title: Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans.
abstract: OBJECTIVE
  Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature.
  
  
  METHODS
  The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration-response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors.
  
  
  RESULTS
  Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF.
  
  
  CONCLUSIONS
  In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms.
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Sayqa
authors.initials: S
authors.lastname: Arif
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Borgognone
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Erica Lai-Sze
authors.initials: EL
authors.lastname: Lin
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Aine G
authors.initials: AG
authors.lastname: O'Sullivan
authors.affiliation: Department of Cardiology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Vishal
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Drury
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Ashvini
authors.initials: A
authors.lastname: Menon
authors.affiliation: Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mascaro
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bonser
authors.affiliation: Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
authors.affiliation: Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Madhani
mesh_terms: D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D003484:Cyanamide / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D024101:Mitochondrial Proteins; D020030:Nitric Oxide Donors; D009573:Nitrites; D014665:Vasodilator Agents; C091861:spermine nitric oxide complex; D013096:Spermine; D003484:Cyanamide; C005556:propionaldehyde; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D005996:Nitroglycerin