Characterization of the Role of Nitric Oxide and Its Clinical Applications

Abstract

Nitric oxide (NO) has long been known as endothelium-derived relaxing factor. It is a vasodilator, modulating vascular tone, blood pressure and hemodynamics, a role exploited by nitrate donor therapy for angina, heart failure, pulmonary hypertension and erectile dysfunction. In addition, its powerful antioxidant, anti-inflammatory and antithrombotic actions are antiatherogenic with antiatherothrombotic impact. NO signaling modulates skeletal muscle and myocardial contractility and metabolism and is intimately linked with insulin signaling. Vascular and muscle NO signaling coordinate skeletal muscle and myocardial energy demand with supply and are critical for both carbohydrate and fatty acid total-body homeostasis. NO signaling in mitochondria underlies much of NO’s metabolic effect, which, at low physiologic levels, links cellular energy demand with mitochondrial energy supply, while beneficially affecting mitochondrial oxidative stress and calcium handling. Mitochondria are also the site for the life-threatening deleterious effects arising from inflammation-related excessive NO levels. NO-deficient states are characterized by cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes mellitus. NO-enriching therapy would be expected to be of benefit not only for its hemodynamic but also for its metabolic impact. In contrast, strategies are needed to curtail excessive NO in states such as septic shock.

Nitric oxide as a possible regulator of energy-dependent Ca2+ transport in mitochondria of uterine smooth muscle

“…Оксид азоту характеризується широким спектром функціональної активності, яка включає регуляцію серцево-судинної, нерво-вої, ендокринної, імунної, репродуктивної систем організму [1][2][3][4]. Фізіологічні ефекти NO часто опосередковуються взаємодією із численними внутрішньо-та позаклітинними ефекторними молекулами і супрамолеку-лярними комплексами, включаючи хромо-протеїни, тіоли, супероксид-аніон [5][6][7].…”

Cervical Ganglion Block Attenuates the Progression of Pulmonary Hypertension via Nitric Oxide and Arginase Pathways

“…6 NO dilates blood vessels by stimulating guanylyl cyclase and also exerts anti-inflammatory and antithrombotic effects by inhibiting leukocyte adhesion and platelet aggregation. 7 In addition to NO, arginase activity is known to be inadequately increased in PAH. 8 Arginase shares the substrate l-arginine with eNOS, resulting in competitive inhibition of eNOS and subsequent vascular endothelial dysfunction.…”

Vascular failure and recent anti-diabetic drugs

“…Imbalances in the production of endothelium-derived relaxing and contracting factors are important contributors to endothelial dysfunction 1) . Decreased synthesis and/or increased degradation of NO can contribute to impairment of its bioavailability as a consequence of enhanced production of reactive oxygen species (ROS) 7,8) . Tetrahydrobioptein (BH4) binds to NOS as a cofactor and suppresses superoxide production 9) .…”

“…However, insufficient BH4 directs NOS to produce superoxide rather than NO 10) , and increased oxidative stress can oxidize BH4, resulting in the uncoupling of eNOS and reduced NO production 11,12) . Moreover, the absence of BH4 increases oxidative stress through transfer of electrons to molecular oxygen, forming oxidant species that further consume NO and increase oxidative stress 7,11,12) . Given that superoxide converts NO into peroxynitrite, generates hydroxyl radicals, and injures cells, the balance of production and the existence of NO, superoxide, and related factors in vascular endothelial cells play important roles in vascular endothelial injury.…”

“…Elevated levels of asymmetric dimethylarginine (ADMA) may reduce NO production, because ADMA is an endogenous inhibitor of eNOS through competition with Larginine 7) . Endothelial dysfunction can affect vasoconstrictor levels, including endothelin-1 and angiotensin II, and other vasodilators, including endothelial-derived hyperpolarizing factor (EDHF) and prostacyclin 7,8) .…”