Nitric oxide is a small, unstable free radical that acts as a biological messenger in many physiological responses. Because it can diffuse freely in all directions from its site of origin, regulation of the activity of nitric oxide is primarily through control of its synthesis. Formation of nitric oxide occurs through oxidation of the amino acid l-arginine, a reaction catalyzed by the enzyme nitric oxide synthase (NOS), to produce nitric oxide and l-citrulline. The forms of NOS differ in their cellular location and expression (constitutive expression versus inducible expression). Activation of synthesis of the inducible form of NOS results in continued synthesis of nitric oxide for several hours. Inhibitors of NOS are analogues of argi-nine, including l-Nw nitroarginine (l- NNA) and l-Nw methylarginine (l-NMA), both of which decrease nitric oxide synthesis.
Physiological sites proposed for nitric oxide action include the immune system, where nitric oxide acts as a cytostatic agent, is tumoricidal, and can inhibit viral replication. In the cardiovascular system, nitric oxide is the biological mediator of vasodilator responses to agents such as acetylcholine and bradykinin, which act as receptors on endothelial cells to activate NOS and stimulate nitric oxide production. Diffusible nitric oxide then activates guanylate cyclase in vascular smooth muscle cells, leading to the production of cyclic guano-sine monophosphate (GMP) and vasodilation. In the brain, stimulation of N-methyl-d-aspartate receptors on neurons leads to activation of the brain form of NOS and stimulates production of nitric oxide. The function of brain nitric oxide is thought to involve actions as a retrograde neurotransmitter whereby nitric oxide diffuses back to the presynaptic neuron to activate guanylate cyclase and increase cyclic GMP levels. Through these retrograde actions nitric oxide is thought to play a role in the neural circuitry involved in memory.
Even though nitric oxide is the physiological mediator of a variety of responses, excess nitric oxide is toxic to many cells as a result of its role in the production of per-oxynitrite and resultant lipid oxidation. Inhibitors of the NOS enzyme are in clinical trials for the treatment of hypotension associated with septic shock. Administration of low concentrations of nitric oxide through respiratory ventilators has been implemented to treat persistent pulmonary hypertension of the newborn.
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