Effects of carboxy-PTIO on systemic hemodynamics, liver energetics, and concentration of liver metabolites during endotoxic shock in rabbits: A P-31 and H-1 magnetic resonance spectroscopic study

Objective: To investigate the effects of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1 -oxyl-3-oxide (carboxy-PTIO), a nitric oxide scavenger, on the lipopolysaccharide-induced hypotension, hepatocellular dysfunction, and liver damage in endotoxic rabbits. Design: Experimental, comparative study. Setting: Laboratory of a university hospital. Subjects: Eighteen Japanese white rabbits (3.0 to 3.2 kg body weight) anesthetized with ketamine-xylazine were studied. Interventions: We randomly divided the rabbits into three groups: saline controls (group 1, n = 5); animals receiving lipopolysaccharide (400 mu g/kg) alone (group 2, n = 8); and animals receiving lipopolysaccharide plus carboxy-PTIO at a rate of 0.17 mg/kg/min for 3 hrs (group 3, n = 5). Blood gases and mean arterial pressure (MAP) were monitored. In vivo phosphorus-91 magnetic resonance spectra were continuously obtained every 30 mins. In addition, the livers were sampled and underwent fractionation at 7 hrs after lipopolysaccharide administration. The hydrophilic and hydrophobic extracts from the livers were analyzed by in vitro hydrogen-1 and phosphorus-31 magnetic resonance spectroscopy. Measurements and Main Results: After the administration of lipopolysaccharide, the first phase of decrease in MAP within 30 mins was followed by partial recovery within the next 30 mins. In group 2, MAP started to decrease progressively within 180 mins after lipopolysaccharide administration (second phase) and decreased by 33% from the baseline value to 49 +/- 9 mm Hg at 420 mins. In contrast, the infusion of carboxy-PTIO significantly attenuated the second decrease in MAP (68 +/- 10 mm Hg, at 420 mins). In group 2, a slow and progressive decrease in adenosine triphosphate (ATP) and increase in inorganic phosphate concentrations occurred from 120 mins after lipopolysaccharide administration, and continued throughout the observation period. These changes were accompanied by a progressive decrease in intracellular pH. On the other hand, in group 3, there were no significant changes in ATP and inorganic phosphate concentrations compared with the controls from 120 to 360 mins after lipopolysaccharide administration. Moreover, restorations of both arterial and hepatocellular acidosis were observed in group 3. The differences of the degree of liver damage-as determined by the total amount of phospholipid, free fatty acids concentration, and membrane fluidity-were not significant among the three groups. Three of eight rabbits in group 2 died within 7 hrs, but no animal in the other two groups died during the study. Conclusions: The results of this study indicate that the infusion of carboxy-PTIO: a) prevented the delayed hypotension associated with endotoxic shock in rabbits; b) returned the hepatocellular ATP concentrations nearly to the level of the controls and alleviated hepatocellular acidosis; c) normalized various hydrophilic metabolites, such as lactate and alanine in the liver; and d) did not exacerbate liver injury after the administration of lipopolysaccharide. These findings indicate that carboxy-PTIO, a nitric oxide scavenger, may have a positive vasopressor effect during hypodynamic septic shock without exacerbating liver injury.