NO deficiencies in the body may present as a variety of different health conditions. Most commonly, individuals with low levels of NO will have signs and symptoms of cardiovascular disease such as atherosclerosis, hypertension, CAD, and stroke. In addition, NO deficiency can present as inflammatory conditions or erectile dysfunction. Because NO produced by white blood cells is bacteriocidal and tumoricidal, individuals with deficiencies may present with infections and possibly malignancies.
Because of their physiologic effects on the body, manipulation of NO levels can provide avenues for health modification. Cardiovascular diseases such as atherosclerosis, stroke, hypertension, and CAD can be attenuated by increases in NO synthesis and activity. Anemia, cancer, diabetes, and erectile dysfunction can also be ameliorated by NO manipulation. Both natural therapies and pharmaceuticals can augment NO bioavailability.
Atherosclerosis, hypertension, and CAD have all been shown to have a connection to endothelial dysfunction, which often is the result of lowered NO levels. Platelet aggregation and adhesion as well as arterial stiffness are also affected by NO activity. These cardiovascular conditions have been shown to be the result of abnormal NOS expression, decreased NO availability, or resistance to endothelium-dependent vasodilators.14,15 Studies have indicated that NO, when combined with low oxygen levels as a result of circulatory insufficiency, sensitizes neurons to hypoxia-induced death. Thus, neurons in the brain may be more likely to be damaged from ischemic or hypoxic damage from NO produced as a result of excitotoxicity or inflammation.16 However, NO combined with normal oxygen levels does not increase neuronal cell death.17 In addition, NO increases cerebral blood flow, which may actually mean that NO can be protective during an ischemic attack.18 In short, NO's modulatory effects appear to have a built-in protective effect regardless of oxygen status. With increased NO levels, oxygen delivery is enhanced, thus providing protection from otherwise-ischemic conditions.
Individuals with various forms of anemia have been shown to experience endothelial-cell dysfunction. Pulmonary hypertension—the result of such dysfunction—is the leading cause of death in both sickle-cell anemia and thalassemia, both of which have chronic anemia and intravascular hemolysis as their hallmarks. Chronic intravascular hemolysis is associated with endothelial dysfunction and results in decreased NO availability with a lack of vasodilation.19
Individuals with diabetes are more vulnerable to oxidative stress, leading to an increase in superoxide anions and a subsequent decrease in NO bioavailability.20 Endothelium-dependent vasodilation is impaired in individuals with either type 1 or type 2 diabetes. Many explanations have been suggested for this impairment, including abnormalities in substrate availability or signal transduction, release of endothelium-derived relaxing factors, destruction of endothe-lium-derived relaxing factors, decreased sensitivity of the vascular smooth muscle to endo-thelium-derived relaxing factors, and increased release of endothelium-constricting factors.21 Studies have shown that NO increases basal and insulin-stimulated glucose uptake in skeletal muscle in rats with type 2 diabetes. However, high concentrations of NO inhibit this uptake.22
Erectile dysfunction is significantly increased in individuals with cardiovascular disease, diabetes, and hypercholesterolemia. Erectile dysfunction is believed to be a condition of vascular origin that may be caused by endothelial damage or dysfunction. Such damage has been correlated with oxidative stress and the resulting decrease in NO.23 Research has demonstrated that men with erectile dysfunction and without overt cardiovascular disease or diabetes do, in fact, have endothelial dysfunction.24 Although there are many noncirculatory forms of erectile dysfunction—such as psychogenic, drug-induced, and other types—NO modulation helps patients who experience the condition as a result of circulatory problems.
The role of NO in neoplastic disease is controversial; research indicates that inducible NOS may have either negative or positive influences on metastasis, malignant transformation, and angiogenesis. NO derived from macrophages has a potentially cytotoxic action on malignant cells.25 Studies indicate that tumor cells that produce high levels of NO undergo apoptosis. Induction of inducible NOS in sarcoma cells increases NO such that the tumors studied showed complete regression.26
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