EFFECT OF AMINOGUANIDINE ON PLASMA NITRIC-OXIDE BY-PRODUCTS AND BLOOD-FLOW DURING CHRONIC PERITONEAL SEPSIS

We hypothesized that plasma nitric oxide (NO), generated via inducible NO synthase (iNOS) or endothelial constitutive NO synthase and measur ed via its by-products NO2- and NO3- (NO2- + NO3- = NOx) would increas e and remain elevated during chronic peritoneal sepsis. We further hyp othesized that treatment with aminoguanidine (AG; 50 mg/kg), a selecti ve iNOS inhibitor, would decrease NO production and alter blood flow. Sprague Dawley rats were randomized to septic and nonseptic groups. Se ptic rats received an intraperitoneal cecal slurry (200 mg of cecal ma terial/5 mt 5% dextrose-H2O/kg); control rats received sterile 5% dext rose-H2O (5 mL/kg) only. Plasma NOx and hemodynamics were measured 0, 4, 12, 24, and 48 h after sepsis or sham induction. We also examined t he effect of AG, an iNOS inhibitor, on plasma NOx levels and tissue bl ood flow at 24 h. Septic rats uniformly displayed signs of sepsis, inc luding lethargy, piloerection, and diarrhea. NOx levels were significa ntly elevated compared with controls at 4, 12, 24, and 48 h (p less th an or equal to.05). Septic rats also demonstrated hypotension (t = 12, 24, and 48 h) and tachycardia (t = 4, 12, 24, and 48 h). The infusion of AG (50 mg/kg intravenously for 30 min) at 24 h significantly decre ased plasma NOx in septic animals. Plasma NOx concentrations returned to basal levels by 90 min after infusion of AG. In addition, blood flo w studies demonstrated that AG treatment in nonseptic rats resulted in a significant decrease in blood flow to the stomach, skin, and adipos e tissue, whereas AG infusion did not significantly alter the regional perfusion profile in septic animals. Furthermore, treatment with AG d id not significantly alter mean arterial pressure in either group; how ever, nonseptic animals exhibited a decrease in stroke volume, and sep tic animals demonstrated an increase in heart rate. In contrast to the rise and fall of NOx levels in endotoxemia, this study demonstrates t hat the initial rise is sustained during 48 h of peritoneal sepsis. Th is sustained increase in NOx levels in this model correlated with the observable signs of systemic infection and may relate to enhanced iNOS activity. AG infusion demonstrated variable effects on regional tissu e blood flow profiles in septic and nonseptic animals and attenuated t he increase in plasma NOx levels in septic animals, an index of iNOS a ctivity.