Nitrate Therapy for Stable Angina Pectoris

Parker, John D.; Parker, John O.

doi:10.1097/00132586-199902000-00007

Cited by 93 publications

(150 citation statements)

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“…have generally been attributed to its bioconversion into the relaxant agent nitric oxide (NO), which acts on the enzyme soluble guanylate cyclase (sGC). [1][2][3] However, most studies that support the existence of such a pathway have demonstrated increases of NO only when GTN concentrations considerably exceeded the plasma levels reached during clinical dosing. 4 Moreover, the involvement of other NO-related species in the actions of GTN when used at clinically relevant concentrations is also under debate.…”

mentioning

confidence: 99%

Complex I Dysfunction and Tolerance to Nitroglycerin

Esplugues

Rocha

Núñez

et al. 2006

Circulation Research

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Abstract-Nitroglycerin (GTN) tolerance was induced in vivo (rats) and in vitro (rat and human vessels). Electrochemical detection revealed that the incubation dose of GTN (5ϫ10 Ϫ6 mol/L) did not release NO or modify O 2 consumption when administered acutely. However, development of tolerance produced a decrease in both mitochondrial O 2 consumption and the K m for O 2 in animal and human vessels and endothelial cells in a noncompetitive action. GTN tolerance has been associated with impairment of GTN biotransformation through inhibition of aldehyde dehydrogenase (ALDH)-2, and with uncoupling of mitochondrial respiration. Feeding rats with mitochondrial-targeted antioxidants (mitoquinone [MQ]) and in vitro coincubation with MQ (10 Ϫ6 mol/L) or glutathione (GSH) ester (10 Ϫ4 mol/L) prevented tolerance and the effects of GTN on mitochondrial respiration and ALDH-2 activity. Biotransformation of GTN requires functionally active mitochondria and induces reactive oxygen species production and oxidative stress within this organelle, as it is inhibited by mitochondrial-targeted antioxidants and is absent in HUVEC 0 cells. Experiments analyzing complex I-dependent respiration demonstrate that its inhibition by GTN is prevented by mitochondrial-targeted antioxidants. Furthermore, in presence of succinate (10ϫ10 Ϫ3 mol/L), a complex II electron donor added to bypass complex I-dependent respiration, GTN-treated cells exhibited O 2 consumption rates similar to those of controls, thus suggesting that complex I was affected by GTN. We propose that, following prolonged treatment with GTN in addition to ALDH-2, complex I is a target for mitochondrially generated reactive oxygen species. Our data also suggest a role for mitochondrial-targeted antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use. ) have generally been attributed to its bioconversion into the relaxant agent nitric oxide (NO), which acts on the enzyme soluble guanylate cyclase (sGC). [1][2][3] However, most studies that support the existence of such a pathway have demonstrated increases of NO only when GTN concentrations considerably exceeded the plasma levels reached during clinical dosing. 4 Moreover, the involvement of other NO-related species in the actions of GTN when used at clinically relevant concentrations is also under debate. 5,6 Different enzymes have been implicated in the bioconversion of GTN, in particular, glutathione S-transferases, 7 the cytochrome p450 system, 8 and xanthine oxidoreductase, 9 although the most recent evidence suggests a central role for mitochondrial aldehyde dehydrogenase (ALDH)-2. 10 -13 The medical use of GTN is limited by the development of tolerance, which occurs following prolonged administration or the application of high doses. This phenomenon has been related to various mechanisms, in particular, desensitization of sGC, 14 and, mainly, impairment of GTN biotransformation by inhibition of ALDH-2. 10 -12 These actions, like others associated with GTN, have been linked to a...

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confidence: 99%

Complex I Dysfunction and Tolerance to Nitroglycerin

Esplugues

Rocha

Núñez

et al. 2006

Circulation Research

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“…For eccentric dosing (1,2,10), patches were applied at 8:00 AM, and exfoliated at 8:00 PM in patients with anginal attacks on effort during the daytime, whereas patches were applied after bathing, and exfoliated at 8:00 AM the next morning in patients with attacks at night or early in the morning. For continuous dosing, patches (nitroglycerin) were applied for 24 h, and an oral agent (ISMN) was administered in the morning and evening twice a day.…”

Section: Methodsmentioning

confidence: 99%

“…Eccentric dosing does not prevent cardiac events (22)(23)(24). However, the appearance of tolerance, rebound phenomena, neurohumoral regulation, and enhancement of vascular sensitivity have all been associated with the dosing of nitrates (1,(25)(26)(27)(28).…”

Section: Tolerance To Nitratesmentioning

confidence: 99%

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Inhibition of Nitrate Tolerance without Reducing Vascular Response during Eccentric Dosing of Nitrates

et al. 2006

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It has been reported that the nitrate tolerance related to continuous dosing of nitrates reduces drug efficacy, and therefore eccentric dosing of nitrates is recommended. In this study, we investigated the appearance of nitrate tolerance related to continuous dosing of nitrates and prevention of nitrate tolerance during eccentric dosing by comparing the grade of coronary dilatation after sublingual nitroglycerin. Of 26 patients with ischemic heart disease who underwent elective cardiac catheterization, 8 patients were continuously administered nitrates, 8 patients were eccentrically administered nitrates, and 10 patients were not treated. We compared the coronary response to sublingual nitroglycerin among the 3 groups. In a coronary vessel without significant stenosis, the coronary vessel area, coronary lumen area, and mean coronary blood flow velocity after sublingual nitroglycerin were measured using intravascular ultrasound (IVUS). In the continuous dosing group, the maximal rate of change in the vessel area after sublingual nitroglycerin was 105 ± 1

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“…It is highly lipophilic and has a half-life of 3 to 5 hours, even though the duration of action is higher. It is indicated in cases of high blood pressure [5], angina [6] and some arrhythmias [7,8], frequently with two or more daily doses taken orally. It was one of the first beta-blockers that showed benefits.…”

Section: Most Frequently Used Beta-blockersmentioning

confidence: 99%

Nebivolol: Does the key lie in β3 agonism?

Arazi¹,

Gonzalez²

2017

Vascul Dis Ther

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Beta-blockers are drugs indicated in the treatment of multiple cardiovascular pathologies. The review highlights the mechanisms of action of Nebivolol and its particular potential effect on β3 receptors that increases nitric oxide that may mark very significant differences, which are traduced to benefits in clinical results.Nebivolol has an special place in the treatment of adrenergic hypertension associated with tachycardia and emotional stress, more frequently in young individuals, and may be considered adequate even in patients with glucose and lipid metabolism disorders due to its pleiotropic effect.In patients with heart failure, Nebivolol showed effectiveness and safety in patients over 75 years old.Nebivolol showed a reduction of cardiomyocyte apoptosis and improvement of contractile function through a mechanism related to β3 receptor agonism after an acute coronary syndrome.Because of all these actions Nebivolol should be considered not only a third-generation Beta-blocker.

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Nitrate Therapy for Stable Angina Pectoris

Cited by 93 publications

References 0 publications

Complex I Dysfunction and Tolerance to Nitroglycerin

Complex I Dysfunction and Tolerance to Nitroglycerin

Inhibition of Nitrate Tolerance without Reducing Vascular Response during Eccentric Dosing of Nitrates

Nebivolol: Does the key lie in β3 agonism?

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