The discovery of nitric oxide (NO) 1 as a uniquely diffusible and reactive molecular messenger in the vascular and immune systems motivated searches for NO biosynthesis throughout the body. NO was soon found in abundance in the central and peripheral nervous systems (1–3). Indeed, NO synthase (NOS), the enzyme that produces NO from L-arginine, occurs at higher levels in brain than in any other tissue, which facilitated the initial isolation of an NOS protein and cloning of an NOS cDNA (4). Intensive studies over the past 10 yr have determined that NO mediates diverse physiological functions associated with neurons. In the peripheral nervous system, NO acts much like a classical neurotransmitter in regulating gastrointestinal motility, regional blood flow, and neuroendocrine function. In the brain, NO acts as a neuromodulator to control behavioral activity, influence memory formation, and intensify responses to painful stimuli. Furthermore, NO biosynthesis in excitable tissues is not restricted to neurons. Recent studies have identified skeletal muscle as a major source for NO in the body (5, 6) where NO regulates both metabolism and muscle contractility.

NO biosynthesis in excitable tissues is regulated by increases in intracellular calcium, which activate NOS through the enzyme’s dependence upon calmodulin (7). Although small amounts of NO synthesized during neural and skeletal muscle activity mediate physiological functions, excess NO production can mediate tissue injury. For example, large amounts of NO produced during periods of cerebral ischemia mediate neuronal injury in various forms of stroke (8). Similar NO-mediated damage may account for neurodegeneration in other conditions as well, including Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. NO signaling is also perturbed in various muscle diseases, particularly in Duchenne muscular dystrophy, and these derangements may