While there are clearly a large number of natural therapies that can address NO dysfunctions, there are also pharmaceuticals that are aimed at the problem. Nitroglycerin, sodium ni-troprusside, and other nitrates and nitrites increase NO in the endothelium and cause vasodilation of the arteries. These drugs are used to treat hypertensive crisis, angina pectoris, acute myocardial infarction, and heart failure. Tadalafil (Cialis), vardenafil (Levitra), and sildenafil (Viagra) are pharmaceuticals prescribed for erectile dysfunction. They are phosphodiesterase inhibitors that cause vasodilation and hypotension. They are contraindicated for patients who are taking nitrates because NO increases cGMP by activating the enzyme guanyl cyclase and phosphodiesterase metabolizes cGMP. In other words, the enhancement of NO activity by pharmaceuticals may potentiate the effects of the nitrates.67 It is prudent to use these pharmaceuticals cautiously, especially with patients who have leukemia, sickle-cell anemia, and other underlying health conditions. Some studies have shown that NO may play a significant role in increasing the chemosensitivity of cancer cells. Via the cGMP pathway, NO may be used therapeutically to improve the efficacy of chemotherapeutic agents such as doxorubicin.68 Statin drugs—or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors—are prescribed to lower cholesterol and decrease the risk of cardiovascular disease and stroke. Studies performed on the statin drug Mevastatin have shown that some of its cardioprotective benefits are the result of this drug's ability to increase endothelial NOS, which has been shown to improve cerebral blood flow in addition to relaxing vascular smooth muscle and inducing vasodilation.69 Steroid hormones, such as estrogen and DHEA, have also been shown to be cardioprotective and affect NO activity. Studies using 17 beta-estradiol showed an increase in activity of endothelial NOS, which may at least partially explain the antiatherosclerotic effects of estrogen.70
MAKING "NO"-POSITIVE CHANGES IN DIET AND LIFESTYLE
NO levels can be manipulated by dietary intake of specific nutrients such as folic acid, L-arginine, fish oil, and soy foods. The Mediterranean diet—which is high in vegetables, olive oil, red wine, and fish—has been shown to improve endothelial function as well.71 Eicosa-pentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 fatty acids found in the oils offish such as salmon, cod, and mackerel. These fatty acids compete with arachidonicacid in the lipo-oxygenase and cyclooxygenase pathways, leading to a decrease in inflammatory eicosanoids.72-74 Fish oils high in DHA and EPA reduce the production of pro-inflammatory cytokines including interleukin-1, interleukin-2, and tumor necrosis factor.75-77 Cofactors for NOS such as vitamins B2 and B3 and folic acid will improve NO production. In addition, antioxidants such as vitamin C, vitamin E, glutathione, and alpha-lipoic acid improve NO levels by decreasing reactive oxygen species.78 Vitamins B6 and B12 can decrease cardiovascular risk factors further by decreasing homocysteine. Physical activity has been shown to increase NO activity.79 Studies have indicated that even low-frequency exercise improves endothelial function as well as decreasing blood pressure (at least in patients with mild hypertension) and raising high-density lipoprotein levels.80
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