PEROXYNITRITE - A MEDIATOR OF INCREASED MICROVASCULAR PERMEABILITY

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 o f superoxide and NO) is involved in proinflammatory processes. The pre sent study has investigated the ability of peroxynitrite to induce oed ema formation in the rat cutaneous microvasculature. 2. Peroxynitrite was synthesized from hydrogen peroxide and acidified nitrite, Spectrop hotometry was used to measure the concentration and breakdown of perox ynitrite, It was also used to determine maximum amounts of hydrogen pe roxide and sodium nitrite remaining after synthesis. 3. Oedema formati on in response to intradermally (i.d.) injected peroxynitrite, hydroge n peroxide and sodium nitrite was measured by the extravascular accumu lation of i.v. [I-125]-albumin in the anaesthetized rat. 4. Peroxynitr ite (40, 100 and 200 nmol/site) acted in a dose-dependent manner to ca use a mean (+/- SEM) increase in plasma extravasation of 24 +/- 2, 55 +/- 5 and 69 +/- 6 mu L, respectively (n = 4), with resulting inflamma tory oedema, Peroxynitrite induced significantly larger plasma extrava sation than equivalent vehicle controls at doses of 100 (P > 0.05) and 200 mmol (P > 0.001). This increased extravasation appears to be a di rect microvascular response to peroxynitrite administration and not du e to either a raised pH, necessary to stabilize the peroxynitrite, or contaminating concentrations of hydrogen peroxide or sodium nitrite fr om which peroxynitrite is formed. 5. These results suggest that peroxy nitrite acts to increase microvascular permeability and oedema formati on, Therefore, peroxynitrite may mediate vascular pro-inflammatory eff ects in addition to its direct cytotoxic activity.