The ability of O2 metabolites derived from the xanthine-xanthine oxidase system to inhibit mitochondrial function was examined using freshly isolated rat liver mitochondria. Under 2,4-dinitrophenol-uncoupled conditions, mitochondria exposed to free radicals exhibited a significant decrease in O2 consumption supported by NAD(+)-linked substrates, but showed almost no change in O2 consumption in the presence of succinate and ascorbate. Oxidative stress caused the loss of intramitochondrial nicotinamide nucleotides, and addition of NAD+ fully prevented any fall in O2 consumption with NAD(+)-linked substrates. The activity of electron-transfer complex I (NADH oxidase and NADH-cytochrome c oxidoreductase) and the energy-dependent reduction of NAD+ by succinate were unaltered by oxidative stress. Exposure to free radicals also had an uncoupling effect at all three coupling sites. The degree of mitochondrial swelling was closely correlated with the inhibition of State-3 oxidation of site-I substrates and with the increase in State-4 oxidation of succinate. The immunosuppressive agent cyclosporin A completely prevented the mitochondrial damage induced by oxygen free radicals (swelling, Ca2+ release, sucrose trapping, uncoupling and selective inhibition of the mitochondrial respiration of site-I substrates). The same protective effect was found when Ca2+ cycling was prevented, either by chelating Ca2+ with EGTA or by inhibiting Ca2+ reuptake with Ruthenium Red. These findings suggest that the deleterious effect of free radicals on mitochondria in the present experimental system was triggered by the cyclosporin A-sensitive and Ca(2+)-dependent membrane transition, and not by direct impairment of the mitochondrial inner-membrane enzymes.
A healthy, nonepileptic 16-month-old child ingested a massive overdose (approximately 4000 mg) of valproic acid (VPA). Upon admission to the hospital, he was in a deep coma and had generalized hypotonicity and no response to pain. His serum and urinary concentrations of VPA were 1316.2 and 3289.5 micrograms/mL, respectively. Urinary concentrations of the beta-oxidation metabolites of VPA were low, whereas concentrations of omega- and omega 1-oxidation metabolites were high. Moreover, 4-en-valproate (a potential hepatotoxin) was detected in the urine. Gastric lavage and general supportive measures were undertaken, including intravenous infusion to increase urine output and oral L-carnitine to correct hypocarnitinemia. Subsequently, the beta-oxidation metabolites increased, the omega- and omega 1-oxidation metabolites decreased, and 4-en-valproate was no longer detected. The patient recovered completely and was discharged on the eighth hospital day without any sequelae. This case suggests that enhanced drug excretion and L-carnitine supplementation may prevent potentially fatal hepatic dysfunction after VPA overdose.
The activities of palmitoyl-coenzyme A (CoA) synthetase, carnitine acetyltransferase (CAT), and carnitine palmitoyltransferase (CPT) and the levels of ketone bodies, reduced coenzyme A (CoASH), carnitine, and their esters, which are involved in fatty acid metabolism, in rat liver and plasma were measured after the administration of Escherichia coli lipopolysaccharide (LPS). We also studied the effect of L-carnitine treatment before LPS administration on survival and on hepatic fatty acid metabolism. The activities of CAT and CPT and the concentrations of ketone bodies, CoA, and carnitine derivatives (except for malonyl-CoA) declined in the liver after LPS administration. The activity of palmitoyl-CoA synthetase was changed little after LPS administration, and the level of hepatic malonyl-CoA increased significantly, suggesting that LPS causes activated fatty acids to undergo esterification and lipogenesis rather than oxidation. Treatment of rats with L-carnitine before LPS greatly increased the survival rate, but did not affect enzymes that metabolize fatty acids, CoA, or carnitine derivatives in the liver. Further studies are necessary to elucidate the mechanism of the effect of carnitine on post-LPS survival.
This study was conducted to investigate the role of nitric oxide (NO) in the development of adult respiratory distress syndrome (ARDS). An experimental model of endotoxemia-induced ARDS was prepared in guinea pigs and the following parameters were measured: pulmonary vascular permeability, the nitrate and nitrite concentrations in blood and bronchoalveolar lavage fluid (BALF), and the activities of constitutive and inducible NO synthase in lung tissue following the administration of lipopolysaccharide (LPS). Following the intravenous administration of 0.5 mg/kg LPS, the pulmonary vascular permeability increased, as did the concentrations of nitrate and nitrite in the BALF and blood. The activities of both constitutive and inducible NO synthase (NOS) increased significantly in the lung tissue 4 h after the intravenous administration of LPS, the constitutive form showing significantly higher activity than the inducible form. Furthermore, the increase of vascular permeability in the lungs after LPS injection was blocked by the subcutaneous administration of N(G)-monomethyl-l-arginine. These observations indicate that the intrapulmonary generation of NO may play an important role in the development of ARDS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.