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Biological Effects of NO

NO produces a wide variety of biological effects. Unfortunately, we are particularly ignorant of NO's role in modulating cellular processes in the nervous system. NO's role in regulating the vasculature is well documented and it appears to play a similarly important role in the nervous system.

Vasodilator

Under normal circumstances, NO contributes to the control of blood flow through the cerebrovasculature. A rapid feedback mechanism necessarily exists to supply more active areas of the brain with the necessary nutrients. This mechanism is necessary because of the brain's feeble reserve of energy stores. NO is produced in neurons containing NOS that are undergoing sustained activity. These conditions favor activation of NMDA receptors, which is known to cause NO production. NO diffuses from these localized areas of high neuronal activity to the surrounding microvasculature (Figure 14.11) causing vasodilatation and increased blood flow.

Although the exact mechanisms by which NO produces vasodilatation are not yet defined, it is known that activation of cGMP-dependent protein kinase in smooth muscle cells causes a relaxation of the vessels. Since one of NO's main targets is guanylyl cyclase (which produces cGMP and activates cGMP-dependent protein kinase), it is presumed that one major pathway for NO's vasodilatory actions is through cGMP-dependent protein kinase. Activation of this kinase leads indirectly to decreased Ca²⁺-levels in the smooth muscle cells and subsequently to the dephosphorylation of the myosin contractile apparatus which causes relaxation (Figure 14.12). In smooth muscle cells, NO also appears to directly hyperpolarize cells possibly by activating K⁺-channels, leading to the secondary closure of Ca²⁺ channels which also produces muscle relaxation. In conclusion, one of NO's main functions appears to be integrating the level of neuronal activity with local alterations in cerebral blood flow to maintain adequate perfusion of metabolically active tissue.

Neuromodulator

NO is also thought to act as a locally diffusible messenger. It is produced by any action that elevates Ca²⁺ in cells containing NOS, such as glutamate stimulation of NMDA receptors. Through subsequent activation of guanylyl cyclase and production of cGMP, NO production influences a variety of secondary processes. These include direct modulation of ion channels, stimulation of cGMP-dependent protein kinase, and both up-regulation or down-regulation of cAMP-phosphodiesterase. Downstream effects are then numerous and include up and down regulation of Ca²⁺ channels, increased excitability (increases neuronal firing rate), increased or decreased neurotransmitter release, and changes in neuron morphology.

Toxicity

NO in excess is toxic to cells. However, a paradox exists for NO toxicity. Apparently, cells that produce high levels of NO are resistant to its toxic effects. For example, NO toxicity is used by macrophages and neutrophils as a mechanism to kill tumor cells and bacteria. However, neither cell type producing NO is susceptible to its damaging effects. This finding is also true for neurons in the central nervous system. Excess glutamate induces neurotoxicity in the brain and is thought to be the primary cause of neuronal death in diseases such as Huntington's or Alzheimer's or after acute stroke or trauma. Excess production of NO is thought to play some role in this neuronal loss due to its toxicity when produced in excess. Interestingly, cells that stain positive for the enzyme NOS are spared in degenerating areas of the brain affected by these diseases. The resistance of these cells appears to be similar to the resistance of the immune cells described above.

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