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Inhaled nitric oxide (iNO) has many extrapulmonary effects. As the half-life of nitric oxide (NO) in blood is orders of magnitude less than the circulation time from lungs to the brain, the mediator of systemic effects of iNO is unknown. We hypothesized that concentrations of nitrite, a circulating byproduct of NO with demonstrated NO bioactivity, would increase in blood and cerebrospinal fluid (CSF) during iNO therapy. iNO (80 ppm) was given to six newborn lambs and results compared with six control lambs. Blood and CSF nitrite concentrations increased 2-fold in response to iNO. cGMP increased in blood but not CSF suggesting brain guanylate cyclase activity was not increased. When sodium nitrite was infused i.v. blood and CSF nitrite levels increased within 10 min and reached similar levels of 14.6 +/- 1.5 microM after 40 min. The reactivity of nitrite in Hb-free brain homogenates was investigated, with the findings that nitrite did not disappear nor did measurable amounts of s-nitroso, n-nitroso, or iron-nitrosyl-species appear. We conclude that although nitrite diffuses freely between blood and CSF, due to its lack of reactivity in the brain, nitrite's putative role as the mediator of the systemic effects of iNO is limited to intravascular reactions.

Effect of Inhaled Nitric Oxide on Cerebrospinal Fluid and Blood Nitrite Concentrations in Newborn Lambs