Randomized, Double-Blind, Placebo-Controlled Study of Ascorbate on the Preventive Effect of Nitrate Tolerance in Patients With Congestive Heart Failure

Abstract

These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

“…A decrease in platelet steady-state cGMP has been previously described in response to the continuous administration of organic nitrates. 7,12 In the present studies, platelet cGMP concentration increased in tandem with NO release in response to continuous nitrate administration, whereas NO release was suppressed and cGMP concentration remained unchanged with coadministration of ascorbate. Although methodological considerations and differing treatment regimens may account for the discrepant findings, Martin et al 36 have highlighted that platelet cGMP levels used either as an index of NTG effect or as a biochemical marker of tolerance require cautious interpretation.…”

“…It has been proposed that decreased bioavailability of NO, derived from both endogenous sources and NTG, occurs as a consequence of the interaction of NO with superoxide and contributes to the development of tolerance. Enhancing antioxidant status and the scavenging of O 2 ·Ϫ with ascorbate has been shown not only to attenuate the development of hemodynamic tolerance 4,5,12 but also the platelet activation accompanying continuous nitrate administration. 4,5 These indirect observations suggest that reactive oxygen species O 2 ·Ϫ and NO influence cellular redox-sensitive signaling cascades that play an important role in blunting the therapeutic efficacy of organic nitrates.…”

Mechanisms Underlying Nitroglycerin-Induced Superoxide Production in Platelets

“…13 The present study also indicates that concomitant treatment with vitamin C was able to inhibit NTG-induced stimulation of superoxide production in platelets from NTG-treated subjects. This report fits with previous observations, where vitamin C was able to prevent the development of hemodynamic tolerance in patients with congestive heart failure 24 and in healthy volunteers, 13 as well as to restore the activity of the cGMP-dependent protein kinase in vascular tissue. 25 Because the prevention of tolerance by vitamin C has been shown to be associated with a reduction in vascular superoxide levels, 25 it is conceivable that the inhibitory effects of vitamin C on platelet-superoxide production observed in the present study is due to free radical scavenging effects.…”

EUK-8, a Superoxide Dismutase and Catalase Mimetic, Reduces Cardiac Oxidative Stress and Ameliorates Pressure Overload-Induced Heart Failure in the Harlequin Mouse Mutant

“…Reactive oxygen species have been implicated in a wide range of disorders, including Alzheimer's disease, Parkinson's disease, myocardial arrhythmias, and heart failure, regardless of etiology (21,28). Proof of principle in animal models has been obtained with antioxidants, notably vitamins C and E (29,30), albeit at higher doses than used in clinical trials (31,32). Consequently, many studies have attempted to ameliorate or attenuate the progression of cardiovascular disease by chronic or acute antioxidant treatment.…”