Reversibility of mitochondrial and contractile changes in the myocardium after cessation of prolonged ethanol intake

Weishaar, Ronald E.; Sarma, J. S. M.; Maruyama, Yukio; Fischer, Renate; Bertuglia, Silvia; Bing, Richard J.

doi:10.1016/0002-9149(77)90071-6

Cited by 65 publications

(17 citation statements)

References 28 publications

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“…Over the past 20 yr, light and electron microscopic changes in mitochondrial structure and function have been documented in myocardium from animals (11,12) and human subjects (13,14) exposed to ethanol. After a lag period of ethanol exposure in vivo, mitochondria isolated from the heart exhibit impaired rates of oxygen consumption, diminished respiratory control, and reduced P/O ratios (15)(16)(17)(18). Although such changes may regress in vivo with cessation of exposures to ethanol, reversibility is not immediate but requires up to 8 wk (17).…”

Section: Methodsmentioning

confidence: 99%

“…After a lag period of ethanol exposure in vivo, mitochondria isolated from the heart exhibit impaired rates of oxygen consumption, diminished respiratory control, and reduced P/O ratios (15)(16)(17)(18). Although such changes may regress in vivo with cessation of exposures to ethanol, reversibility is not immediate but requires up to 8 wk (17).…”

Section: Methodsmentioning

confidence: 99%

“…Consumption of alcohol over several weeks leads to gross morphological changes in heart mitochondria in laboratory animals (11,12) and human subjects (13,14). Impairment of mitochondrial function has been noted as well and it includes diminished phosphate/oxygen ratios (P/O)' and respiratory control ratios (15)(16)(17)(18); these are changes that do not occur after exposure of mitochondria to ethanol in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol.

Lange¹,

Sobel²

1983

J. Clin. Invest.

230

106

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A B S T R A C T Mechanisms responsible for alcohol-induced heart muscle disease have been difficult to elucidate partly because of previously obscure, demonstrable cardiac metabolism of ethanol. Recently, fatty acid ethyl esters were identified in our laboratory and found to be myocardial metabolites of ethanol. In the present study, they have been shown to induce mitochondrial dysfunction. Incubation of isolated myocardial mitochondria with fatty acid ethyl esters led to a concentration-dependent reduction of the respiratory control ratio index of coupling of oxidative phosphorylation and decrement of maximal rate of oxygen consumption. Furthermore, fatty acid ethyl esters were demonstrated to bind to mitochondria in vitro, and, importantly, 72% of intracellularly synthesized ethyl esters were found to bind to mitochondria isolated from intact tissue incubated with ethanol. Protein binding of fatty acid ethyl esters was markedly less than that of fatty acids. Because uncoupling of mitochondrial oxidative phosphorylation correlated with the cleavage of fatty acid ethyl ester shown to be initially bound to mitochondria, with resultant generation of fatty acid, a potent uncoupler, in a locus in or near the mitochondrial membrane, fatty acid ethyl esters may contribute to a potentially toxic shuttle for fatty acid with transport from physiological intracellular binding sites to the mitochondrial membrane; direct effects of fatty acid ethyl esters may also be deleterious. Operation of this shuttle as a result of ethanol ingestion and subsequent accumulation of fatty acid ethyl esters may account for the impaired mitochondrial function and inefficient energy production associated with toxic effects of ethanol on the heart.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol.

Lange¹,

Sobel²

1983

J. Clin. Invest.

230

106

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“…(Circ Res 52: 479-482, 1983) ALCOHOL-INDUCED heart muscle disease afflicts more than 200,000 patients (Bridgen and Robinson, 1964;Fink et al, 1979) and accounts for 3% of all cardiac admissions to city hospitals in the United States (Kramer et al, 1968). Manifestations include accumulation of myocardial triglycerides (Lochner et al, 1969;Regan et al, 1966;Ferrans et al, 1965;Kikuchi and Kako, 1970), decreased /J-oxidation of fatty acids (Kramer et al, 1968;Lochner et al, 1969;Regan et al, 1966;Segal at al., 1979), high grade atrial and ventricular arrhythmias, and congestive heart failure (Schwartz et al, 1975;Weishaar et al, 1977;Bing, 1978;Demakis et al, 1974). These and other abnormalities result from ethanol abuse even in the absence of vitamin and caloric deprivation (Segal et al, 1979;Robin and Goldschlager, 1970;Regan et al, 1977).…”

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confidence: 99%

Myocardial metabolites of ethanol.

Lange¹,

Sobel²

1983

Circulation Research

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SUMMARY. Because of the importance of alcohol-induced heart muscle disease and the obscurity of its pathogenesis, this study was undertaken to determine whether fatty acid ethyl esters, myocardial metabolites of ethanol recently described in our laboratory to be synthesized in cell-free extracts of rabbit myocardium, accumulate in hearts of human subjects exposed to ethanol in vivo. Lipid extracts were prepared from left ventricular samples obtained at necropsy from six subjects who had been exposed to ethanol acutely or chronically. Fatty acid ethyl esters were present in each extract in concentrations ranging from 9 to 115 JUM. In contrast, they were consistently absent from analogous samples obtained from hearts of abstainers (n = 5). In parallel studies in experimental animals, we found that fatty acid ethyl esters are formed not only in the heart but also in the pancreas and liver-targets of injury associated with chronic alcohol abuse. These results demonstrate the presence in human myocardium of a novel metabolite of ethanol that potentially may serve as a marker for exposure to alcohol and that could be relevant to the pathophysiology of excessive alcohol consumption leading to cardiac abnormalities. (Circ Res 52: [479][480][481][482] 1983)

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“…Studying alcoholic cardiomyopathy in the chronic animal experiment, many different species have been investigated: mice (1,4,5,14), rats (13,17,18,21,24,25,26,30,31,35,39,40), guinea pigs (7), rabbits (19,32), dogs (3,9,20,28,33), rhesus monkeys (38).…”

Section: Discussionmentioning

confidence: 99%

Is the rat a suitable model for studying alcoholic cardiomyopathy? Hemodynamic studies at various stages of chronic alcohol ingestion

Hepp¹,

Rudolph²,

Kochsiek³

1984

Basic Res Cardiol

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Three groups of wistar rats with chronic alcohol consumption were studied: 10% ethanol for 6 months, 20% ethanol for 7 months, 20% ethanol for 12 months. In the intact heart in situ, left ventricular parameters of pressure, volume, and blood flow were recorded. On the average, body weight and heart weight of the alcohol-fed rats (A) were diminished by 10% as compared with controls (C). If end-diastolic volume is related to heart weight, no significant differences in the pressure-volume relations between C and A were obtained. There were no differences in the rate of pressure rise, nor in the end-systolic pressure-volume relations. According to these findings and the results of other authors, it is concluded that the rat is not very suitable for studying "alcoholic cardiomyopathy".

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Reversibility of mitochondrial and contractile changes in the myocardium after cessation of prolonged ethanol intake

Cited by 65 publications

References 28 publications

Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol.

Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol.

Myocardial metabolites of ethanol.

Is the rat a suitable model for studying alcoholic cardiomyopathy? Hemodynamic studies at various stages of chronic alcohol ingestion

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