Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans

Research output: Contribution to journalArticle

Authors

  • Sayqa Arif
  • Erica Lai-sze Lin
  • Aine G O'sullivan
  • Vishal Sharma
  • Ashvini Menon
  • Peter Nightingale
  • Jorge Mascaro
  • Robert S Bonser
  • John D Horowitz
  • Martin Feelisch
  • Michael P Frenneaux

External organisations

  • Department of Cardiology; Royal Liverpool University Hospital; Liverpool UK
  • Wellcome Trust Clinical Research Facility; Queen Elizabeth Hospital; Edgbaston Birmingham UK
  • Department of Cardiothoracic Surgery; Queen Elizabeth Hospital; University Hospitals Birmingham; Edgbaston Birmingham UK
  • Basil Hetzel Institute, Queen Elizabeth Hospital; University of Adelaide; Adelaide Australia
  • Clinical and Experimental Sciences; Faculty of Medicine; University of Southampton; Southampton UK
  • University of Aberdeen
  • Centre for Cardiovascular Sciences; College of Medical and Dental Sciences; University of Birmingham; Birmingham UK

Abstract

Background and Purpose
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.

Experimental Approach
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.

Key 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 and Implications
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.

Details

Original languageEnglish
Pages (from-to)3341-3352
Number of pages12
JournalBritish Journal of Pharmacology
Volume172
Issue number13
Early online date29 Apr 2015
Publication statusPublished - 12 Jun 2015