Nitric oxide signaling: would you believe that a simple free radical could be a second messenger, autacoid, paracrine substance, neurotransmitter, and hormone?

Nitric oxide signaling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas with an unshared electron can regulate an ever-growing list of biological processes. In most instances, nitric oxide mediates its biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis. However, effects of nitric oxide that are independent of cyclic GMP are also growing at a rapid rate. Nitric oxide can interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids, and other reactive species. The effects of nitric oxide can mediate important physiological regulatory events in cell regulation, cell-cell communication, and signaling. However, as with any messenger molecule, there can be too much or too little of the substance and pathological events ensue. Methods to regulate either nitric oxide formation, metabolism, or function have been used therapeutically for more than a century, as with nitroglycerin therapy. Current and future research should permit the development of an expanded therapeutic armamentarium for the physician to manage effectively a number of important disorders. These expectations have undoubtedly fueled the vast research interests in this simple molecule.