ENDOGENOUS NITRIC-OXIDE PROTECTS AGAINST PLATELET-ACTIVATING-FACTOR INDUCED BOWEL INJURY IN THE RAT

Platelet-activating factor (PAF) causes bowel necrosis in animal model s that is histologically identical to that seen in neonatal necrotizin g enterocolitis, but little is known about endogenous mechanisms that might protect against PAF-induced bowel injury. We hypothesized that e ndogenous nitric oxide might represent such a protective mechanism. Ad ult male Sprague-Dawley rats were pretreated with 2.5 mg/kg N(G)-nitro -L-arginine methyl ester (L-NAME), a potent nitric oxide synthase inhi bitor, and given injections of 1.5 mug/kg PAF 15 min later. Animals tr eated with normal saline placebo, L-NAME alone, and PAF alone were als o studied. Superior mesenteric artery blood flow and blood pressure we re continuously recorded. At the end of 2 h or upon death of the anima l, hematocrit was measured and intestinal samples were taken for histo logic examination and determination of myeloperoxidase activity, a mea sure of intestinal neutrophil content. Compared with animals given PAF alone, animals pretreated with L-NAME followed by PAF developed signi ficantly worse bowel injury (median injury scores: 2.5 versus 0.5, p = 0.005), hemoconcentration (final hematocrit 65.2 +/- 2.0% versus 53.9 +/- 1.0%, p < 0.001), and intestinal myeloperoxidase activity (12.45 +/- 1.94 U/g versus 6.51 +/- 0.57 U/g, p < 0.01). The last two effects were further accentuated when 10 mg/kg L-NAME was given before PAF. T reatment with sodium nitroprusside, a nitric oxide donor, for 10 min b efore and after PAF administration reversed the effects Of L-NAME. Ani mals pretreated with phenylephrine rather than L-NAME did not develop worse injury than animals treated with PAF alone despite comparable re ductions in superior mesenteric blood flow before PAF treatment. Treat ment with superoxide dismutase and catalase did not ameliorate the eff ects of L-NAME on PAF-induced injury, hemoconcentration, and neutrophi l infiltration into the bowel. We conclude that endogenous nitric oxid e defends against PAF-induced bowel injury by antagonizing certain imm ediate effects of PAF, particularly those leading to capillary leakage and neutrophil infiltration into the bowel. Our studies also suggest that the mechanism of action does not involve vasodilatation or scaven ging of oxygen radicals.