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Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans
Author(s) -
Arif Sayqa,
Borgog Alessandra,
Lin Erica LaiSze,
O'Sullivan Aine G,
Sharma Vishal,
Drury Nigel E,
Me Ashvini,
Nightingale Peter,
Mascaro Jorge,
Bonser Robert S,
Horowitz John D,
Feelisch Martin,
Frenneaux Michael P,
Madhani Melanie
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13122
Subject(s) - nitrite , vasodilation , nitric oxide , aldh2 , in vivo , pharmacology , aldehyde dehydrogenase , hypoxia (environmental) , chemistry , biochemistry , endocrinology , medicine , enzyme , oxygen , biology , nitrate , microbiology and biotechnology , organic chemistry
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 ( ALDH 2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. Experimental Approach The role of ALDH 2 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) ALDH 2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance‐independent inactivation of ALDH 2 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 ALDH 2 inhibitors. Key Results Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH 2 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 ALDH 2. 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.