Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

/pdf/flow-mediated-endothelial-mechanotransduction-281f54bq52.pdf

Flow-mediated endothelial mechanotransduction

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

Endothelium-derived relaxing factor (EDRF) activity has been attributed to the highly labile nitric oxide radical (NO). In view of the fact that the plasma and cellular milieux contain reactive species that can rapidly inactivate NO, it has been postulated that NO is stabilized by a carrier molecule that preserves its biological activity. Reduced thiol species are candidates for this role, reacting readily in the presence of NO to yield biologically active S-nitrosothiols that are more stable than NO itself. Because sulfhydryl groups in proteins represent an abundant source of reduced thiol in biologic systems, we examined the reaction of several sulfhydryl-containing proteins of diverse nature and function upon exposure to authentic NO and EDRF. We demonstrate that S-nitroso proteins form readily under physiologic conditions and possess EDRF-like effects of vasodilation and platelet inhibition. These observations suggest that S-nitrosothiol groups in proteins may serve as intermediates in the cellular metabolism of NO and raise the possibility of an additional type of cellular regulatory mechanism.

https://www.pnas.org/content/pnas/89/1/444.full.pdf

S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds

We designed a novel system to study flow-mediated endothelium-dependent vasodilation. Vascular rings of rabbit thoracic aorta were mounted for isometric tension recording in a flow chamber filled with physiological saline solution. The flow chamber contained a stir bar and was mounted on a magnetic stirrer to induce vortical flow. Norepinephrine (NE, 10(-6) M) induced contraction of the vascular rings. Bovine endothelial cells on microcarrier beads added to the chamber had little effect on contraction to NE in the absence of flow. Flow induced endothelium-dependent relaxation of the vascular rings that was dependent on the flow rate. Relaxations were annulled or reversed to a contraction with methylene blue, bovine hemoglobin, or N-monomethyl-L-arginine. Conversely, N-acetyl-L-cysteine augmented the flow-mediated relaxation. Furthermore, in the presence of N-acetyl-L-cysteine, the half-life of the endothelium-dependent relaxing factor was increased. In conclusion, the stimulus of flow induces the release by endothelial cells of a diffusible, short-lived factor with the attributes of a nitrovasodilator. The action of this endogenous vasodilator is augmented by the reduced thiol N-acetyl-L-cysteine.

Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol.

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.

Methylene blue reverses endotoxin-induced hypotension.

Methylene Blue Reverses Endotoxin-Induced Hypotension

We studied the effects of a unique vasoactive agent, S-nitrosocaptopril (SnoCap), in an anesthetized canine preparation. We have previously demonstrated that this agent manifests the properties of both a direct nitrovasodilator and an angiotensin-converting enzyme inhibitor in vitro. The present investigation was performed to evaluate the effects of SnoCap in vivo. Intravenous administration of SnoCap produced immediate reductions in blood pressure and significantly attenuated the pressor response to angiotensin I. Equieffective doses of SnoCap had a greater duration of action after intravenous bolus administration compared with nitroglycerin (15.3 +/- 2.6 min vs. 3.2 +/- 0.5 min, respectively; P less than .01); importantly, this effect was apparent despite the relatively short plasma half-life of the compound (T1/2 alpha = 0.48 min, T1/2 beta = 5.54 min) and did not appear to be the result of inhibition of angiotensin-converting enzyme. Another unexpected property of SnoCap was that its nitrovasodilator effect was 10- to 30-fold less potent than nitroglycerin when administered as a bolus, but more efficacious when given by continuous infusion. These data support the view that SnoCap is a vasoactive substance with the properties of a nitrovasodilator and an angiotensin-converting enzyme inhibitor, as well as the unique properties of an extended duration of action and greater potency when administered by continuous intravenous infusion than by bolus injection. The clinical utility of this compound in humans and in individuals with specific disease states remains to be demonstrated.

The hemodynamic effects of S-nitrosocaptopril in anesthetized dogs.

Flow activates a specific endothelial potassium channel to release an endogenous nitrovasodilator

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