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(Circulation Research. 2006;99:1067.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Complex I Dysfunction and Tolerance to Nitroglycerin

An Approach Based on Mitochondrial-Targeted Antioxidants

Juan V. Esplugues, Milagros Rocha, Cristina Nuñez, Irene Bosca, Sales Ibiza, Jose R. Herance, Angel Ortega, Juan M. Serrador, Pilar D’Ocon, Victor M. Victor

From the Departamento de Farmacologia (J.V.E., M.R., P.D.), Facultad de Medicina, Universitat de Valencia; Unidad Mixta Centro Nacional de Investigaciones Cardiovasculares (CNIC)-Universitat de Valencia (C.N., I.B., S.I., J.M.S., V.M.V.); Instituto de Alta Tecnologia (J.R.H.), Parque de Investigaciones Biomedicas, Barcelona; and Unidad Central de Investigacion (A.O.), Universitat de Valencia, Spain.

Correspondence to Dr Victor M. Victor, Unidad Mixta CNIC-Valencia, Departamento de Farmacologia, Avda Blasco Ibañez 15-17, Valencia, Va 46010, Spain. E-mail vmvictor{at}cnic.es

Nitroglycerin (GTN) tolerance was induced in vivo (rats) and in vitro (rat and human vessels). Electrochemical detection revealed that the incubation dose of GTN (5x10^–6 mol/L) did not release NO or modify O₂ consumption when administered acutely. However, development of tolerance produced a decrease in both mitochondrial O₂ consumption and the K_m for O₂ in animal and human vessels and endothelial cells in a noncompetitive action. GTN tolerance has been associated with impairment of GTN biotransformation through inhibition of aldehyde dehydrogenase (ALDH)-2, and with uncoupling of mitochondrial respiration. Feeding rats with mitochondrial-targeted antioxidants (mitoquinone [MQ]) and in vitro coincubation with MQ (10^–6 mol/L) or glutathione (GSH) ester (10^–4 mol/L) prevented tolerance and the effects of GTN on mitochondrial respiration and ALDH-2 activity. Biotransformation of GTN requires functionally active mitochondria and induces reactive oxygen species production and oxidative stress within this organelle, as it is inhibited by mitochondrial-targeted antioxidants and is absent in HUVEC⁰ cells. Experiments analyzing complex I–dependent respiration demonstrate that its inhibition by GTN is prevented by mitochondrial-targeted antioxidants. Furthermore, in presence of succinate (10x10^–3 mol/L), a complex II electron donor added to bypass complex I–dependent respiration, GTN-treated cells exhibited O₂ consumption rates similar to those of controls, thus suggesting that complex I was affected by GTN. We propose that, following prolonged treatment with GTN in addition to ALDH-2, complex I is a target for mitochondrially generated reactive oxygen species. Our data also suggest a role for mitochondrial-targeted antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use.

Key Words: nitroglycerin • endothelium • oxidative stress • mitochondria • antioxidant

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