Organ Systems Dependent on Nitric Oxide and the Potential for Nitric Oxide‐Targeted Therapies in Related Diseases

Abstract

Nitric oxide (NO) is a universal messenger mol-1 This simple molecule appears to occur in virtually every tissue, and impairment of NO bioactivity has been documented in a wide array of diseases.1,2 There are 3 known isoforms of NO synthase (NOS), the enzyme necessary for the production of NO from its substrate, L-arginine.1,2 These isoforms include endothelial NOS (eNOS), found primarily in the endothelium of blood vessels and airway epithelium; neuronal NOS (nNOS), concentrated in nerve endings and in tissues of the central and peripheral nervous systems, as well as skeletal muscle; and inducible NOS (iNOS), expressed in a variety of tissues.2 The eNOS and nNOS isoforms are primarily constitutively expressed and dependent on increased intracellular calcium and calmodulin binding to generate NO, while iNOS is calciumindependent and primarily induced by the presence of inflammatory factors, including cytokines.3,4 All 3 isoforms can be induced, although by varying stimuli, and all 3 can be constitutively expressed in some cells or tissues. 4 Because NO bioactivity plays important physiologic roles in diverse organs including the blood vessels, brain, lungs, liver, kidney, stomach, and the immune, musculoskeletal, and reproductive systems, impairment of NO bioactivity could be an important factor in a wide range of disease states. 1,2The complexity of NO bioactivity, however, makes it difficult to identify its precise functions in many areas, and to target and modulate these actions or pathways therapeutically.1 Under conditions of oxidative stress, inflammation, and ischemia, NO may be produced at excessive levels and become dysfunctional or "uncoupled," reacting R e v i e w P a p e r

The role of inflammatory processes in Alzheimer’s disease

“…It has even been postulated that AD is primarily a vascular disorder with neurodegenerative consequences, with the initial pathogenic insult arising from cerebral hypoperfusion, and with impairment of NO bioactivity contributing to the progression of the disease (Hollenberg 2006). Indeed, reduced cerebral blood flow (Iadecola et al 1999) and a reduction in vasoreactivity (Vicenzini et al 2007) have been found in AD patients.…”

“…Inducible NOS (iNOS) is produced by astroglial cells and neurons in response to inflammatory conditions. Endothelial NOS (eNOS) influences vasodilation, and thus the state of cerebral perfusion (Hollenberg 2006).…”

Flavanols, the Kuna, cocoa consumption, and nitric oxide

“…Nitric oxide is a messenger molecule that performs diverse biologic functions, appears to occur in virtually every tissue, and impairment of nitric oxide bioactivity has been documented in a wide variety of diseases (22). Nitric oxide has been suggested to play a role in diseases of blood vessels, the heart, brain, lungs, liver, kidney, stomach, the immune system, musculoskeletal, and reproductive systems.…”

Nitric oxide in health and disease – its role in the practice of medicine

“…30,31 Indeed, drugs that provide or "donate" NO have been used for many years to treat or prevent angina pectoris pain or to manage hypertensive crises.…”