V B Patel

University of Westminster, Londinium, England, United Kingdom

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Publications (59)240.87 Total impact

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    ABSTRACT: Chronic ethanol consumption causes increased production of reactive oxygen species in hepatic mitochondria accompanied by elevations in products of lipid peroxidation such as 4-hydroxynonenal (4-HNE). In the current study we investigated the effects of chronic ethanol consumption on a prominent protein-4-HNE adduct in liver mitochondria. Male Sprague-Dawley rats were fed a liquid diet for 31 days in which ethanol constituted 36% of total calories. Immunoblot analyses of liver mitochondria from ethanol-fed and control animals, using an antibody to a 4-HNE-protein adduct, demonstrated elevated 4-HNE binding (+50%) to a mitochondrial protein of approximately 55 kDa due to chronic ethanol consumption. Analysis of this protein using AspN digestion and tandem mass spectrometry identified it as the mitochondrial form of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase. Activity of the activated form of this enzyme was unchanged in livers from ethanol-fed animals, but the protein level was elevated by 36%, which suggests a compensatory mechanism to maintain constant levels of synthase activity in the mitochondrion in the face of continuous inactivation by 4-HNE. Treatment of isolated mitochondria with 4-HNE demonstrated that the enzyme activity decreased as a function of 4-HNE concentration and with time of exposure. This study demonstrates that ethanol consumption increases the formation of a 4-HNE adduct with mitochondrial HMG-CoA synthase, which has the potential to inactivate the enzyme in situ.
    Free Radical Biology and Medicine 01/2008; 43(11):1499-507. DOI:10.1016/j.freeradbiomed.2007.08.004 · 5.71 Impact Factor
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    ABSTRACT: Previous immunohistochemical studies have shown that the post-translational formation of aldehyde-protein adducts may be an important process in the aetiology of alcohol-induced muscle disease. However, other studies have shown that in a variety of tissues, alcohol induces the formation of various other adduct species, including hybrid acetaldehyde-malondialdehyde-protein adducts and adducts with free radicals themselves, e.g. hydroxyethyl radical (HER)-protein adducts. Furthermore, acetaldehyde-protein adducts may be formed in reducing or non-reducing environments resulting in distinct molecular entities, each with unique features of stability and immunogenicity. Some in vitro studies have also suggested that unreduced adducts may be converted to reduced adducts in situ. Our objective was to test the hypothesis that in muscle a variety of different adduct species are formed after acute alcohol exposure and that unreduced adducts predominate. Rabbit polyclonal antibodies were raised against unreduced and reduced aldehydes and the HER-protein adducts. These were used to assay different adduct species in soleus (type I fibre-predominant) and plantaris (type II fibre-predominant) muscles and liver in four groups of rats administered acutely with either [A] saline (control); [B] cyanamide (an aldehyde dehydrogenase inhibitor); [C] ethanol; [D] cyanamide+ethanol. Amounts of unreduced acetaldehyde and malondialdehyde adducts were increased in both muscles of alcohol-dosed rats. However there was no increase in the amounts of reduced acetaldehyde adducts, as detected by both the rabbit polyclonal antibody and the RT1.1 mouse monoclonal antibody. Furthermore, there was no detectable increase in malondialdehyde-acetaldehyde and HER-protein adducts. Similar results were obtained in the liver. Adducts formed in skeletal muscle and liver of rats exposed acutely to ethanol are mainly unreduced acetaldehyde and malondialdehyde species.
    Alcohol and Alcoholism 09/2005; 40(6):485-93. DOI:10.1093/alcalc/agh196 · 2.09 Impact Factor
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    ABSTRACT: Liver disease has been shown to affect the cardiovascular system and may influence cardiac protein metabolism. This hypothesis was tested by measuring rates of cardiac protein synthesis in 2 models of liver disease in rats. The study consisted of 5 groups--group 1: control, injected with saline and fed ad libitum; group 2: acute liver injury, by dosage with 400 mg/kg galactosamine; group 3: injected with saline and pair-fed to group 2; group 4: chronic liver disease, using bile duct ligation; and group 5: sham-operated and pair-fed to group 4. Rates of cardiac protein synthesis were measured using the flooding dose technique. After 1 week, galactosamine injection caused the following cardiac changes, i.e. group (2) versus (3): an increased RNA content, RNA/DNA ratio, and RNA/protein ratio. However, there was no change in DNA or protein content, or protein/DNA ratio. There was an increase in the fractional rate of protein synthesis, and the absolute synthesis rate. Cellular efficiency was increased, but RNA activity remained unchanged. Comparison of groups 4 and 5 showed that bile duct ligation caused no change in any parameters measured. Although comparison of the ad libitum-fed group 1 with the bile duct ligation group 4 showed reduced cardiac weight, protein, and RNA content, with decreased right ventricular absolute synthesis rates; this was also seen in the pair-fed group 5, suggesting that these effects were due solely to reduced oral intake. Thus, although galactosamine-induced acute liver injury caused marked changes in cardiac biochemistry, bile duct ligation per se did not. This study also illustrates the importance of including a pair-fed group.
    Metabolism 09/2004; 53(8):964-8. DOI:10.1016/j.metabol.2003.11.015 · 3.61 Impact Factor
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    ABSTRACT: This article represents the proceedings of a symposium at the 2002 RSA-ISBRA Meeting in San Francisco. The chairs were Vinood B. Patel and Victor R. Preedy. The presentations were (1) Macromolecular structural analysis, by Vinood B. Patel; (2) Profiling and imaging of proteins in tissue sections using mass spectrometry as a discovery tool in biological research, by Pierre Chaurand and Richard M. Caprioli; (3) The use of SELDI ProteinChip trade mark arrays, by Brian M. Austen, Emma R. Frears, Francesca Manca, and Huw Davies; (4) DNA hybridization array technologies, by Kent E. Vrana; and (5) Adeno- and adeno-associated viral mediated gene transfer approaches for alcoholic liver disease, by Michael Wheeler. Concluding remarks were by Victor R. Preedy.
    Alcoholism Clinical and Experimental Research 03/2003; 27(2):348-53. DOI:10.1097/01.ALC.0000052580.14492.21 · 3.31 Impact Factor
  • Hepatology 01/2003; 38:393-393. DOI:10.1016/S0270-9139(03)80526-8 · 11.19 Impact Factor
  • Vinood B Patel, Carol C Cunningham
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    ABSTRACT: Chronic ethanol consumption decreases the synthesis of all 13 polypeptides encoded by the hepatic mitochondrial genome. This alteration in mitochondrial protein synthesis is due to modifications in mitochondrial ribosomes. In the current study, the nature of these alterations was investigated by determining some of the hydrodynamic properties, namely sedimentation coefficient, shape, and mass of mitochondrial ribosomes. The effect of ethanol consumption on the capacity for mitochondrial ribosomes to translate proteins was also determined using an in vitro Poly (U) assay system. Rats were fed the Lieber-DeCarli diet for 31 days with ethanol as 36% of total calories. The sedimentation coefficient, measured by sedimentation velocity analyses, was slightly, but significantly lower in ethanol mitochondrial ribosomes (53.2 +/- 0.5S) when compared with pair-fed controls (54.1 +/- 0.5S) (P = 0.04). Mitochondrial ribosomes from ethanol-fed animals also had a greater tendency to dissociate into subunits. The diffusion coefficient, determined by dynamic light scattering, was lower in mitochondrial ribosomes from ethanol-fed rats than pair-fed controls and this indicated a significantly greater diameter for ethanol ribosomes (42.1 +/- 0.2 nm) than for preparations from pair-fed controls (39.1 +/- 0.5 nm; P = 0.008). These alterations to ethanol mitochondrial ribosomes occurred despite no change in molecular mass, which suggested a significant ethanol-related shape change in the ribosomes. The translation capacity of mitochondrial ribosome preparations from ethanol-fed animals was markedly reduced due to dissociation of the monosome into light and heavy subunits. In summary, these observations demonstrate that chronic ethanol consumption causes significant structural and functional alterations to mitochondrial ribosomes. The loss in ribosome function leads to impaired mitochondrial polypeptide synthesis and is an example of a pathology giving rise to an alteration in the mitochondrial ribosome structure.
    Archives of Biochemistry and Biophysics 03/2002; 398(1):41-50. DOI:10.1006/abbi.2001.2701 · 3.04 Impact Factor
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    ABSTRACT: Heavy alcohol consumption from either long-term misuse or binge drinking is associated with poor cardiac contractility, mitochondrial dysfunction, and ventricular arrhythmias. The aim of this study was to measure circulating cardiac troponin-T as a marker for myocardial damage following acute and chronic alcohol administration. In acute studies, male Wistar rats were treated with alcohol (75 mmol/kg body weight, intraperitoneal) and plasma was collected 2.5 hr after alcohol administration for analysis of rat cardiac troponin-T. In addition, rats were pretreated with cyanamide (an inhibitor of acetaldehyde dehydrogenase), various beta-blockers, xanthine oxidase inhibitors, or lisinopril before acute alcohol dosing. In chronic studies, rats were fed alcohol (as 35% of total dietary calories) for 6 weeks. The results of the time course study showed that acute alcohol administration significantly raised plasma cardiac troponin-T levels after 2.5 hr and 6 hr, but not after 24 hr. The effects of alcohol on cardiac troponin-T were potentiated with cyanamide pretreatment. Acute ethanol, alone or with cyanamide pretreatment, decreased systolic blood pressure and increased heart rates. Beta-blocker pretreatment with propranolol reduced the alcohol-induced increase in plasma troponin-T, whereas lisinopril potentiated this effect. The beta-blockers, atenolol and metoprolol, and the xanthine oxidase inhibitors, allopurinol and oxypurinol, were unable to reduce elevated troponin-T. However, pretreatment with the beta-blocker timolol moderated the acute alcohol-induced increase in troponin-T. In the chronic alcohol rat model, no differences were observed between alcohol and control pair-fed rats, suggesting the inducement of tolerance. In conditions of acute exposure, ethanol-induced lesions are characterized by raised plasma cardiac troponin-T possibly due to beta1 and/or beta2 adrenergic activation.
    Alcoholism Clinical and Experimental Research 07/2001; 25(6):882-9. DOI:10.1097/00000374-200106000-00014 · 3.31 Impact Factor
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    ABSTRACT: Alcohol-induced liver damage is associated with oxidative stress, which might be linked to disturbances in liver antioxidant defense mechanisms. The effect of chronic ethanol consumption on the mitochondrial and cytosolic glutathione/glutathione peroxidase-1 (GSHPx-1) system and oxidative modification of proteins was therefore studied in the rat. Male Sprague-Dawley rats were fed liquid diets that provided 36% total calories as ethanol for at least 31 days. Pair-fed controls received isocaloric diets with ethanol calories substituted with maltose-dextrins. Mitochondrial and cytosolic fractions were prepared from livers and assayed for GSHPx-1 and glutathione reductase activities and total and oxidized concentrations of glutathione. Catalase activity was measured in the postmitochondrial supernatant. Levels of GSHPx-1, lactate dehydrogenase, and the beta subunit of the F1 portion of the ATP synthase protein were determined by western blot analysis. Concentrations of mitochondrial and cytosolic protein carbonyls were measured to assess ethanol-induced oxidation of proteins. Chronic ethanol consumption significantly decreased cytosolic and mitochondrial GSHPx-1 activities by 40% and 30%, respectively. Levels of GSHPx-1 protein in cytosol were unaffected by ethanol feeding, whereas there was a small decrease in GSHPx-1 protein levels in mitochondria isolated from ethanol-fed rats. Glutathione reductase activities were increased in both intracellular compartments and catalase activity was increased as a consequence of ethanol exposure. Cytosolic total glutathione was mildly decreased, whereas ethanol feeding increased mitochondrial levels of total glutathione. Chronic ethanol feeding significantly increased both cytosolic and mitochondrial concentrations of protein carbonyls by 30% and 60%, respectively. This study demonstrates that chronic ethanol-induced alterations in the glutathione/GSHPx-1 antioxidant system might promote oxidative modification of liver proteins, namely those of the mitochondrion, which could contribute to the adverse effects of ethanol on the liver.
    Alcoholism Clinical and Experimental Research 06/2001; 25(5):726-33. DOI:10.1111/j.1530-0277.2001.tb02273.x · 3.31 Impact Factor
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    ABSTRACT: Although chronic diarrhea affects heart function and morphology, the pathogenic mechanisms are unknown. It was our hypothesis that diarrhea imposes metabolic stress to inhibit the synthesis of new contractile proteins. To test this hypothesis, we investigated the effects of lactose-induced diarrhea in rats. The groups were: 1) freely fed controls, 2) rats with lactose-induced diarrhea or 3) pair-fed rats. After 1 wk, hearts from the rats were subjected to subcellular fractionation techniques to isolate the major protein fractions, including myofibrillar proteins. The rates of protein synthesis were measured with concomitant assay of cardiac composition and plasma analytes. In comparison with the control group, diarrhea induced the following changes (P < 0.05): a decrease in heart weight, reduced RNA and mixed protein contents and a reduction in the fractional rate of mixed protein synthesis. There was a reduction in the content of all protein fractions. The fractional synthesis rate was reduced only for the myofibrillar fraction. Plasma insulin-like growth factor-I, but not corticosterone, was reduced. Plasma cholesterol and triglyceride concentrations were also reduced. In comparison with the pair-fed group, diarrhea induced the following changes (P < 0.05): a reduction in heart weight and fractional rate of mixed protein synthesis, reduced myofibrillar absolute synthesis rate and increased sarcoplasmic/myofibrillar fractional synthesis rate ratio. Plasma bicarbonate, triglyceride and urea concentrations were reduced, with an increase in albumin. Diarrhea impaired cardiac biochemistry, including a reduction in protein content and synthesis. A substantial proportion of these changes is due to anorexia, but the selective reduction in the synthesis of contractile proteins is a feature exclusive to the diarrhea group and may be due to reductions in plasma insulin-like growth factor-I.
    Journal of Nutrition 06/2001; 131(5):1513-9. · 4.23 Impact Factor
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    ABSTRACT: This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Albert Y. Sun. The presentations were (1) Ethanol-inducible cytochrome P-4502E1 in alcoholic liver disease, by Magnus Ingelman-Sundberg and Etienne Neve; (2) Regulation of NF-kappaB by ethanol, by H. Matsumoto, Y. Nishitani, Y. Minowa, and Y. Fukui; (3) Chronic ethanol consumption increases concentration of oxidized proteins in rat liver, by Shannon M. Bailey, Vinood B. Patel, and Carol C. Cunningham; (4) Antiphospholipids antibodies and oxidized modified low-density lipoprotein in chronic alcoholic patients, by Tomas Zima, Lenka Fialova, Ludmila Mikulikova, Ptr Popov, Ivan Malbohan, Marta Janebova, and Karel Nespor; and (5) Amelioration of ethanol-induced damage by polyphenols, by Albert Y. Sun and Grace Y. Sun.
    Alcoholism Clinical and Experimental Research 06/2001; 25(5 Suppl ISBRA):237S-243S. · 3.31 Impact Factor
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    ABSTRACT: This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Carol C. Cunningham and Victor R. Preedy. The presentations were (1) Ribosomal content, ribosomal localization and the levels of ribosomal protein mRNA and rRNA in rat skeletal muscle exposed to ethanol, by Alistair G. Paice, John E. Hesketh, Timothy J. Peters, and Victor R. Preedy; (2) Altered hepatic mitochondrial ribosome structure after chronic ethanol administration, by Vinood B. Patel and Carol C. Cunningham; (3) Clinical aspects of hepatic protein metabolism and alcohol, by Elena Volpi; and (4) Effects of oral intake of alanine plus glutamine on ethanol metabolism and ethanol-related depression in motor activity, by Kazunori Mawatari, H. Masaki, M. Mori, and Kunio Torii.
    Alcoholism Clinical and Experimental Research 06/2001; 25(5 Suppl ISBRA):262S-268S. DOI:10.1111/j.1530-0277.2001.tb02406.x · 3.31 Impact Factor
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    ABSTRACT: Anthracycline antibiotics are effective anticancer agents but their use is limited due to unwanted adverse side effects. The toxic effects of doxorubicin (adriamycin) include the development of defined cardiac lesions leading to cardiomyopathy in some patients. This has been reported to be due to reductions in cardiac protein synthesis. However, virtually all of these previous studies have failed to consider the specific radioactivity of the precursor pool in their measurements or have carried out their studies in vitro. To further resolve the above we measured fractional rates of cardiac protein synthesis using the "flooding dose" method in rats treated with adriamycin (5 mg/kg body wt). Controls were identically treated and injected with saline. At 2.5 or 24 h after adriamycin injection, rates of protein synthesis were measured with a flooding dose of l-[4-(3)H]phenylalanine. Measurements included free (S(i)) and protein-bound (S(b)) phenylalanine-specific radioactivities, the protein synthetic capacity (RNA/protein ratio; C(s)), the fractional rates of protein synthesis calculated from the ratio S(b)/S(i), and the protein synthetic efficiency calculated from the ratio k(s)/C(s). Complementary analyses included assays of lysosomal (cathepsins B, D, H, and L and diaminopeptidases I and II) and cytoplasmic proteases (alanyl aminopeptidase, arginyl aminopeptidase, leucyl aminopeptidase, diaminopeptidase IV, tripeptidyl aminopeptidase, and proline endopeptidase). These enzymes constitute the most active proteases in this tissue and represent an index of protein degradation capacity in cardiac muscle. The results showed that in 2.5-h dosed rats, adriamycin had no effect on S(i), S(b), C(s), k(s), or k(RNA) (P > 0.05, not significant (NS) in all instances). In 2.5-h dosed rats, levels of diaminopeptidase I activity were reduced (P < 0.05), whereas the activities of other proteases were not significantly altered (NS in all instances). In 24-h dosed rats, adriamycin reduced cardiac S(b) (P < 0.001), which would normally be interpreted as a reduction in protein synthesis. However, S(i) was also decreased in 24-h adriamycin-injected rats (P < 0.025%). C(s) was not changed (NS). Consequently, the calculated k(s) and k(RNA) values were not significantly affected in 24-h adriamycin-dosed rats (NS). There were also significant reductions in proline endopeptidase activities in rats exposed for 24 h to adriamycin. The activities of other proteases were not significantly affected at this time point (NS in all instances). In conclusion, adriamycin reduces amino acid labeling of cardiac proteins, an effect that is a consequence of altered free phenylalanine-specific radioactivities. There was some evidence of limited altered intracellular proteolysis.
    Experimental and Molecular Pathology 05/2001; 70(2):154-61. DOI:10.1006/exmp.2000.2353 · 2.88 Impact Factor
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    ABSTRACT: This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Albert Y. Sun. The presentations were (1) Ethanol-inducible cytochrome P-4502E1 in alcoholic liver disease, by Magnus Ingelman-Sundberg and Etienne Neve; (2) Regulation of NF-κB by ethanol, by H. Matsumoto, Y. Nishitani, Y. Minowa, and Y. Fukui; (3) Chronic ethanol consumption increases concentration of oxidized proteins in rat liver, by Shannon M. Bailey, Vinood B. Patel, and Carol C. Cunningham; (4) Antiphospholipids antibodies and oxidized modified low-density lipoprotein in chronic alcoholic patients, by Tomas Zima, Lenka Fialova, Ludmila Mikulikova, Ptr Popov, Ivan Malbohan, Marta Janebova, and Karel Nespor; and (5) Amelioration of ethanol-induced damage by polyphenols, by Albert Y. Sun and Grace Y. Sun.
    Alcoholism Clinical and Experimental Research 04/2001; 25:237S - 243S. DOI:10.1111/j.1530-0277.2001.tb02402.x · 3.31 Impact Factor
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    ABSTRACT: In the present study, the physiochemical properties of rat liver mitochondrial ribosomes were examined and compared with Escherichia coli ribosomes. The sedimentation and translational diffusion coefficients as well as the molecular weight and buoyant density of rat mitochondrial ribosomes were determined. Sedimentation coefficients were established using the time-derivative algorithm (Philo, J. S. (2000) Anal. Biochem. 279, 151-163). The sedimentation coefficients of the intact monosome, large subunit, and small subunit were 55, 39, and 28 S, respectively. Mitochondrial ribosomes had a particle composition of 75% protein and 25% RNA. The partial specific volume was 0.688 ml/g, as determined from the protein and RNA composition. The buoyant density of formaldehyde-fixed ribosomes in cesium chloride was 1.41 g/cm(3). The molecular masses of mitochondrial and E. coli ribosomes determined by static light-scattering experiments were 3.57 +/- 0.14 MDa and 2.49 +/- 0.06 MDa, respectively. The diffusion coefficient obtained from dynamic light-scattering measurements was 1.10 +/- 0.01 x 10(-7) cm(2) s(-1) for mitochondrial ribosomes and 1.72 +/- 0.03 x 10(-7) cm(2) s(-1) for the 70 S E. coli monosome. The hydration factor determined from these hydrodynamic parameters were 4.6 g of water/g of ribosome and 1.3 g/g for mitochondrial and E. coli ribosomes, respectively. A calculated hydration factor of 3.3 g/g for mitochondrial ribosomes was also obtained utilizing a calculated molecular mass and the Svedberg equation. These measurements of solvation suggest that ribosomes are highly hydrated structures. They are also in agreement with current models depicting ribosomes as porous structures containing numerous gaps and tunnels.
    Journal of Biological Chemistry 04/2001; 276(9):6739-46. DOI:10.1074/jbc.M005781200 · 4.60 Impact Factor
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    ABSTRACT: Changes in tissue protein synthesis in hypertension have usually been measured in vitro in heart from acutely hypertensive rats without consideration of changes in atrial or pulmonary tissue or changes occurring in long-standing hypertension. The objective of the study was to investigate the in vivo changes in cardiopulmonary protein synthesis in three different rat models of chronic hypertension. Hypertension in aortic constriction, the Goldblatt model, and the bromoethylamine model were induced in rats for 30 days. At the end of the experimental period, in vivo rates of protein synthesis were measured with a flooding dose of [3H]phenylalanine (a method which effectively considers precursor pools). Concomitant measurements included quantification of contractile protein and RNA and DNA contents. Indices of protein breakdown were also assessed by selective measurement of protease activities. At the end of 30 days, aortic constriction induced marked increases in protein contents of the left ventricle, septum, left atria, and lungs. Accompanying changes included concomitant increases in RNA and DNA contents. Left ventricular myofibrillary, sarcoplasmic, and stromal protein contents increased in the aortic constriction model. Less marked changes occurred in the Goldblatt model, though the left atria were not significantly affected. In contrast, the bromoethylamine model had no effect on the protein or RNA contents of any region. In all cardiac regions of all three models, fractional rates of protein synthesis were not significantly affected. However, protein synthesis increased in the lungs of both the Goldblatt and bromoethylamine models at 30 days. Protease activities were decreased in the left ventricles of all three models at 30 days, with lysosomal protease activities declining in the aortic constriction model and cytoplasmic protease activities declining in the other two models. The failure of chronic hypertension to increase ventricular synthesis rates may represent inherent limitations in the time frame for measuring protein synthesis in vivo. However, at earlier time points (i.e., 10 days), the aortic constriction model was characterized by marked increases in left ventricular and atrial protein contents, RNA contents, and fractional rates of protein synthesis. This was consistent with the supposition that, in acute phases of hypertrophy, rates of protein synthesis increase, whereas in established hypertrophy, synthesis rates remain unchanged or decrease. The applicability of the aortic constriction model was investigated by examining the effects of the angiotensin converting enzyme inhibitor lisinopril (5 mg/kg/day). After 30 days treatment, lisinopril impeded the increase in left ventricular mixed and myofibrillar proteins. This effect was accompanied by an apparent increase in protein synthesis. In conclusion, although all three chronic models are able to induce hypertension, varying degrees of hypertrophy develop, which are more pronounced in the aortic constriction model. Accompanying changes include hypertrophy in the atria, reduced rates of ventricular proteolytic activity, and altered rates of protein metabolism in the lungs.
    Experimental and Molecular Pathology 03/2001; 70(1-70):19-30. DOI:10.1006/exmp.2000.2333 · 2.88 Impact Factor
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    ABSTRACT: Some studies have shown that reductions in tissue protein synthesis, under a variety of cytotoxic conditions, are ameliorated by a-tocopherol (ATC) supplementation. We have also shown evidence of increased oxidative stress and reduced protein synthesis rates in alcohol-exposed muscle. Serum levels of ATC fall and rates of muscle protein synthesis are reduced in patients with alcoholic myopathy. We therefore tested the hypothesis that treatment with ATC could ameliorate the ethanol-induced changes in muscle protein synthesis, a contributory event in the pathogenesis of alcoholic muscle disease. Studies were carried out on gastrocnemius (Type II fiber-predominant and usually considered representative of the musculature as a whole), soleus (Type I fiber- predominant) and plantaris (Type II fiber-predominant) muscles. For comparative purposes, we also investigated the liver. Young male Wistar rats (90 g body weight) were injected intraperitoneally (i.p.) daily with ATC (30 mg/kg body weight) in Intralipid fat emulsion (0.1 mL/100 g body, i.p.) for 5 d. Controls were similarly injected with the Intralipid vehicle alone. After ATC supplementation, rats were given ethanol (75 mmol/kg body weight, i.p., 2.5 h) or saline (0.15 mol/L NaCl, i.p.). Fractional rates of tissue protein synthesis (i.e., the percentage of the tissue protein pool renewed each day, ks, %/d) and RNA activities (i.e., the amount of protein synthesis each day per unit RNA, kRNA, mg protein/d/mg RNA)) were then measured. Supplementation increased ATC concentrations in plasma, gastrocnemius and liver. There was no effect of ATC supplementation alone on ks in any of the tissues. ATC supplementation in the absence of alcohol increased kRNA in the plantaris muscle. In nonsupplemented groups, acute ethanol treatment reduced skeletal muscle (soleus, plantaris and gastrocnemius) ks. Hepatic ks was not altered by ethanol, although ATC concentrations in this tissue increased due to ethanol. However, none of the changes in muscle ks or kRNA due to ethanol were significantly affected by ATC supplementation. In conclusion, ATC supplementation does not appear beneficial in ameliorating acute alcohol toxicity in skeletal muscle as defined by reductions in protein synthesis. J. Nutr. 130: 3045-3049, 2000.
    Journal of Nutrition 01/2001; · 4.23 Impact Factor
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    ABSTRACT: Rats were acutely injected with alcohol (75 mmol/kg body weight) and at the end of 2.5 h changes in cardiac synthesis rates were assessed with a 'flooding dose' of L-[4-(3)H]phenylalanine. The results showed that acute alcohol dosage reduced the fractional rates of cardiac protein synthesis (k(S), %/day). This effect was also seen when data were expressed relative to either RNA (i.e. k(RNA), mg protein/day/mg RNA) or DNA (i.e. k(DNA), mg protein/day/mg DNA). Both left and right ventricles responded similarly to ethanol. However, propranolol pre-treatment (at doses of 17 and 170 micromol/kg body weight; i.p.) did not prevent these effect of ethanol in either the left or right ventricle. Indeed, there was evidence that propranolol per se perturbed cardiac protein synthesis in vivo in control (i.e. without ethanol) rats particularly in the right ventricle. In conclusion, the results suggest that alcohol is cardiotoxic to the myocardium, which may cause its effects on protein synthesis independently of beta-receptors and/or xanthine oxidase inhibition.
    Clinica Chimica Acta 11/2000; 300(1-2):1-12. DOI:10.1016/S0009-8981(00)00267-9 · 2.76 Impact Factor
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    ABSTRACT: 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.
    Clinica Chimica Acta 09/2000; 299(1-2):1-10. DOI:10.1016/S0009-8981(00)00270-9 · 2.76 Impact Factor
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    ABSTRACT: 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.
    Life Sciences 09/2000; 67(12):1409-21. DOI:10.1016/S0024-3205(00)00739-6 · 2.30 Impact Factor
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    ABSTRACT: We investigated whether the imposition of chronic alcohol in hypertension leads to greater biochemical and cellular abnormalities of the myocardium than those arising in normotension. Fifteen-week-old spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed ethanol-containing diets for six weeks. Particular attention was focused on the composition of contractile proteins identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), fractional rate of protein synthesis, and synthesis rates relative to RNA (RNA activity) or DNA (cellular efficiency). In addition, myocardial enzymes and adenine nucleotides were measured. In both SHR and WKY rats chronic ethanol caused a general decrease in the contents of all nine contractile proteins with myosin heavy chain predominantly affected. Fractional rates of mixed (i.e., total) and myofibrillary proteins remained unaltered in both WKY rats and SHR, as were cellular efficiencies. The RNA activity was significantly reduced in ethanol-treated SHR but not in WKY rats. In ethanol-treated SHR, cardiac creatine kinase (CK) and malate dehydrogenase (MDH) activities were increased, AMP levels were elevated, whilst ATP levels and the energy charge were reduced. In WKY rats, the only significant change related to increased aspartate aminotransferase activities in response to alcohol feeding. Although there were only subtle differences between the response of the normotensive and hypertensive rats due to ethanol dosage, the reduced ATP levels and increased CK and MDH activities in SHR may reflect a greater susceptibility to ischaemic damage. Reduced contractile protein content, particularly myosin heavy chain, may contribute to contractile defects, a common feature of subclinical and clinical alcoholic cardiomyopathy.
    Electrophoresis 07/2000; 21(12):2454-62. DOI:10.1002/1522-2683(20000701)21:12<2454::AID-ELPS2454>3.0.CO;2-Z · 3.16 Impact Factor

Publication Stats

689 Citations
240.87 Total Impact Points


  • 2001–2008
    • University of Westminster
      • Department of Biomedical Sciences
      Londinium, England, United Kingdom
    • University of Occupational and Environmental Health
      Kitakyūshū, Fukuoka, Japan
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Regional Neurosciences Centre
      Newcastle-on-Tyne, England, United Kingdom
  • 1994–2004
    • King's College London
      • Department of Nutrition and Dietetics
      London, ENG, United Kingdom
  • 2000–2002
    • Wake Forest School of Medicine
      • Department of Biochemistry
      Winston-Salem, North Carolina, United States
  • 1994–1997
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom
  • 1995
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States