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

Sayqa Arif; Alessandra Borgognone; Erica Lai-Sze Lin; Aine G O'Sullivan; Vishal Sharma; Nigel E Drury; Ashvini Menon; Peter Nightingale; Jorge Mascaro; Robert S Bonser; John D Horowitz; Martin Feelisch; Michael P Frenneaux; Melanie Madhani

doi:10.1111/bph.13122

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

Sayqa Arif, Alessandra Borgognone, Erica Lai-Sze Lin, Aine G O'Sullivan, Vishal Sharma, Nigel E Drury, Ashvini Menon, Peter Nightingale, Jorge Mascaro, Robert S Bonser, John D Horowitz, Martin Feelisch, Michael P Frenneaux, Melanie Madhani

Applied Medicine

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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	https://doi.org/10.1111/bph.13122
Publication status	Published - Jul 2015

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Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans
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Arif, S., Borgognone, A., Lin, E. L-S., O'Sullivan, A. G., Sharma, V., Drury, N. E., Menon, A., Nightingale, P., Mascaro, J., Bonser, R. S., Horowitz, J. D., Feelisch, M., Frenneaux, M. P., & Madhani, M. (2015). Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans. British Journal of Pharmacology, 172(13), 3341-3352. https://doi.org/10.1111/bph.13122

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

Arif, S, Borgognone, A, Lin, EL-S, O'Sullivan, AG, Sharma, V, Drury, NE, Menon, A, Nightingale, P, Mascaro, J, Bonser, RS, Horowitz, JD, Feelisch, M, Frenneaux, MP & Madhani, M 2015, 'Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans', British Journal of Pharmacology, vol. 172, no. 13, pp. 3341-3352. https://doi.org/10.1111/bph.13122

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. / Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 13. pp. 3341-3352.

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title = "Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans",

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.",

author = "Sayqa Arif and Alessandra Borgognone and Lin, {Erica Lai-Sze} and O'Sullivan, {Aine G} and Vishal Sharma and Drury, {Nigel E} and Ashvini Menon and Peter Nightingale and Jorge Mascaro and Bonser, {Robert S} and Horowitz, {John D} and Martin Feelisch and Frenneaux, {Michael P} and Melanie Madhani",

note = " This article is protected by copyright. All rights reserved. {\textcopyright} 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). ",

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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.

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DO - 10.1111/bph.13122

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