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Nitric oxide (NO) synthesised from l-arginine subserves multiple physiological functions in the cardiovascular, respiratory, gastrointestinal, genitourinary, and central and peripheral nervous systems.1 But synthesis of NO also contributes to host defence and seems to have cytostatic and cytotoxic effects against certain pathogens, and even against host cells themselves.1 How is this double act achieved? What determines the switch from physiological mediator to lethal gas and how is bacterial killing achieved?
The simple and standard answer to the dual action of NO is that its effects depend on the amounts generated and the local concentrations achieved. In the nanomolar concentrations generated by constitutive NO synthase (NOS) isoforms, NO acts as a cell signalling molecule and interacts preferentially with its physiological target enzymes—the most significant of which seem to be soluble guanylyl cyclase and possibly cytochrome C oxidase. At the higher concentrations generated when the other enzymes become targets for NO action the cytokine induced isoform of NOS (iNOS) is expressed in cells. Haem containing enzymes, enzymes with Fe-S clusters including aconitase, NADH dehydrogenase and succinate dehydrogenase, the non-haem metalloenzymes, ribonucleotide reductase and DNA itself are all susceptible to inhibition or damage when NO output is high. Consistent with this high versus low output explanation, soluble guanylyl cyclase and cytochrome C oxidase are reversibly affected by NO (stimulation and inhibition respectively) with near maximal effects occurring in the nanomolar range of NO concentrations whereas effects on other enzymes occur only in the micromolar range and are often irreversible.
Despite the simplicity and attractiveness of the low versus high output theory, it is almost certainly only partially correct. Many reports indicate that organisms which seem to be killed following induction of the l-arginine/NO pathway in immune cells are resistant to the effects of NO …
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