NO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress.
  
  
  
  A combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension.
  
  
  
  Ex vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart.
  
  
  
  The novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase.
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Dept. of Medical Cell Biology, Uppsala University, Uppsala, Sweden.|Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Suênia K P
authors.initials: SK
authors.lastname: Porpino
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christa
authors.initials: C
authors.lastname: Zollbrecht
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Peleli
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Maria C R
authors.initials: MC
authors.lastname: Brandão
authors.affiliation: Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Petrônio F
authors.initials: PF
authors.lastname: Athayde-Filho
authors.affiliation: Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Maria S
authors.initials: MS
authors.lastname: França-Silva
authors.affiliation: Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Dept. of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Persson
authors.affiliation: Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil.
authors.forename: Valdir A
authors.initials: VA
authors.lastname: Braga
authors.affiliation: Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlström
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009566:Nitrates / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D011407:Propane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C576760:2-nitrate-1,3-dibuthoxypropan; D009566:Nitrates; D000804:Angiotensin II; D009569:Nitric Oxide; D019255:NADPH Oxidases; D011407:Propane