Biochemical, Hemodynamic, and Vascular Evidence Concerning the Free Radical Hypothesis of Nitrate Tolerance

Milone, Stephen D.; Pace-Asciak, Cecil R.; Reynaud, Dénis; Azevêdo, Eduardo Ribeiro de; Newton, Gary E.; Parker, John D.

doi:10.1097/00005344-199905000-00002

Cited by 25 publications

(19 citation statements)

References 38 publications

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“…The translation of these results to clinical practice is limited by the fact that oral administration of an effective antioxidant has proved to be more complicated than initially thought. 98 This failure appears to mirror the lack of efficacy of oral antioxidants in improving cardiovascular prognosis. 99 Although intra-arterial administration of high-dose vitamin C consistently appears to reverse tolerance, 66 a positive effect of oral formulations appears to be much less reproducible.…”

Section: Antioxidantsmentioning

confidence: 99%

“…99 Although intra-arterial administration of high-dose vitamin C consistently appears to reverse tolerance, 66 a positive effect of oral formulations appears to be much less reproducible. 98 The development of more potent, more targeted, and more bioavailable antioxidants, particularly targeted at the mitochondria will address these issues 54 (Figure 9). …”

Section: Antioxidantsmentioning

confidence: 99%

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Nitrate Therapy

2011

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A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

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Section: Antioxidantsmentioning

confidence: 99%

Section: Antioxidantsmentioning

confidence: 99%

Nitrate Therapy

2011

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“…3 In vivo, supplementation with the antioxidant vitamin C prevented tolerance both in animal and in human studies, 10,11 despite being unable to reverse it. 12 In sum, there is now a body of evidence suggesting that some nitrates, particularly GTN, are associated with increased vascular oxygen free radical generation, and that these responses are involved in the genesis of tolerance. The sources of ·O 2 Ϫ that have been proposed include membrane NAD(P)H and xanthine oxidases, mitochondria, and the endothelial nitric oxide synthase (NOS).…”

Section: The Vascular Free Radical Hypothesis Of Nitrate Tolerancementioning

confidence: 99%

The Puzzle of Nitrate Tolerance

Gori

Parker

2002

Circulation

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“…Baseline forearm blood flow (FBF; Hokanson Inc) was measured with forearm venous occlusion strain gauge plethysmography, as previously described. 5,16 Subjects were subsequently given the first dose of GTN in the form of a 0.6 mg/h transdermal patch (Transderm Nitro, Ciba Geigy), and repeat standing blood pressure and heart rate measurements were taken 3 hours later.…”

Section: Study Daymentioning

confidence: 99%

Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance

et al. 2001

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Background-In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. Methods and Results-On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 g/min), N-monomethyl-L-arginine (1, 2, and 4 mol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (PϽ0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (PϽ0.05). Conclusion-Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

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Biochemical, Hemodynamic, and Vascular Evidence Concerning the Free Radical Hypothesis of Nitrate Tolerance

Cited by 25 publications

References 38 publications

Nitrate Therapy

Nitrate Therapy

The Puzzle of Nitrate Tolerance

Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance

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