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(Circulation Research. 2005;97:1063.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO

Cristina Núñez^*, Víctor M. Víctor^*, Remedios Tur, Alberto Alvarez-Barrientos, Salvador Moncada, Juan V. Esplugues, Pilar D’Ocón

From the Departamento de Farmacología (J.V.E.) and Unidad Mixta Universidad de Valencia–Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (C.N., V.M.V., R.T., P.D.), Facultad de Medicina, Universidad de Valencia, Blasco Ibáñez, Valencia, Spain; Unidad de Citometria, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (A.A.-B.), C/Melchor Fernández Almagro, Madrid, Spain; and The Wolfson Institute for Biomedical Research (S.M.), University College London, United Kingdom.

Correspondence to Pilar D’Ocón, Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Avda Vicent Andres Estelles s/n, Burjassot, 46100 Valencia, Spain. E-mail doconp{at}uv.es

It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the Michaelis constant (K_m) for O₂. GTN did not produce similar effects, and although clinically relevant concentrations of this compound caused clear, concentration-related relaxations, there was neither any increase in NO-related fluorescence nor an augmented K_m for O₂. The nature of these differences suggests that these concentrations of GTN do not release free NO but probably a different species that, although it interacts with soluble guanylyl cyclase in vascular smooth muscle, does not inhibit O₂ consumption by vascular mitochondria.

Key Words: glyceryl trinitrate • nitric oxide • mitochondria • vascular relaxation • NO donors

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