The Oxidative Stress Concept of Nitrate Tolerance and the Antioxidant Properties of Hydralazine

Autor: Matthias Oelze, Alexander Mülsch, Thomas Münzel, Andreas Daiber, Hanke Mollnau, Ulrich Hink, Ascan Warnholtz
Rok vydání: 2005
Předmět:
Male
medicine.medical_specialty
Maximum Tolerated Dose
genetic structures
Drug Resistance
Myocardial Ischemia
Pharmacology
Coronary Angiography
medicine.disease_cause
Severity of Illness Index
Drug Administration Schedule
Nitric oxide
Nitroglycerin
chemistry.chemical_compound
Internal medicine
medicine
Animals
Humans
Drug Interactions
chemistry.chemical_classification
Clinical Trials as Topic
Reactive oxygen species
Dose-Response Relationship
Drug
business.industry
Hydralazine
Long-Term Care
eye diseases
Disease Models
Animal
Oxidative Stress
chemistry
Heart Function Tests
Exercise Test
Cardiology
Female
Vascular Resistance
Endothelium
Vascular
sense organs
Sodium nitroprusside
Cardiology and Cardiovascular Medicine
Soluble guanylyl cyclase
business
Nicotinamide adenine dinucleotide phosphate
Peroxynitrite
Oxidative stress
medicine.drug
Zdroj: The American Journal of Cardiology. 96:25-36
ISSN: 0002-9149
Popis: The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O 2 − ) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C contribute to the development of tolerance. Nicotinamide adenine dinucleotide phosphate oxidase and the uncoupled endothelial nitric oxide synthase may be O 2 − -producing enzymes. Nitric oxide (NO) and O 2 − , both derived from NTG and the vessel wall, form peroxynitrite in a diffusion-limited rapid reaction. Peroxynitrite, O 2 − , or both may be responsible for the development of nitrate tolerance and cross-tolerance to direct NO donors (eg, sodium nitroprusside, sydnonimines) and endothelium-dependent NO synthase-activating vasodilators. Hydralazine is an efficient reactive oxygen species (ROS) scavenger and an inhibitor of O 2 − generation. When given concomitantly with NTG, hydralazine prevents the development of nitrate tolerance and normalizes endogenous rates of vascular O 2 − production. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates NTG (ie, mitochondrial aldehyde dehydrogenase isoform 2 [ALDH2]) and mitochondria as potential sources of ROS. NTG-induced ROS inhibit the bioactivation of NTG by ALDH2. Both mechanisms increase oxidative stress and impair NTG bioactivation, and now converge at the level of ALDH2 to support a new theory for NTG tolerance and NTG-induced endothelial dysfunction. The consequences of these processes for NTG downstream targets (eg, soluble guanylyl cyclase, cyclic guanosine monophosphate–dependent protein kinase), toxic effects contributing to endothelial dysfunction (eg, prostacyclin synthase inhibition) and novel applications of the antioxidant properties of hydralazine are discussed.
Databáze: OpenAIRE
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