Endogenous nitric oxide protects against platelet-activating factor-induced bowel injury in the rat.
Platelet-activating factor (PAF) causes bowel necrosis in animal models that is histologically identical to that seen in neonatal necrotizing enterocolitis, but little is known about endogenous mechanisms that might protect against PAF-induced bowel injury. We hypothesized that endogenous nitric oxide might represent such a protective mechanism. Adult male Sprague-Dawley rats were pretreated with 2.5 mg/kg NG-nitro-L-arginine methyl ester (L-NAME), a potent nitric oxide synthase inhibitor, and given injections of 1.5 micrograms/kg PAF 15 min later. Animals treated with normal saline placebo, L-NAME alone, and PAF alone were also studied. Superior mesenteric artery blood flow and blood pressure were continuously recorded. At the end of 2 h or upon death of the animal, hematocrit was measured and intestinal samples were taken for histologic examination and determination of myeloperoxidase activity, a measure of intestinal neutrophil content. Compared with animals given PAF alone, animals pretreated with L-NAME followed by PAF developed significantly 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. Treatment with sodium nitroprusside, a nitric oxide donor, for 10 min before and after PAF administration reversed the effects of L-NAME. Animals pretreated with phenylephrine rather than L-NAME did not develop worse injury than animals treated with PAF alone despite comparable reductions in superior mesenteric blood flow before PAF treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
MacKendrick
W
W
Department of Pediatrics, Evanston Hospital, Illinois 60201.
Caplan
M
M
Hsueh
W
W
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006400:Hematocrit; D007422:Intestines / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D010972:Platelet Activating Factor; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D009195:Peroxidase; D019331:NG-Nitroarginine Methyl Ester