The nature and mechanism of action of uncoupling agents present in mitochrome preparations

Hülsmann, W.C.; Elliott, W.B.; Slater, E.C.

doi:10.1016/0006-3002(60)90163-3

Cited by 123 publications

(24 citation statements)

References 22 publications

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“…Early attention centered on the actions of FFA to interfere with mitochondrial respiration. It was determined that excess FFA uncoupled electron transport from oxidative phosphorylation, inhibited oxidation per se, impaired ATP-inorganic phosphate exchange, and stimulated mitochondrial ATPase (2,(29)(30)(31) Carnitine, an abundant normal constituent in myo-URE 4 Mechanical functions in FFA-supplemented hearts cardium, functions as a carrier of activated long-chain iving either DL-carnitine (closed triangles) or L-carnitine fatty acyl groups from the cytoplasm to the intramiton triangles). In general, during control and ischemic chondrial sites of fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms for this action are not yet known, but most likely they relate to the increased local concentrations of various fatty acid intermediates and their inhibitory effects on intracellular enzyme systems and membrane transport functions (2)(3)(4)(5)(6)(7). The esters of long-chain acyl CoA represent one such group ofthese inhibitory FFA intermediates.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Carnitine in Ischemic and Fatty Acid Supplemented Swine Hearts

Liedtke¹,

Nellis²,

Copenhaver³

1979

J. Clin. Invest.

102

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A B S T R A C T Free fatty acids (FFA) in excess FFA: albumin molar ratios have been determined to additionally compromise mechanical performance in ischemic hearts. Carnitine, an intracellular carrier of FFA and an agent which is lost to the heart during ischemia, has been postulated to in part restore function with its replacement. To test whether its benefits are also operative in a setting of excess FFA, these studies were performed. In the main protocol, four groups ofperfused swine hearts (n = 45) were compared during 50 min of control flow (179.7 ml/min) and 40 min of global ischemia (106.1 ml/min). Initial base-line serum FFA:albumin molar ratios and carnitine levels in all groups were 1.3:1 and 8.5 nmol/ml, respectively. In two of these groups FFA:albumin ratios were increased to 5.9:1 with constant infusions of Intralipid. In two alternate groups (one with and one without extra FFA supplements) DL-carnitine was supplied, sufficient to increase serum levels nearly 200-fold. Ischemia per se in 14 hearts significantly decreased several parameters of global and regional mechanical function including left ventricular (LV) and mean aortic pressures, LV isovolumetric pressure development (max dp/dt), LV epicardial motion, and LV work, together with concomitant decreases in myocardial oxygen consumption. Elevated FFA in 12 hearts rendered similarly ischemic further decreased mechanical function (LV pressure: -20.8%, P < 0.05; mean aortic pressure -26.9%, P < 0.05; LV max dp/dt: -39%, P < 0.05; regional LV shortening: -51.1%, P < 0.05; and LV work: -50.3%, P < 0. 15 March 1979. 440 dynamic performance. However, DL-carnitine in 10 high FFA-ischemic hearts effected several improvements as compared with the untreated group: LV pressure was increased 25.6%, P < 0.025; mean aortic pressure: +43.5%, P < 0.05; LV max dp/dt: +41.5%, P < 0.05; regional LV shortening: +241.3%, P < 0.001; and LV work: +76.2%, P < 0.05 at comparable levels of myocardial oxygen consumption. In a separate protocol, the effects of stereospecificity were also studied by comparing L-with DL-carnitine in globally perfused, palmitate-supplemented hearts (five hearts in each treatment group). At similar conditions of flow and serum FFA, changes in mechanical function were comparable, except for a tendency to perform greater LV work at reduced flows in the L-carnitine-treated hearts. Thus, it was demonstrated that carnitine in ischemic hearts is capable of preserving mechanical function under conditions of excess FFA, presumably by modifying the toxic effects of FFA intermediates. The major therapeutic actions appeared to derive from the L-isomer of carnitine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Carnitine in Ischemic and Fatty Acid Supplemented Swine Hearts

Liedtke¹,

Nellis²,

Copenhaver³

1979

J. Clin. Invest.

102

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“…It is also possible that at least part of the initial stimulation of 02 consumption is due to the ability of fatty acids to uncouple oxidative phosphorylation. 40 The diminution in the supply of ATP that would thus result, would however in time lead to a failure of the re-esterification process with a consequent greater accumulation of fatty acids.…”

mentioning

confidence: 99%

On the Action of Hormones Which Accelerate the Rate of Oxygen Consumption and Fatty Acid Release in Rat Adipose Tissue in Vitro

Ball¹,

Jungas²

1961

Proc. Natl. Acad. Sci. U.S.A.

180

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“…13,35). WAith plant mitochondria there are fewv details on the nature of fatty acid uncoupling, but there is considerable evidence that uncouipling does occur.…”

mentioning

confidence: 99%