Results from in vitro experiments suggest that development of nitrate tolerance is due to a depletion of vascular thiol compounds (ie, cysteine and glutathione [GSH]) necessary for the bioconversion of organic nitrates. However, it is unknown whether in vivo tolerance development is associated with changes in thiol levels. This study measures plasma and vessel tissue GSH and cysteine levels in ...

With glycerol trinitrate (GTN) as the prototype, nitrates represent one of the safest and most rapidly effective pharmacological means to reduce acute symptoms of myocardial ischemia attributable to obstructive coronary disease. This has led, over the years, to the development of long-acting oral and topical preparations. However, efficacy with chronic administration is more difficult to achiev...

Nitroglycerin (NTG) is an important cardiovascular agent, but tolerance during continuous administration limits its clinical utility. Increased vascular superoxide production may mediate nitrate tolerance via a reduction in nitric oxide availability. Because superoxide anion and nitric oxide react avidly to form peroxynitrite, an aggressive cellular toxicant that nitrates protein tyrosine resid...

PRECONDITIONING IS CHARACTERIZED by a remarkable ability to adapt to ischemic stress in a variety of organs (or tissues) with the highest clinical impact in the heart and brain (10, 24). Preconditioning can be induced by several interventions such as ischemia (blockade of blood supply), rapid pacing (increased oxygen demand), or administration of pharmacological agents (pharmacological precondi...

To better understand the mechanism of nitrate tolerance in patients with congestive heart failure, 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion, mean arterial pressure had returned to baseli...

BACKGROUND In experimental animal models, long-term in vivo treatment with nitroglycerin (NTG) induces both endothelial dysfunction and tolerance to nitrates. However, it is still controversial whether nitrate tolerance in humans is associated with both endothelial dysfunction and impaired vascular response to nitrovasodilator-derived NO. METHODS AND RESULTS Patients undergoing elective bypas...

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 (MV(O2)) and the ability of endogenous nitric oxide (NO) to modulate MV(O2) during exercise. In chronically instrumented dogs (n = ...

OBJECTIVES This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure. BACKGROUND The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade wit...