Nitric oxide biological actions

Little is known about the mode of action of nitrosothiols regarding their biological properties. There appears to be no direct connection between their reactivities towards nitric oxide loss and biological activity38,48. However, the experiments which have been carried out in these studies relating to rates of nitric oxide formation do not recognize... 

A variety of nitrogen oxides (NO ) such as nitric oxide (NO) and nitrogen dioxide (NO2) as well as nitrous oxide (N2O) are present in the atmosphere. The sources of these oxides are biological actions and organic decomposition in the soil and in the ocean... 

Despite the many decades amyl nitrite and glyceryl trinitrate have been used in therapy, it is only in recent years that the molecular mechanism of action of the nitrovasodilators has begun to be understood [3-5]. The drugs act by releasing nitric oxide (NO, a neutral radical usually written simply as NO), which produces smooth muscle relaxation in blood vessels and exhibits a range of other biological effects [6]. Thus, bioactivation to yield NO precedes the main therapeutic effect of nitrovasodilators and would justify their classifica-... 

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 A-methyl-o-aspartate receptors on... 

Among the primary lines of evidence for demonstrating the action of EDRF is enhanced biological activity in the presence of superoxide dismutase (Moncada et al., 1991). Furthermore, superoxide-generating compounds are well known to inactivate EDRF. When nitric oxide was proposed to be the principal form of EDRF, the reason for its inactivation by superoxide was obvious. Both superoxide... 

FIGURE 3.12 Time-related inhibition of nitric oxide synthase following a single administration of lOmg/kg, i.p. of Nuj-nitro-L-arginine (a slowly reversible enzyme inhibitor). If a 60% inhibition of enzymatic activity is considered biologically and statistically meaningful, dien the duration of action is approximately 20h at the administered dose. Source Redrawn from Carreau et al. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

Closely related are the 1-benzylamino-l-deoxylactitol dithiocarbamate salts developed by Eybl and co-workers316 317 for the same purpose. However, the most important application of 175 is, probably, its use as a nontoxic, water-soluble nitric oxide probe in vivo. In view of the central importance that this gaseous free-radical species plays in regulating a broad range of important biological functions, its detection and quantification near its site of production and action is of prime importance. For this purpose, the ferrous salt of MGD, which forms a stable water-soluble mononitrosyl iron-dithiocarbamate complex (176) with a characteristic electron spin resonance (ESR) spectrum at room temperature, is currently used.318-323... 

See also Actions of Nitric Oxide, S-Sdenosylmethionine and Biological Methylation, Polyamines... 

---