Nitric oxide (NO) and oxidative stress.

Nitric oxide (NO) is a gas with a very short half life that is produced endogenously in the body. It has roles in many essential functions including vasodilation, neurotransmission, inflammation, erection, and immunity. It is also implicated in many chonic illnesses especially those involving chronic inflammation.

Nitric oxide is produced by the NOS (nitric oxide synthase) family of enzymes, which convert 1 molecule of arginine to 1 molecule of citrulline and NO. They require several cofactors, the most important of which is BH4 (tetrahydrobiopterin). 2 molecules of BH4 are needed for normal NOS enzyme function. However when there is insufficient BH4, NOS can also produce superoxide, which combines with NO to form peroxynitrite, turning the NOS enzymes into a potent source of oxidising free radicals. This change in NOS output is known as 'uncoupling', because its become uncoupled from its normal function of NO production.

The free radical peroxynitrite (ONOO−) has the ability to oxidise BH4 to BH3 which causes further NOS uncoupling. Vitamin C can prevent peroxynitrite induced uncoupling by recycling BH3 back to BH4. NO and peroxynitrite can inhibit mitochondrial function. Peroxynitrite and its breakdown products also inhibit the key homocysteine degrading CBS enzyme and trigger inflammation pathways (iNOS) leading to more NO and peroxynitrite formation. High levels of NO and/or peroxynitrite can also contribute to excitotoxicity, since both can inhibit enzymes involved in energy metabolism, causing ATP depletion.

NO-OONO
M.Pall has put together a theory (NO-OONO theory) to explain CFS and other multisystemic illnesses which is based upon NOS decoupling, the resultant oxidative stress, and a theoretical visous cycle involving chronic inflammation. This theory is eludicated in his book, 'explaining unexplained illnesses'.

References
- Role of oxidative stress and nitric oxide in atherothrombosis.
- Mitochondrial function and dysfunction in sepsis.
- Nitric oxide and oxidative stress in vascular disease.
- Peroxynitrite is the major species formed from different flux ratios of co-generated nitric oxide and superoxide: direct reaction with boronate-based fluorescent probe.
- Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitric oxide synthase: transition from reversible to irreversible enzyme inhibition.
- Persistent mitochondrial damage by nitric oxide and its derivatives: neuropathological implications.
- Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury.
- The multiple actions of NO.
- Inactivation of cystathionine beta-synthase with peroxynitrite.
- Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome.
- Multiple pathways of peroxynitrite cytotoxicity.
- Ascorbate enhances iNOS activity by increasing tetrahydrobiopterin in RAW
264.7 cells.
- Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols:
implications for uncoupling endothelial nitric-oxide synthase.
- Interactions of peroxynitrite with uric acid in the presence of ascorbate and
thiols: implications for uncoupling endothelial nitric oxide synthase.
- L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical
stabilization of tetrahydrobiopterin.
- 'Explaining unexplained illnesses' (paperback) M.Pall

General NO info
- http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/N/NO.html
- http://en.wikipedia.org/wiki/Biological_functions_of_nitric_oxide