Nitric oxide as an antioxidant

Kanner, J., Harel, S., and Granit, R., 1991, Nitric oxide as an antioxidant. Arch. Biochem. Biophys. 289 130-136. 

The administration of Qio or quercetin to rats protected against endotoxin-induced shock in rat brain [252]. It was found that the pretreatment with these antioxidants diminished the shock-induced increase in brain MDA and nitric oxide levels. Interesting data have been obtained by Yamamura et al. [253] who showed that ubiquinone Qi0 is able to play a double role in mitochondria. It was found that on the one hand, Q10 enhanced the release of hydrogen peroxide from antimycin A- or calcium-treated mitochondria, but on the other hand, it inhibited mitochondrial lipid peroxidation. It was proposed that Q10 acts as a prooxidant participating in redox signaling and as an antioxidant suppressing permeability transition and cytochrome c release. 

Vitamin C appears to be more promising. Theoretically, this vitamin functions as an antioxidant that would enhance the synthesis or prevent the breakdown of nitric oxide, a naturally occurring gas produced in the lining of the arteries that keeps those vessels flexible and more capable of vasodilation. Studies have shown reductions in systolic blood pressure though not in diastolic pressure, when subjects were treated with vitamin C. A randomized, placebo-controlled trial with thirty-nine patients yielded nice results. Subjects took a 2 gram loading dose and then 500 mg daily for thirty days. Systolic blood pressure was reduced by 13 mm Hg, but vitamin C had no effect on diastolic pressure. 

Calcium dobesilate is an antioxidant that has been used to treat diabetic retinopathy, in which it slows progression of the disease during long-term oral treatment by reducing microvascular permeability, leading to improved visual acuity (1). It not only acts as an antioxidant but also stimulates endothelial production of nitric oxide. 

A-Acetylcysteine is administered in the ace-toaminophen toxicity. It replenishes the hepatic stores of glutathione (Chapter 17). A-Acetylcysteine is also used in the treatment of pulmonary diseases including cystic fibrosis (Chapter 12). In patients with chronic renal insufficiency, prophylactic oral administration of A-Acetylcysteine have been used in the prevention of further renal impairment due to administration of radiographic contrast agents. In this setting presumably A-Acetylcysteine functions as an antioxidant and augments the vasodilatory effect of nitric oxide via the formation of S-nitrosothiol (Chapter 17). 

Recently there has been a widespread interest in thiol antioxidants, glutathione, and related enzymes, hydrogen sulfide, sesame oil components, L-arginine (L-Arg) and other nitric oxide modulators [129]. While the former compounds may have direct antioxidant actions, L-Arg is both a direct precursor of nitric oxide as well as an antioxidant [110]. These compounds may assist in lowering high blood pressure. 

Nitric oxide (NO) produced by NO synthase in the endothelium is important in the maintenance of vascular tone it suppresses the expression of proinflammatory cytokines, adhesion molecules, and MCP-1. It also inhibits platelet adhesion, maintains the integrity of the arterial wall, and acts as an antioxidant. Vitamin E can reduce the inhibition of NO synthase by reactive oxygen species, thus maintaining NO production, either through its antioxidant activity or perhaps by suppressing PKC activity in smooth muscle. 

Belkner et al. [32] demonstrated that 15-LOX oxidized preferably LDL cholesterol esters. Even in the presence of free linoleic acid, cholesteryl linoleate continued to be a major LOX substrate. It was also found that the depletion of LDL from a-tocopherol has not prevented the LDL oxidation. This is of a special interest in connection with the role of a-tocopherol in LDL oxidation. As the majority of cholesteryl esters is normally buried in the core of a lipoprotein particle and cannot be directly oxidized by LOX, it has been suggested that LDL oxidation might be initiated by a-tocopheryl radical formed during the oxidation of a-tocopherol [33,34]. Correspondingly, it was concluded that the oxidation of LDL by soybean and recombinant human 15-LOXs may occur by two pathways (a) LDL-free fatty acids are oxidized enzymatically with the formation of a-tocopheryl radical, and (b) the a-tocopheryl-mediated oxidation of cholesteryl esters occurs via a nonenzymatic way. Pro and con proofs related to the prooxidant role of a-tocopherol were considered in Chapter 25 in connection with the study of nonenzymatic lipid oxidation and in Chapter 29 dedicated to antioxidants. It should be stressed that comparison of the possible effects of a-tocopherol and nitric oxide on LDL oxidation does not support importance of a-tocopherol prooxidant activity. It should be mentioned that the above data describing the activity of cholesteryl esters in LDL oxidation are in contradiction with some earlier results. Thus in 1988, Sparrow et al. [35] suggested that the 15-LOX-catalyzed oxidation of LDL is accelerated in the presence of phospholipase A2, i.e., the hydrolysis of cholesterol esters is an important step in LDL oxidation. 

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