Table 1. Dietary factors regulating NO production.
| Dietary factor | Regulation of NO production (health) | Relation to disease | Reference |
|---|---|---|---|
| Protein and amino acids | |||
| Dietary protein | Low protein results in decreased NO production by reducing arginine availability, and reducing NOS expression and cofactor availability | Cardiovascular abnormalities and compromised immune function with protein deficiency | [34, 35] |
| Arginine | Dose-dependent stimulation of NO production, as substrate of NOS by increasing BH4 synthesis and NOS2 expression; arginine reduces glucosamine and ROS formation; arginine deficiency results in superoxide formation by NOS | Arginine supplementation improves endothelial relaxation in patients with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity, insulin resistance, and aging) or patients with cardiovascular disorders (coronary and peripheral artery disease, ischemia/reperfusion injury, heart failure, and erectile dysfunction); conflicting ideas on its utilization in inflammatory conditions. | [9, 34-37] |
| Citrulline | Stimulates NO production via de novo arginine production | Citrulline supplementation can reduce blood pressure in hypertension; supplementation can be particularly useful for patients with elevated ammonia concentrations, impaired arginine transport, or enhanced intestinal arginine catabolism, or in trauma/after surgery | [26, 34, 35, 38] |
| Glutamine | Inhibition of endothelial NO production (by activating glucosamine synthetic pathway); required for adequate expression of NOS2 in macrophages; impedes citrulline utilization by macrophages | Lowered glutamine levels, occurring in catabolic conditions such as infection, injury, sepsis, trauma, and cancer contributes to impaired host defense to immunologic challenge; glutamine needed under conditions of immunological activation to kill pathogenic microorganisms; suggested to control excessive NO production | [34, 35, 38] |
| Glutamate | Increase of neuronal NO production through activation of NOS1 (by stimulating Ca2+ influx); regulating NOS2 expression in brain | Explanation for long-standing glutamate neurotoxicity | [35] |
| Lysine | Inhibition of NO production by reducing intracellular arginine transport (especially at relatively low plasma arginine) in various cell types | [34, 35, 39] | |
| Glycine | Binds to NMDA receptor resulting in Ca2+ influx and NOS1 activation for NO production; reduces NOS2 activity | Attenuates hepatic injury under inflammatory conditions | [34, 35] |
| Taurine | Stimulates NO production by cNOS; Inhibits NOS2 expression and subsequent NO production in various cell types | Suggested to protect the host against oxidant-induced tissue damage | [34, 35] |
| Homocysteine/Methionine | Dose-dependent decrease in NO production, which seems due to elevated ADMA; promotes NOS2 expression in vascular smooth muscle cells | Impaired endothelium-dependent relaxation with high homocysteine; increased NOS2-induced oxidative stress may be responsible for atherosclerosis in obese and diabetics | [34, 35, 40] |
| Carbohydrates | |||
| Glucose | NO production is dependent of glucose (as source of NADPH), but hyperglycemia inhibits NO production by NOS3 in large vessels (by activating the glucosamine-synthetic pathway) while stimulates NO in capillaries; inhibition of NOS2 mediated NO production | Hyperglycemia has a role e in development and progression of endothelial dysfunction in diabetes and induction of insulin insensitivity; role in pathogenesis retinal degradation, beta-cell dysfunction and nephropathy in diabetes | [35, 37] |
| Fructose | Inhibition of endothelial NO suggested, which could be due to BH4 deficiency; inhibition of NOS2 mediated NO production | Fructose impairs vascular relaxation, hypertension and insulin resistance | [35] |
| Fats | |||
| Saturated fats and triglyceridemia | Impaired endothelial NO production with lower NOS3 phosphorylation and insulin-mediated vasodilation; increased NOS2 activity | Hypercholesterolemic patients have reduced NO production with endothelial dysfunction; role of saturated fatty acids, cholesterol, and LDL in the pathogenesis of beta-cell destruction or dysfunction and of liver, gastrointestinal, vascular (including hypertension), and neurological diseases | [35, 41**] |
| Unsaturated fatty acids: n-3 (fish oil, EPA, DHA); n-6 (linoleic acid); n-9 (oleic acid) | n-3 and n-6 PUFA increase NO production by endothelial cells; n-9 PUFA inhibit NO production by decreasing NOS3 activity. Proportion of cellular n-3 and n-6 FA concentration is a major determinant for NO production by NOS2 | PUFAs regulate vascular endothelial function partially through alterations in NO production; Fishoil, DHA and EPA considered beneficial for cardiovascular function; increasing plasma concentrations of n-9 FA may contribute to the pathogenesis of endothelial dysfunction; involved in inflammatory response. | [35] |
| Vitamins | |||
| Vitamin C, A, E, folic acid; vitamin K and carotenoids | VitC, A, E and folic acid increase NO production in endothelial cells; increased NO production in neuronal cells (VitA and E). VitC acts by stabilizing BH4 and scavenging reactive oxygen species; VitA reduces ADMA and increases NOS1. Differential effects of VitA on NOS2 in various cells. VitK and carotenoids inhibit NOS2 | Consistent with role of vitamins C, A, E and folic acid as anti-atherosclerotic agents and improved endothelium-dependent relaxation in hypercholesterolemic patients; vitamin C may improve microvascular function in sepsis through accumulation in miccrovascular endothelial cells with increased NO production | [35, 42] |
| Minerals | |||
| Calcium | Increasing extracellular and intracellular Ca2+ stimulate NO production by endothelial cells | A high calcium diet attenuates the development of hypertension (in the spontaneous hypertensive rat) | [35] |
| Iron | Iron availability modulates NO production (iron-containing heme is an essential component of NOS); interaction with other molecules affects regulation NOS2 expression | Iron deficiency reduces NOS activity | [35] |
| Zinc | Modulates NO production by its bounding to NOS; NO production inhibited at higher levels. Inhibits NOS2 expression | Role of zinc in modulating vascular, immunological, and intestinal function | [35] |
| Magnesium | Dose-dependent stimulation of NO production by endothelial cells | Vasodilator effect | [35] |
| Other | |||
| Glucosamine (metabolite from glucose and glutamine) | Inhibits NO production by decreasing cellular free NADPH availability; decrease NOS2 dependent NO production | May have implications for endothelial insulin resistance and cardiovascular complications in diabetic and obese subjects; may be beneficial in preventing and treating NO-mediated chronic inflammatory diseases such as arthritis | [35, 37] |
| Plant-derived isoflavones (phytoestrogens) | Enhanced NOS3 mediated NO production and endothelium-dependent relaxation | Cardioprotective effects | [35] |
ADMA, NG-methyl-L-arginine; BH4, tetrahydrobiopterin; DHA, docosahexaenoic acid (C22:6 n-3); EPA, eicopentaenoic acid (C20:5 n-3); NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; cNOS, constitutive NOS (NOS1 and NOS3); PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; Vit, vitamin.