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Biomedical subjects

D Mantle

Publications and source records attributed to D Mantle.

At least 37 records · Page 2Linked to original sources
PubMed2000

Poor regression of myocardial hypertrophy following concomitant chronic alcohol ingestion and angiotensin converting enzyme (ACE) inhibition.

In the following study we examined the combined effect of chronic alcohol administration and anti-hypertensive drug treatment in spontaneously hypertensive rats (SHR). SHR were fed alcohol for six weeks while taking the angiotensin converting enzyme (ACE) inhibitor lisinopril. After six weeks, protein synthesis rates, contractile protein levels and protease activities were examined in control; alcohol; control+lisinopril; alcohol+lisinopril groups. Lisinopril treatment significantly reduced left ventricular mass, protein content and contractile proteins in control rats, but these effects were not as pronounced in alcohol+lisinopril rats. Protein synthesis rates in both mixed and myofibrillar fractions were not significantly different in any of the 4 groups. The enzyme activities of the proteases cathepsin D and dipeptidyl aminopepetidase I increased in control+lisinopril rats, however, this effect was not evident in alcohol+lisinopril rats. Contractile proteins identified by one-dimensional electrophoresis showed that lisinopril treatment reduced all contractile proteins in control rats. However, in alcohol+ lisinopril rats, myosin heavy chain was higher than in control+lisinopril rats. In summary, alcohol ingestion impairs the regression of the hypertrophic myocardium in SHR on ACE-inhibitor treatment, which was reflected by altered protein metabolism. This study suggests that successful anti-hypertensive treatment may not be achieved if alcohol misuse is evident.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

The selectin superfamily: the role of selectin adhesion molecules in delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage.

Cerebral ischaemia and reperfusion injury may be exacerbated by leukocyte recruitment and activation. Adhesion molecules play a pivotal role in leukocyte recruitment. We report a prospective study of the potential role of the selectin family of adhesion molecules (E-, P- and L-selectin) in delayed cerebral ischaemia (DID) following aneurysmal subarachnoid haemorrhage. In patients with good grade SAH, we have compared serum concentrations of E-, P- and L-selectin, between patients who do, and do not develop delayed cerebral ischaemia. There was no difference in E-selectin concentration between the two groups (44.0 ng/ml vs. 37.4 ng/ml). Serum P-selectin concentration was significantly higher in patients with DID compared to those patients without DID (149.5 ng/ml vs. 112.9 ng/ml, p = 0.039). Serum L-selectin concentrations were significantly lower in patients with DID (633.8 ng/ml vs 897.9 ng/ml, p = 0.013). We conclude that P- and L-selectin are involved in the pathogenesis of DID following aneurysmal subarachnoid haemorrhage. The results of this study do not elucidate the exact role of each selectin in DID.

Brain↗
PubMed2000

Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro.

Oxidative damage to normal human brain tissue was induced following exposure to hydroxyl (OH.) or superoxide (O2-.) free radical species generated by CO60 irradiation in vitro. Both enzymic and cytoskeletal proteins showed substantial (dose dependent) oxidative damage following exposure to OH. or O2-., as quantified by SDS-polyacrylamide gel electrophoretic analysis. Extracts of Ginkgo biloba or Panax ginseng showed a remarkable capacity to protect brain tissue proteins from oxidative damage in vitro, even at extreme (2000 kRads) dosage levels of OH. or O2-.. We suggest, therefore, that the beneficial effect of these plant extracts in preventing brain tissue damage in vivo (e.g. following ischemia-reperfusion) may result from their action in protecting brain proteins from oxidative damage, in addition to their previously reported capacity to reduce free radical induced lipid peroxidation.

Brain Damage, Chronic↗
PubMed2000

The role of proteolytic enzymes in focal ischaemic brain damage.

Although various neuroprotective and fibrinolytic drugs are currently under evaluation in the acute stages of ischaemic stroke, their therapeutic potential is likely to be limited by unwanted side effects and a narrow time window of opportunity for intervention. Proteolytic enzymes are involved in the catabolism of peptide neurotransmitters and structural cellular proteins in normal brain and have been implicated in the pathogenesis of neurodegenerative disorders. We hypothesised that activation of these enzymes might also play a crucial role in effecting ischaemic neuronal injury, thereby providing a potential site for therapeutic intervention in human stroke. Focal cerebral ischaemia was induced by thermocoagulation of the left middle cerebral artery in aged (30 month) male Wistar rats who were pre-treated with saline or the competitive N-methyl-D-Aspartate antagonist D-CPP-ene, which has been shown to be neuroprotective in young animal models of stroke. Major protease activities were analysed in the left (ischaemic) and right (non-ischaemic) hemispheres, following tissue homogenisation. Data have been analysed using Mann-Whitney tests and are presented as means +/- standard errors. Enzyme activity decreased in ischaemic brain; for example, the mean activity of dipeptidyl aminopeptidase I was 23 +/- 3 and 43 +/- 6 nmol substrate/hour/ml brain extract in the left and right hemispheres respectively (n = 10, p < 0.05). Ischaemic neuronal injury is not effected by the early activation of proteolytic enzymes and protease inhibitors are therefore unlikely to be of benefit in human stroke.

Animals↗
PubMed2000

Effects of lisinopril and amlodipine on antioxidant status in experimental hypertension.

The objective of this investigation was to compare changes in antioxidant status (together with other metabolites relevant to hypertension) in plasma and cardiac tissue from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), following 8 weeks of treatment with lisinopril (angiotensin converting enzyme inhibitor) or amlodipine (Ca(2+) channel antagonist) respectively. There was no significant difference in the levels of total antioxidant capacity, retinol, urea, albumin or triglyceride in plasma from SHR or WKY rats, with or without lisinopril or amlodipine treatment. However in SHR rats, levels of alpha-tocopherol were substantially reduced in both plasma (-54% WKY, P<0.01) and cardiac tissue (-43% WKY, P<0.05). Treatment with lisinopril ameliorated reduced levels of plasma alpha-tocopherol in SHR rats, but not in cardiac tissue. Amlodipine treatment had no effect on alpha-tocopherol levels in plasma or cardiac tissue in SHR rats. In SHR rats total cholesterol levels were significantly lower thanWKY controls (-36%, P<0.001). This effect was reversed in lisinopril treated SHR rats (+27%, P<0.01). Plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were reduced in untreated SHR rats (P<0.025) when compared to WKY controls; neither lisinopril nor amlodipine treatment significantly altered these parameters. These findings suggest possible alternative mechanisms of action for lisinopril, and reinforce its use in hypertensive patients or patients with left ventricular hypertrophy.

Amlodipine↗
PubMed2000

Comparative antioxidant potential of anaesthetics and perioperative drugs in vitro.

We have investigated the comparative antioxidant capacity of a range of anaesthetics (inhaled and intravenous) and perioperative neurosurgical drugs (at clinically relevant concentrations) using different radical species and assay methods in vitro. The highest levels of antioxidant activity against the ABTS(.+) radical were obtained with propofol (100 mmol/LTE) and dopamine (1080 mmol/LTE), respectively. However, only dopamine (12 mmol/l) showed antioxidant activity in protecting proteins in normal brain tissue from oxidative damage (assessed via SDS-PAGE analysis) induced by OH(.) or O(2)(-.) generated radiolytically in vitro. Neither dopamine nor propofol showed antioxidant activity against O(2)(-.) generated chemically via reaction between xanthine and xanthine oxidase in vitro. From these data, together with data on the relative antioxidant properties of anaesthetics/drugs obtained by other research groups which we have reviewed, we conclude that the apparent antioxidant activity of a given compound may depend entirely on the free radical species and/or the method of generation or assay employed. Finally, we suggest that on the basis of data obtained showing protection of brain proteins from oxidative damage induced by OH(.), or O(2)(-.) in vitro, further investigation into the in vivo antioxidant therapeutic potential of dopamine (or its analogues) on neurosurgical patients may be warranted.

Anesthetics, Inhalation↗
PubMed2000

Oxidative-stress: comparison of species specific and tissue specific effects in the marine bivalves Mytilus edulis (L.) and Dosinia lupinus (L.).

This study describes a novel approach to the objective of identifying a suitable biomarker of oxidative-stress in marine animals and evaluates an established assay under controlled experimental conditions in vivo and in vitro. Live animals and tissue homogenates of the euryoxic blue mussel Mytilus edulis (L.), and the stenoxic smooth artemis Dosinia lupinus (L.), were exposed to oxidative-stress generated using a 60Co gamma-radiation source. In live organisms, mortality-rates were significantly different between species. M. edulis showed zero mortality and D. lupinus 30% mortality over 18 h. Protein-carbonyl (PC=O) content was determined by colourimetric assay (total protein-carbonyl) or immunodetection (for individual proteins) in four tissue types: digestive gland, mantle, adductor muscle and foot. In tissue homogenates, digestive gland and adductor muscle of both species showed significant increases (greater for D. lupinus) in PC=O content following irradiation in vitro. All tissues from live animals (with the exception of M. edulis mantle and adductor muscle of D. lupinus which died under irradiation) showed significantly different levels of PC Os following irradiation; D. lupinus PC=O levels were increased whilst in M. edulis PC=O content decreased. In D. lupinus which died during irradiation, PC=O content was greater than in those D. lupinus which survived, particularly in the adductor muscle, the former were inceased by 74% above controls. The findings support the hypothesis that species-specific adaptations to euryoxic and stenoxic environments, and metabolic requirements of different tissues, should result in differing ROS defences.

Animals↗
PubMed2000

Comparison of relative antioxidant activities of British medicinal plant species in vitro.

We have determined the relative levels of endogenous antioxidant activity in a range of British medicinal plant species (representative of a variety of plant families, selected on the basis of their widespread use in traditional herbal medicine), via competitive scavenging of the ABTS(z.rad)(+) or O(2)(-)(z.rad) radicals in vitro. A number of plant species with appreciable levels (i.e. greater than or comparable with the activity in corresponding extracts of Ginkgo biloba or Panax ginseng, as recognised phytological sources of antioxidant activity) of antioxidant activity against the ABTS(z.rad)(+) radical were identified as potentially novel sources of free radical scavenging compounds; however none of these extracts showed measurable antioxidant activity when assayed against the O(2)(-)(z.rad) radical. It, therefore, follows that any comparative determination of antioxidant activity should clearly define the radical species and assay method employed. For those extracts showing activity against the ABTS(z.rad)(+) radical, in general, it was not possible to predict the potential antioxidant capacity of a given plant species (or the most active part of the plant) on a taxonomical basis, or from its use in traditional or modern medicine. In the longer term further characterisation of the active compounds from plant species with appreciable antioxidant activity identified in the present investigation may prove of value for treatment of disorders such as Alzheimer's disease, in which free radical induced tissue damage has been implicated.

Antioxidants↗
PubMed2000

Protein and mRNA levels of the myosin heavy chain isoforms Ibeta, IIa, IIx and IIb in type I and type II fibre-predominant rat skeletal muscles in response to chronic alcohol feeding.

Alcoholic myopathy occurs in between one and two-thirds of all alcohol misusers and is thus one of the most prevalent muscle disorders (2000 cases per 100,000 population). It is characterised by myalgia, muscle weakness and loss of lean tissue mass. Histological features include a reduction in the diameter of Type II muscle fibres, particularly the IIb fibre subset. In contrast, Type I fibres are relatively protected. It is possible that the myopathy is due to perturbations in myosin protein and mRNA expression. To test this hypothesis, we fed rats a liquid diet containing 35% of calories as ethanol. Control rats were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. At the end of 6 weeks, total myofibrillary proteins and myosin heavy chain (MyoHC) Ibeta, IIa, IIx and IIb protein and mRNA were analysed in the plantaris (Type II fibre-predominant) and soleus (Type I fibre-predominant) muscles. The data showed that there were significant reductions in the total myofibrillary protein content in the plantaris of ethanol fed rats compared to pair-fed controls (P < 0.05). These changes in the plantaris were accompanied by reductions in total myosin (P < 0.025), as a consequence of specific reductions in the Ibeta, (P < 0.01), IIx (P < 0.05) and IIb (P < 0.05) protein isoforms. The mRNA levels of Ibeta were significantly reduced in the plantaris (P < 0.05). However, mRNA levels of IIa, IIx and IIb in the plantaris were not significantly affected by alcohol feeding. Other changes in the plantaris included significant reductions in desmin (P < 0.01), actin (P < 0.025), and troponin-I (P < 0.05) compared to pair-fed controls. In the soleus, the only significant changes related to a fall in Ibeta mRNA levels and a decline in troponin-C content. We conclude that in the rat, alcoholic myopathy is a feature of Type II fibre rich muscles and is accompanied by multiple protein changes. The decline in specific myosin protein levels, such as IIx and IIb in the absence of corresponding reductions in their mRNAs, is probably due to altered proteolysis or more likely reductions in translational efficiencies, rather than changes in transcription.

Alcohol Drinking↗
PubMed2000

Comparison of proteolytic enzymes and glutathione S-transferase levels in non-heart-beating donors' (NHBD) kidney perfusates.

UNLABELLED: In order to identify biochemical markers of kidney damage prior to transplantation, we determined the levels of activity of a range of proteolytic enzymes in kidney perfusate samples from non-heart-beating donor (NHBD) cases. Urinary protease activities have been described as indices of kidney damage in renal disease; their potential as markers of tissue damage in kidneys before transplantation has not been assessed. In an attempt to identify additional/improved biochemical markers, the present study compared the levels of total glutathione S-transferase (GST) with corresponding levels of several proteolytic enzymes in perfusate fluid from machine perfused NHBD kidneys. Proteases were selected to represent factors that may influence enzyme efflux, such as intracellular localization or molecular size. METHODS: Perfusate samples were obtained over an 8-hour period from machine-preserved NHBD kidneys. Protease activities in these samples were determined by fluorometric assays and comparison made with total GST activity. Individual proteases were analysed in the transplanted and non-transplanted kidney groups (discarded on the basis of other viability parameters). RESULTS: A correlation between protease activity and total GST was obtained for only leucyl- and pyroglutamyl aminopeptidase. Furthermore, in the transplanted group, it was possible to set nominal upper limits of activity for alanyl-arginyl- and dipeptidyl IV-aminopeptidase (AP). In the non-transplanted kidney group protease levels were increased above "normal" upper limits for the same enzyme types. By the use of alanyl AP it was possible to discriminate 75% of unsuitable kidneys discarded by the use of other criteria. CONCLUSION: The lack of correlation between total GST and protease activity for most of the enzymes investigated and alanyl AP levels in perfusate samples could be related to differences in cellular localisation, suggesting that assays of alanyl AP may give complimentary biochemical information relating to kidney tissue damage. Quantification of alanyl AP in machine perfusate samples may be a valuable additional independent biomarker of tissue damage.

Endopeptidases↗
PubMed2000

Assessment of non-heart-beating donor (NHBD) kidneys for viability on machine perfusion.

UNLABELLED: The shortage of organs has resulted in renewed interest in organs from non-heart-beating donors (NHBD). Viability assessment of such organs may reduce the incidence of delayed graft function and primary non-function. In Phase III of the NHBD programme, introduction of machine perfusion enabled the assessment of these marginal donors. Since then the graft survival has been 88.4% compared with the previous phase where machine perfusion or viability assessment was not done (45.5%). The parameters used were total glutathione S-transferase (GST) in the perfusate, the intrarenal vascular resistance (IRVR) and flow characteristics over time. METHODS: All NHBD kidneys were machine perfused through a locally developed perfusion system. The viability was assessed by serial measurements of the above-mentioned parameters. RESULTS: Forty-two local NHBD kidneys were retrieved and one kidney was imported, of which 19 donors (i.e. 38 kidneys) were of the uncontrolled (category II) donors. After viability assessment on machine perfusion; two kidneys were discarded due to positive tests for syphilis, four kidneys had high total GST levels, five kidneys due to high IRVR and poor flow characteristics and one did not flush on retrieval. Three kidneys were exported after viability tests. In 28 NHBD kidney recipients, immediate graft function was seen in two kidneys, 22 (84.6%) developed delayed graft function. One kidney had primary non-function, and two recipients lost their grafts, due to chronic rejection and renal vein thrombosis. There were two deaths, unrelated to transplantation. Graft survival was achieved in 88.4% (23/26 graft survival in phase III) of cases. CONCLUSION: Machine perfusion and assessment of NHBD kidneys has been successfully introduced to the Newcastle NHBD programme. This approach, using renal transplants from largely category II donors produced a success rate of 88.4% which was significantly better than the phase II period (45.5%) of the program (p=0.023, Fisher 2 tail test).

Humans↗
PubMed2000

7alpha- and 7beta-hydroperoxycholest-5-en-3beta-ol in muscle as indices of oxidative stress: response to ethanol dosage in rats.

BACKGROUND: Alcohol-induced muscle disease (AIMD) encompasses both acute and chronic lesions, and affected patients exhibit concomitant functional and structural lesions. The pathogenic mechanisms are unknown, although it is possible that defects in the membrane-lipid domain are involved. Therefore, the effect of acute ethanol on membrane lipid from rat skeletal muscles (control, n = 7; ethanol, n = 7) was investigated. METHODS: Soleus and plantaris skeletal muscles were collected 24 hr after a single dose of 75 mmol/kg of ethanol. Lipids were analyzed by high-performance liquid chromatography with postcolumn chemiluminescence. RESULTS: We found that two cholesterol-derived hydroperoxides, 7alpha-hydroperoxycholest-5-en-3beta-ol (7alpha-OOH) and 7beta-hydroperoxycholest-5-en-3beta-ol (7beta-OOH) were present in soleus muscles of control animals (1.29 nmol/g and 3.20 nmol/g, respectively) and in plantaris (1.83 and 5.18 nmol/g, respectively). These hydroperoxides were significantly elevated by acute ethanol, in not only plantaris but also soleus skeletal muscle of rats. In contrast, protein carbonyl concentration, another indicator of oxidative stress, albeit to proteins, was not significantly affected in either soleus or plantaris muscles of ethanol dosed rats. In addition, gas chromatographic study of fatty acid composition from phospholipid of rat muscle showed a significant increase of 18:2 by ethanol in plantaris as well as soleus. Concomitant decreases occurred in the nonessential/essential fatty acid ratios. CONCLUSIONS: This is the first report on 7alpha-OOH and 7beta-OOH accumulation in rat skeletal muscle, and it seems to reflect greater oxidative stress in the pathology of muscle of rats treated with acute ethanol. Together with the elevation of 18:2, these results signify perturbations in membrane lipids in response to ethanol, which may have important implications for the pathogenesis of alcohol-induced muscle disorders.

Animals↗
PubMed2000

The effects of breed and level of nutrition on whole-body and muscle protein metabolism in pure-bred Aberdeen angus and Charolais beef steers.

Eighteen pure-bred steers (live weight 350 kg) from each of two breeds, Aberdeen Angus (AA) and Charolais (CH), were split into three equal groups (six animals each) and offered three planes of nutrition during a 20-week period. The same ration formulation was offered to all animals with amounts adjusted at 3-week intervals to give predicted average weight gains of either 1.0 kg/d (M/M group) or 1.4 kg/d (H/H group). The remaining group (M/H) were offered the same amount of ration as the M/M group until 10 weeks before slaughter when the ration was increased to H. Data on animal performance, carcass characteristics and fibre-type composition in skeletal muscle are presented elsewhere (Maltin et al. 2000; Sinclair et al. 2000). On three occasions (17, 10 and 2 weeks before slaughter) the animals were transferred to metabolism stalls for 1 week, during which total urine collection for quantification of Ntau-methylhistidine (Ntau-MeH) elimination was performed for 4 d. On the last day, animals were infused for 11 h with [2H5]phenylalanine with frequent blood sampling (to allow determination of whole-body phenylalanine flux) followed by biopsies from m. longissimus lumborum and m. vastus lateralis to determine the fractional synthesis rate of mixed muscle protein. For both breeds, the absolute amount of Ntau-MeH eliminated increased with animal age or weight (P < 0.001) and was significantly greater for CH steers, at all intake comparisons, than for AA (P < 0.001). Estimates of fractional muscle breakdown rate (FBR; calculated from Ntau-MeH elimination and based on skeletal muscle as a fixed fraction of live weight) showed an age (or weight) decline for M/M and H/H groups of both breeds (P < 0.001). FBR was greater for the H/H group (P = 0.044). The M/H group also showed a lower FBR for the first two measurement periods (both at M intake) but increased when intake was raised to H. When allowance was made for differences in lean content (calculated from fat scores and eye muscle area in carcasses at the end of period 3), there were significant differences in muscle FBR with intake (P = 0.012) but not between breed. Whole-body protein flux (WBPF; g/d) based on plasma phenylalanine kinetics increased with age or weight (P < 0.001) and was similar between breeds. The WBPF was lower for M/M compared with H/H (P < 0.001) based on either total or per kg live weight0.75. Muscle protein fractional synthesis rate (FSR) declined with age for both breeds and tended to be higher at H/H compared with M intakes (intake x period effects, P < 0.05). Changing intake from M to H caused a significant increase (P < 0.001) in FSR. The FSR values for AA were significantly greater than for CH at comparable ages (P = 0. 044). Although FSR and FBR responded to nutrition, these changes in protein metabolism were not reflected in differences in meat eating quality (Sinclair et al. 2000).

Age Factors↗
PubMed2000

Free radicals as mediators of toxicity in Alzheimer's disease: a review and hypothesis.

Recent research has increasingly suggested a central role for free radical induced tissue damage in the pathogenesis of Alzheimer's disease (AD). In this paper we review evidence for the interaction between free radicals and other major factors/metabolic areas which have also been implicated in AD, including beta-amyloidosis, inflammatory cytokines, mitochondrial dysfunction and metal ions/homocysteine. We hypothesize that free radicals and antioxidants should not be considered in isolation in the aetiology and treatment of AD. It is the reciprocal induction and self-amplifying interplay between all of the above factors which is important in the pathogenesis of this disorder, and to which multi-pharmacological therapeutic strategies should be directed.

Alzheimer Disease↗
PubMed2000

Therapeutic applications of medicinal plants in the treatment of breast cancer: a review of their pharmacology, efficacy and tolerability.

Various active compounds (or their semi-synthetic derivatives) derived from medicinal plants have been assessed for their efficacy and tolerability in the treatment of breast cancer. Some of these plant species, including Taxus baccata (paclitaxel, docetaxel), Podophyllum peltatum (etoposide), Camptotheca acuminata (camptothecin) and Vinca rosea (vinblastine, vinorelbine) have well recognized antitumour activity in breast cancer, and have been evaluated in clinical trials. For example, results from recent Phase II/III trials have established docetaxel as the most active single agent in the treatment (first or second-line) of advanced metastatic breast cancer. For other plant species such as Panax ginseng and Allium sativum, antitumour activity has been evaluated in experimental studies using cultured cells and animal models, but the therapeutic potential in patients remains to be determined. Antitumour activity derived from medicinal plants may produce results via a number of mechanisms, including effects on cytoskeletal proteins which play a key role in mitosis (paclitaxel), inhibition of activity of topoisomerase enzymes I (camptothecin) or II (etoposide), stimulation of the immune system (Viscum album), or antiprotease-antioxidant activity. Medicinal plant-derived antineoplastic agents may be used in single agent or in combinational therapies, and have been used in first-line or second-line (including anthracycline-refractory patients) treatment of localized or metastatic breast cancer. Adverse effects resulting from the use of these agents include neutropenia and peripheral neuropathies.

Animals↗
PubMed2000

Carbonyl levels in type I and II fiber-rich muscles and their response to chronic ethanol feeding in vivo and hydroxyl and superoxide radicals in vitro.

BACKGROUND: Chronic alcoholic myopathy is characterized by selective reductions in the size of Type II skeletal muscle fibers (i.e., glycolytic, anaerobic fast-twitch). Type I (i.e., oxidative, aerobic, slow twitch) fibers are relatively resistant. It is possible that reactive oxygen species may preferentially damage the Type II fibers because the concentrations of several antioxidant enzymes are lower in Type II compared with Type I fibers. METHODS: To test the hypothesis, we measured protein carbonyl levels in Type I (i.e., soleus) and Type II (i.e., plantaris) fiber-rich muscles of rats subjected to chronic alcohol dosage with the Lieber-DeCarli regimen. Muscles were also exposed to hydroxyl or superoxide radicals in vitro. RESULTS: The Type I fiber-predominant soleus of control animals had less carbonyl than the Type II fiber-predominant plantaris. In rats that were fed ethanol for 6 weeks, the weights of the plantaris muscle were preferentially reduced but changes in soleus weight did not achieve significance. However, carbonyl levels were not significantly altered in any muscle in response to alcohol feeding. Calculation of the data in terms of total carbonyl per whole muscle showed decreases in both soleus and plantaris at the end of the 6-week alcohol feeding period. In response to hydroxyl radical (OH*) generation in vitro, protein carbonyl increased substantially in both soleus and plantaris muscles, but more so in the soleus. The increase in carbonyl in control soleus muscles in response to OH* was significantly lower than in soleus muscles from alcohol-fed animals. The increase in control plantaris muscle was not significantly different from the increase in carbonyl in corresponding muscles from ethanol-fed rats in response to OH*. In response to superoxide radicals, carbonyl in control soleus increased, an effect similar to that recorded in the soleus from ethanol-fed rats. In control plantaris, carbonyl increased in response to superoxide radicals, an effect not significantly different to the increase in plantaris from alcohol-fed rats. CONCLUSIONS: Using increased carbonyl concentrations as an indicator of muscle damage by reactive oxygen species, we concluded (1) there is no evidence of enhanced reactive oxygen species-induced damage to mixed muscle proteins in either Type I or Type II muscles in response to alcohol feeding; (2) Type II muscles have a greater capacity than Type I muscles to protect against damage (as indicated by carbonyl formation) by both hydroxyl and superoxide radicals in vitro; (3) alcohol reduces the capacity of Type I muscle to resist hydroxyl radical-induced protein damage, a mechanism that may arise through impairment of other antioxidant systems or other process not yet elucidated.

Alcoholism↗
PubMed1999

Oxidants, antioxidants and alcohol: implications for skeletal and cardiac muscle.

The chronic form of alcoholic skeletal myopathy is characterized by selective atrophy of Type II fibers and affects up to two thirds of all alcohol misusers. Plasma selenium and alpha-tocopherol are reduced in myopathic alcoholics compared to alcoholic patients without myopathy. Plasma carnosinase is also reduced in myopathic alcoholics, implicating a mechanism related to reduced intramuscular carnosine, an imidazole dipeptide with putative antioxidant properties. Together with the observation that alcoholic patients have increased indices of lipid peroxidation, there is evidence suggestive of free radical (i.e., unpaired electrons or reactive oxygen species) mediated damage in the pathogenesis of alcohol-induced muscle disease. Protein synthesis is a multi-step process that encompasses amino acid transport, signal transduction, translation and transcription. Any defect in one or more of the innumerable components of each process will have an impact on protein synthesis, as determined by radiolabelling of constituent proteins. Both acute and chronic alcohol exposure are associated with a reduction in skeletal muscle protein synthesis. Paradoxically, alcohol-feeding studies in rats have shown that the imidazole dipeptide concentrations are increased in myopathic muscles though alpha-tocopherol contents are not significantly altered. In acutely dosed rats, where protein synthesis is reduced, protein carbonyl concentrations (an index of oxidative damage to muscle) also decline slightly or are unaltered, contrary to the expected increase. Alcoholic cardiomyopathy can ensue from heavy consumption of alcohol over a long period of time. The clinical features include poor myocardial contractility with reduced left ventricular ejection volume, raised tissue enzymes, dilation of the left ventricle, raised auto- antibodies and defects in mitochondrial function. Whilst oxidant damage occurs in experimental models, however this issues remains to be confirmed in the clinical setting. In the rat, circulating troponin-T release increases in the presence of ethanol, a mechanism ascribed to free radical mediated damage, as it is prevented with the xanthine oxidase inhibitor and beta-blocker, propranolol. However, whilst propranolol prevents the release of troponin-T, it does not prevent the fall in whole cardiac protein synthesis, suggestive of localized ischemic damage due to ethanol.

Animals↗