Nitric Oxide (NO) and the Nervous System
Better known as an environmental hazard, nitric oxide (NO) is produced in combustion engines and contributes to smog and acid rain and has been implicated in the catalytic destruction of the ozone layer (Lancaster;1992). Though NO is the bad-boy of the environment, it’s roles in the body are extremely diverse and in some instances can be deleterious or beneficial depending on the circumstances. NO has been connected with immune function, control of blood pressure and hypertension, impotence and penile erection, septic shock, insulin-dependent diabetes mellitus, and macrophage mediated destruction of oncogenic cells (Young;1993, Stroh;1992). However, its activities in the nervous system may be the most exciting discovery yet for this eclectic molecule (Koshland;1992).
Due to NO’s radical structure, it is highly reactive and very short-lived within the body (6-15 sec.) making its detection difficult (Lancaster;1992); as such, it can therefore be synthesized only on demand since radicals are known to disrupt cellular homeostasis. NO is small and uncharged and it rapidly diffuses through cellular membranes from its site of synthesis making it in ideal intercellular paracrine-like messenger or poison (Lancaster;1992). In the body, NO reacts with redox metals such as copper, manganese, or the iron heme-like protein centers, and molecular oxygen forming nitrites and nitrates, the latter constituting the principal manner in which NO is inactivated in vivo (Snyder;1992).
The enzyme which synthesizes NO, nitric oxide synthase (NOS), has been cloned and structurally resembles cytochrome P-450 reductase, possessing many sequence homologies and the same physical sites for binding of identical cofactors (FMN, FAD, and NADPH); in addition, NOS also possesses binding sites for calmodulin and a phosphorylation site which may modulate its activity (Bredt;1991) (Snyder;1992). NO is synthesized by NOS from L-arginine and molecular oxygen with the concomitant release of citrulline; NADPH and tetrahydrobiopterin are required as cofactors (Lancaster;1992).
In order to understand NO’s neurobiological roles, some of NO’s biochemistry and physiology must be discussed. NO’s radical structure, fleeting half-life, and rapid diffusibility make it an ideal neurotransmitter, albeit an unconventional one. In the peripheral vascular blood supply, acetylcholine or bradykinin act on endothelial cells in the vessels which causes a release of endothelium-derived relaxation factor (EDRF) which has been verified to be NO (Snyder;1992). Acetylcholine or bradykinin causes an increase in the intracellular Ca2+ concentration through the action of inositol triphosphate; the increased intracellular Ca+ binds the calmodulin site in NOS and stimulates the synthesis of NO which rapidly diffuses away from its site of synthesis to the tunica muscularis of blood vessels causing vasodilation (Murray;1993). In this manner, NO is a sort of...