Characterization of the role of nitric oxide and its clinical applications.
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.
ABLE Medical Consulting, University of Pittsburgh, Pittsburgh, PA 15217, USA.
Arlene Bradley
AB
Levine
David
D
Punihaole
T Barry
TB
Levine
D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000209:etiology; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors; D004032:Diet; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D015444:Exercise; D006207:Half-Life; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D009569:Nitric Oxide / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D033081:Shear Strength; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000627:therapeutic use
D002317:Cardiovascular Agents; D016207:Cytokines; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III