title: Nitroglycerine causes mitochondrial reactive oxygen species production: in vitro mechanistic insights.
abstract: BACKGROUND
  Nitroglycerine (GTN) is an organic nitrate that has been used for more than 100 years. Despite its widespread clinical use, several aspects of the pharmacology of GTN remain elusive. In a recent study, the authors of the present study showed that GTN causes opening of the mitochondrial permeability transition pore (mPTP) and mitochondrial production of reactive oxygen species (ROS).
  
  
  OBJECTIVE
  In the present study, it was tested whether GTN-induced ROS production depends on mitochondrial potassium ATP-dependent channel or mPTP opening, and/or GTN biotransformation.
  
  
  RESULTS
  Isolated rat heart mitochondria were incubated with succinate (a substrate for complex II) and GTN, causing immediate ROS production, as manifested by chemiluminescence. This ROS production was prevented by concomitant vitamin C incubation. Conversely, inhibitors of potassium ATP-dependent channels, mPTP opening or of GTN biotransformation did not modify ROS production.
  
  
  CONCLUSIONS
  GTN triggers mitochondrial ROS production independently of the opening of mitochondrial channels and/or of GTN biotransformation. The present data, coupled with previous evidence published by the same authors that GTN causes opening of mPTPs, provide further evidence on the pharmacology of GTN. It is proposed that GTN causes direct uncoupling of the respiratory chain, which determines ROS production and subsequent mPTP opening. The clinical implications of these findings are also discussed.
authors.affiliation: Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Italy, and Department of Medicine, Mount Sinai and University Health Network Hospitals, Toronto, Ontario, Canada.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Stolfo
authors.forename: Silvia
authors.initials: S
authors.lastname: Sicuro
authors.forename: Saverio
authors.initials: S
authors.lastname: Dragoni
authors.forename: Monica
authors.initials: M
authors.lastname: Lisi
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Sandro
authors.initials: S
authors.lastname: Forconi
authors.forename: John D
authors.initials: JD
authors.lastname: Parker
mesh_terms: D000818:Animals; D001711:Biotransformation; D066298:In Vitro Techniques; D054086:KATP Channels / Q000187:drug effects; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D023421:Models, Animal; D005996:Nitroglycerin / Q000493:pharmacokinetics / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D005996:Nitroglycerin