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 (1) ALDH2 inhibition by cyanamide or propionaldehyde and the (2) 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 (2.48±0.36 to 1.72±0.15 in pre-and post GTN infusion group, respectively; P=0.08).
CONCLUSIONS AND IMPLICATIONS: In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with heart failure in vivo the role of this enzyme in nitrite bioactivation is at most modest, suggesting the involvement of other more important mechanisms.
| Original language | English |
|---|---|
| Pages (from-to) | 3341-3352 |
| Number of pages | 12 |
| Journal | British Journal of Pharmacology |
| Volume | 172 |
| Issue number | 13 |
| Early online date | 29 Apr 2015 |
| DOIs | |
| Publication status | Published - Jul 2015 |
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Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans. / Arif, Sayqa; Borgognone, Alessandra; Lin, Erica Lai-Sze; O'Sullivan, Aine G; Sharma, Vishal; Drury, Nigel E; Menon, Ashvini; Nightingale, Peter; Mascaro, Jorge; Bonser, Robert S; Horowitz, John D; Feelisch, Martin; Frenneaux, Michael P; Madhani, Melanie.
In: British Journal of Pharmacology, Vol. 172, No. 13, 07.2015, p. 3341-3352.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans
AU - Arif, Sayqa
AU - Borgognone, Alessandra
AU - Lin, Erica Lai-Sze
AU - O'Sullivan, Aine G
AU - Sharma, Vishal
AU - Drury, Nigel E
AU - Menon, Ashvini
AU - Nightingale, Peter
AU - Mascaro, Jorge
AU - Bonser, Robert S
AU - Horowitz, John D
AU - Feelisch, Martin
AU - Frenneaux, Michael P
AU - Madhani, Melanie
N1 - This article is protected by copyright. All rights reserved. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. Funding This work was supported by the British Heart Foundation (FS/10/030/28261).
PY - 2015/7
Y1 - 2015/7
N2 - 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 (1) ALDH2 inhibition by cyanamide or propionaldehyde and the (2) 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 (2.48±0.36 to 1.72±0.15 in pre-and post GTN infusion group, respectively; P=0.08).CONCLUSIONS AND IMPLICATIONS: In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with heart failure in vivo the role of this enzyme in nitrite bioactivation is at most modest, suggesting the involvement of other more important mechanisms.
AB - 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 (1) ALDH2 inhibition by cyanamide or propionaldehyde and the (2) 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 (2.48±0.36 to 1.72±0.15 in pre-and post GTN infusion group, respectively; P=0.08).CONCLUSIONS AND IMPLICATIONS: In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with heart failure in vivo the role of this enzyme in nitrite bioactivation is at most modest, suggesting the involvement of other more important mechanisms.
U2 - 10.1111/bph.13122
DO - 10.1111/bph.13122
M3 - Article
VL - 172
SP - 3341
EP - 3352
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 13
ER -