Translating Nitric Oxide Research to Therapeutics: A Critical Appraisal

Abstract

Nitric oxide (NO) is a signaling molecule with an extensive range of functions in both health and disease. Initially proposed as a regulator of cardiovascular function, the significance of NO has now been realized in the neurological, hematological and immune systems. Recent research has indicated complex roles for NO in skeletal muscle, myocardium, metabolic effects like insulin signaling, neurotransmission and cancer biology. Its emerging role as a gasotransmitter and interactions with other reactive molecules has been in the limelight and both pro and antioxidant effects are proposed. Regulation of NO production is determined by numerous factors including arginine bioavailability, co-factors and expression of endogenous regulators. Low (physiological) levels of NO are mostly protective, whereas high levels tend to be toxic. Mitochondria is 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 and insulin resistance. In sepsis, NO synthesis is dysregulated leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity. NO-enriching therapy may be of benefit not only for its hemodynamic but also for its metabolic impact as well as other effects. In contrast, strategies are needed to curtail excessive NO in states such as septic shock. Thus, both lack and excess of NO production can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation of NO production at the organ level and by the different NOS isoforms. An innovative bench to bedside approach will facilitate the translation of these biological effects at cellular/tissue levels for clinical benefits. Both nutritional and pharmacological approaches are being increasingly adopted to device novel therapeutic strategies by modulating NO levels/activity for several critical pathophysiological conditions.