Depletion of liver glutathione potentiates the oxidative stress and decreases nitric oxide synthesis in a rat endotoxin shock model

Objective: To verify the effects of liver glutathione depletion on redox status and nitric oxide system in a rat endotoxic shock model. Design: Prospective, randomized, controlled study on rats. Setting: A cardiocirculatory research laboratory. Subjects: A total of 28 Sprague-Dawley male rats (200-250 g body weight) were divided into four experimental groups. Interventions: Arterial blood, liver, and lung samples were taken from each animal under sodium pentobarbital (40 mg/kg ip) anesthesia 4 hrs after lipopolysaccharide (LPS group: 5 mg/kg ip; n = 7) or vehicle (control group: isotonic NaCl sterile solution ip; n = 7) treatments,. Phorone (250 mg/kg ip) was injected to deplete glutathione in another two experimental groups of rats 30 mins before LPS (phorone+LPS group; n = 7) or vehicle (phorone group; n = 7) treatments, and 4 hrs later the same samples as in LPS and control groups were taken under anesthesia. Measurements and Main Results: Compared with the control group, the LPS group presented higher plasma concentration of end products of nitric oxide metabolism nitrites/nitrates, higher lung activity of inducible nitric oxide synthase, and oxidative stress defined by increased plasma concentration of the lipid peroxides malonaldehyde and 4-hydroxynonenal, and decreased plasma total antioxidant capacity. Treatment with phorone depleted liver glutathione (80% to 90%). In the liver glutathione-depleted animals, the oxidative stress induced by LPS was potentiated and blunted the increases in inducible nitric oxide synthase and plasma nitrites/nitrates. Conclusion: These results show that depletion of the liver glutathione increases the oxidative stress and decreases nitric oxide synthesis of LPS-induced shock in rats.