Peroxynitrite: A Mediator of Increased Microvascular Permeability?

Abstract

1. Increased expression of inducible nitric oxide synthase (iNOS) and subsequent elevation of nitric oxide (NO) levels at inflammatory sites have led to the suggestion that peroxynitrite (the reaction product of superoxide and NO) is involved in pro-inflammatory processes. The present study has investigated the ability of peroxynitrite to induce oedema formation in the rat cutaneous microvasculature. 2. Peroxynitrite was synthesized from hydrogen peroxide and acidified nitrite. Spectrophotometry was used to measure the concentration and breakdown of peroxynitrite. It was also used to determine maximum amounts of hydrogen peroxide and sodium nitrite remaining after synthesis. 3. Oedema formation in response to intradermally (i.d.) injected peroxynitrite, hydrogen peroxide and sodium nitrite was measured by the extravascular accumulation of i.v. [125I]-albumin in the anaesthetized rat. 4. Peroxynitrite (40, 100 and 200 nmol/site) acted in a dose-dependent manner to cause a mean (+/- SEM) increase in plasma extravasation of 24 +/- 2, 55 +/- 5 and 69 +/- 6 microL, respectively (n = 4), with resulting inflammatory oedema. Peroxynitrite induced significantly larger plasma extravasation than equivalent vehicle controls at doses of 100 (P > 0.05) and 200 nmol (P > 0.001). This increased extravasation appears to be a direct microvascular response to peroxynitrite administration and not due to either a raised pH, necessary to stabilize the peroxynitrite, or contaminating concentrations of hydrogen peroxide or sodium nitrite from which peroxynitrite is formed. 5. These results suggest that peroxynitrite acts to increase microvascular permeability and oedema formation. Therefore, peroxynitrite may mediate vascular pro-inflammatory effects in addition to its direct cytotoxic activity.

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

“…A variety of observations have provided evidence that ONOO Ϫ may have deleterious effects on the integrity of the blood-CNS barrier (5,(31)(32)(33). The current findings support the hypothesis that one therapeutic mode of action of UA in EAE is through interfering with inflammatory cell invasion into the CNS by blocking ONOO Ϫ -mediated permeability changes in the neurovasculature.…”

Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis

“…Administration of a nonspecific scavenger of reactive oxygen species, including ONOO Ϫ , has been demonstrated to reduce blood-CNS barrier disruption in experimental optic neuritis (41). ONOO Ϫ has also been shown to increase microvascular permeability in vitro (42). In addition to its effects on the integrity of the blood-CNS barrier, it is conceivable that ONOO Ϫ may promote cell invasion into the CNS through other means.…”

Sciatic inflammatory neuritis (SIN): Behavioral allodynia is paralleled by peri‐sciatic proinflammatory cytokine and superoxide production

“…Zymosan can induce edema by phagocyte‐dependent processes ( Issekutz et al, 1980 ; Sennerby et al, 1989 ) , suggesting that the edema observed in this study may be caused by substance(s) released by these cells ( Baggiolini et al, 1978 ) . Indeed, phagocyte‐derived substances causing endothelial cell damage and edema include peroxynitrite ( Greenacre et al, 1997 ; Ridger et al, 1997 ) , IL1 ( Campbell et al, 1992 ; Ishida et al, 2000 ) , TNF ( Yi and Ulich, 1992 ) , and degradative enzymes ( Palmblad, 1984 ) . A second candidate mediator is sciatic nerve resident mast cells.…”