[2] These particular gases share many common features in their production and function but carry on their tasks in unique ways which differ from classical signaling molecules.
[4][3] Three candidate gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide, have ironically been discarded as useless toxic gases throughout history.
[5][6] Nitric oxide and hydrogen sulfide are highly reactive with numerous molecular targets, whereas carbon monoxide is relatively stable and metabolically inert predominately limited to interacting with ferrous ion complexes within mammalian organisms.
[8][9] Gasotransmitters are under investigation in disciplines such as: biosensing,[10][11] immunology,[12][13] neuroscience,[14][15] gastroenterology,[16][17][18] and many other fields to include pharmaceutical development initiatives.
[31][32][33] For the human body to generate NO through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite occurs in the mouth by the oral microbiome.
[34] The production of NO is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation.
[35] NO contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium.
[36] In the context of hypertension, the vasodilatory mechanism follows: NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP.
S-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs).
[51] The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron to modulate the normal enzymatic activity of an enzyme such as cytochrome P450.
[53] NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.
The most extensively studied source is the catabolic action of heme oxygenase (HMOX) which has been estimated to account for 86% of endogenous CO production.
Other contributing sources include: the microbiome, cytochrome P450 reductase, human acireductone dioxygenase, tyrosinase, lipid peroxidation, alpha-keto acids, and other oxidative mechanisms.
Unlike NO and H2S, CO is an inert molecule with remarkable chemical stability capable of diffusing through membranes to exert its effects locally and in distant tissues.
[67][71] Recent findings suggest strong cellular crosstalk of NO and H2S,[72] demonstrating that the vasodilatatory effects of these two gases are mutually dependent.