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Nitroglycerin reduces myocardial oxygen consumption during exercise despite vascular tolerance

¹Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; and ²Department of Pharmacology, Center of Biomedical Research Excellence, University of Nevada School of Medicine, Reno, Nevada

Submitted 7 June 2005 ; accepted in final form 28 October 2005

The long-term benefits of nitroglycerin (NTG) therapy are limited by the development of vascular tolerance and endothelial dysfunction in conductance coronary arteries. We have determined whether nitrate tolerance extends to NTG effects on myocardial O₂ consumption (MO₂) and the ability of endogenous nitric oxide (NO) to modulate MO₂ during exercise. In chronically instrumented dogs (n = 8), hemodynamic and MO₂ responses to treadmill exercise were measured before, during tolerance (3 and 7 days of NTG delivery), and 7 days after NTG withdrawal. Acute NTG delivery caused a parallel downward shift of the MO₂-triple product (TP) relations and reversed the disproportionate increases in MO₂ caused by the blockade of NO formation. After 7 days of continuous transdermal NTG delivery, vascular tolerance was displayed as a >75% reduction of coronary blood flow (CBF) responses to NTG boluses. Despite vascular nitrate tolerance, MO₂-TP relations were shifted downward compared with pre-NTG exercise. Seven days after NTG withdrawal, vascular responses to boluses of NTG had recovered from tolerance, and MO₂-TP relations during exercise were back to pre-NTG level. At that time, blockade of NO formation failed to alter MO₂-TP relations. Thus NTG caused a sustained reduction of cardiac MO₂, independent of metabolic demand during exercise, despite tolerance of the coronary microcirculation. NTG-induced vascular tolerance and MO₂ reductions were reversible by NTG withdrawal, but endogenous NO-dependent modulation of O₂ consumption was severely impaired.

nitrates; exercise; nitric oxide

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