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Biomedical subjects

V R Preedy

Publications and source records attributed to V R Preedy.

At least 73 records · Page 4Linked to original sources
PubMed1996

Characterization of contractile and non-contractile protein synthesis in the stomach, small and large intestine and caecum of the rat, and response to acute ethanol dosage.

An investigation was made into the relative composition and synthesis rates of smooth muscle contractile proteins in vivo in different regions of the rat gastrointestinal tract. There was considerable homogeneity in the composition of sarcoplasmic proteins in the small bowel (i.e. 54-58 mg/g) but considerable variability in the large bowel, i.e. highest in the caecum (97 mg/g) and lowest in the colon (21 mg/g). The myofibrillary protein concentration was constant throughout the gastrointestinal tract, i.e. 20-34 mg/g. Stromal fractions varied from 6 to 39 mg/g and was highest in the cardiac region of the stomach and lowest in the duodenum. Fractional rates of protein synthesis were measured with a flooding dose of L-[4-(3)H]phenylalanine. In control rats synthesis rates in sarcoplasmic protein fractions were relatively much higher (43-107%/day) than myofibrillar (27-52%/day) or stromal (6-26%/day) proteins. Fractional rates of stromal protein synthesis showed the greatest variability while myofibrillar synthesis rates the least, throughout the alimentary tract. Jejunal seromuscular layer myofibrillar proteins had the highest synthesis rates (49%/day). In response to acute ethanol injection, protein synthesis in all jejunal fractions fell by 20-30%. Contractile and non-contractile proteins from the cardiac region of the stomach, duodenal seromuscular layer and large bowel seromuscular layer were insensitive to ethanol administration. Protein synthesis of sarcoplasmic proteins from the antrum, ileum seromuscular layer and myofibrillar proteins from the ileum seromuscular layer and caecum were also significantly depressed as a result of ethanol treatment.

Journal Article↗
PubMed1996

The acute and chronic effects of alcohol upon cardiac nucleotide status.

The aim of the investigation was to ascertain the biochemical and morphological basis for the functional impairments in the heart due to alcohol. In chronic studies rats were fed a nutritionally complete liquid diet containing 35% of total calories as ethanol, controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. In acute studies rats were injected with ethanol at a dose of 75 mmol/kg body weight. Pre-treatment of acute ethanol-dosed rats with cyanamide (ALDH inhibitor) was designed to raise acetaldehyde levels. In chronic studies ventricular adenine nucleotides, ATP, ADP and AMP; NAD(+), ATP ratios and the energy charge showed no alteration after 6 weeks of alcohol feeding. Light and electron microscopy sections indicated very little structural damage to muscle fibres and organelles (especially the mitochondria) in both atria and ventricles. Ventricular fibre diameters, throughout the different ranges, showed no significant differences between chronically alcohol and control-fed rats. In acute studies an increase in ventricular AMP levels (micromoles/g wet weight) occurred following cyanamide and cyanamide + ethanol treatment (+57%, p < 0.025 and +76%, p<0.01, respectively), but not as a consequence of ethanol alone. Cyanamide+ethanol caused marked elevation in ADP levels (+28%, p < 0.05) and again ethanol was without effect. ATP and GTP levels were not altered by any of the acute treatments. The energy charge was slightly reduced in both cyanamide and cyanamide+ethanol groups (-8%, p < 0.01 and -7%, p < 0.05, respectively), but not by ethanol alone. In conclusion, chronic alcohol appears to have minimal effects upon cardiac nucleotides which suggest that possible adaptive mechanisms are induced during the 6-week period and that alternative pathways other than defects in adenine nucleotide concentrations are involved in the pathogenesis of AHMD. The acute study suggests that the heart is resilient to toxic levels of alcohol and acetaldehyde in terms of ATP and GTP levels, despite the elevated AMP, ADP and GDP levels.

Journal Article↗
PubMed1996

Ethanol dosage regimes in studies of ethanol toxicity: influence of nutrition and surgical interventions.

In this review we consider some of the practical facets of acute and chronic drug regimes. In particular, we illustrate our arguments with specific reference to alcohol and draw attention to methodological constraints that might alter biochemical or physiological processes. These includes the imposition of nutritional abnormalities and surgical procedures. These two areas are highlighted because there is evidence to show that they have marked influences on metabolic parameters, exemplified by tissue protein synthesis. In general, there is no controversy as to methods for acute studies with alcohol, although some reports have failed to investigate whether intravenous, intragastric or intraperitoneal regimes more accurately mimic the clinical situation. With regard to chronic feeding regimes, evidence is provided to support the argument that, currently, the most appropriate feeding protocol ensures that both control and treated groups receive identical amounts of nutrients albeit with differences in the calories apportioned to ethanol, which is substituted by isocaloric glucose or other carbohydrates in controls. However, there are still other methods being employed: these are subject to misinterpretation as the principle of ensuring that control and ethanol-fed rats receive identical amounts of nutrients, is ignored. In this review we also draw attention to the fact that surgical procedures, which are often employed to facilitate the measurement of body parameters (for example, implantation of cannulae), themselves alter tissue metabolism. The importance of this relates to the concept of metabolic superimposition, which implicates interacting responses when two or more stresses (i.e. surgery and drug administration) are superimposed.

Journal Article↗
PubMed1996

The effects of acute administration of ethanol on jejunal protein synthesis and circulating insulin-like growth factor (IGF)-1 and IGF binding proteins in ad libitum fed and nutritionally restricted rats.

The effects of acute ethanol administration (75 mmol/kg body weight) to male Wistar rats (either ad libitum fed or nutritionally restricted) on fractional rates of protein synthesis in the jejunum was assessed together with the changes in IGF-1 and IGF binding protein concentrations. Acute administration of ethanol resulted in significant decreases in fractional rates of protein synthesis in the whole jejunum and jejunal seromuscular layers of both the ad libitum fed and nutritionally restricted animals. The synthesis rate per unit RNA (k(RNA), mg protein/day/mg RNA) in whole jejunum was reduced by 29% and 24% in the nutritionally restricted and ad libitum fed animals, respectively. Mean IGF-1 levels were lower in the nutritionally restricted group (871 +/- 36.9 microg/l) than the ad libitum animals (960 +/- 27.3 microg/l) although this did not reach significance. In contrast, administration of alcohol to both groups markedly reduced circulating IGF-1 levels (ad libitum: 518 +/- 19.8 microg/l, nutritionally restricted: 417 +/- 33.7 microg/l). Furthermore, ethanol treatment resulted in a three-fold increase in the intensity of a 30 kDa IGF binding protein (IGFBP) in the ad libitum fed animals and a fourfold increase in both 30 and 32 kDa IGFBP bands in the nutritionally restricted group as visualized by Western ligand blotting. Decreases in levels of IGF-1 allied with increased circulating small molecular weight IGFBPs may contribute to the reduction in fractional rates of protein synthesis in the gastrointestinal tract of ethanol-treated rats.

Journal Article↗
PubMed1996

Osmotic diarrhoea and skeletal muscle protein synthesis in vivo.

The pathogenic nature of the wasting seen in diarrhoea is unknown. This study measured protein synthesis in an established model of diarrhoea using lactose for seven days. Comparisons were also made with data obtained from rats fed an identical diet in which lactose was replaced by isocaloric glucose ad libitum (that is, the control diet). To account for diarrhoea induced anorexia, a third group of rats were included, which were fed identical amounts of the control diet as the rats with diarrhoea inducing diet. Comparisons of the diarrhoea induced group with rats fed the control diet ad libitum showed that diarrhoea caused a significant reduction in body weights. Type I and type II muscles showed significant reductions in protein, RNA, and DNA contents, as well as a fall in the derived parameters, RNA/DNA, protein/DNA, and RNA/protein. Fractional rates of protein synthesis (ks) were also reduced. However, synthesis rates of type I and II muscles relative to RNA (kRNA) were unchanged in these muscles in diarrhoea induced rats compared with ad libitum fed controls. In the jejunum there was an increase in the RNA/DNA ratio, and reductions in ks and kRNA. Comparisons were also made between rats with diarrhoea and rats pair fed the control diet. There were no changes in total muscle protein, RNA or DNA contents. This suggests that an important feature of body wasting in diarrhoea is the element of anorexia, which induces severe metabolic changes. The comparison between rats with diarrhoea and the pair fed group showed that histological features of the plantaris were not overtly changed, though diarrhoea caused significant reductions in RNA/DNA, protein/DNA, ks, and kRNA. Similar changes were seen for the soleus; though the reduction in ks failed to attain statistical significance. In the jejunum a comparison of diarrhoea induced rats with pair fed controls, showed increases in the ratios of RNA/DNA and protein/DNA.

Animals↗
PubMed1996

Central effects of morphine and morphine-6-glucuronide on tissue protein synthesis.

The central and peripheral effects of morphine sulfate (Mor) and morphine-6-glucuronide (M6G) on the fractional rates of tissue protein synthesis (kappa s) were determined. We determined ks in conscious rats 2 h after intracerebroventricular injection of Mor (80 micrograms/rat), M6G (1 microgram/rat), or H2O (5 microliters). Intracerebroventricular Mor and M6G administration decreased ks in the liver by 19 and 18% spleen by 19 and 17%, and gastrocnemius by 18 and 17%, respectively. Intravenous injection of Mor (8 mg/kg) or M6G (0.4 mg/kg) did not affect ks in any of the tissues studied. Intracerebroventricular Mor and M6G resulted in an equivalent 10- to 15-fold increase in plasma epinephrine, 2- to 3-fold increase in norepinephrine, and 80-90% increase in corticosterone, with no change in insulin levels. Intracerebroventricular Mor produced a significant 30% decrease in arterial partial O2 pressure (PaO2) and no significant changes in arterial pH and arterial partial CO2 pressure (PacO2). Intracerebroventricular M6G decreased PaO2 (40%) and pH (from 7.44 +/- 0.01 to 7.34 +/- 0.02) and increased Paco2 (36%). The potential contribution of hypoxia to the opiate-induced decrease in ks was assessed in an additional set of rats exposed to 5% O2-95% N2. One or 2 h of hypoxia decreased protein synthesis in the brain by 47 and 56%, liver by 69 and 69%, and skeletal muscle by 51 and 52%, respectively. Our results indicate that Mor and M6G suppress tissue protein synthesis through central mechanisms, most likely mediated by opiate-induced respiratory depression in association with neural and hormonal alterations.

Acute Disease↗
PubMed1996

Differential effects of malnutrition, bile duct ligation and galactosamine injection in young rats on serum levels and gene expression of IGF-binding proteins.

Hepatic gene expression and circulating levels of IGF-binding proteins (IGFBP)-1 to -4 were examined in two rat models of liver disease employing acute hepatitis or chronic structural damage. The study comprised four groups: group 1 (n = 6) was injected intraperitoneally with saline and food was available ad libitum (AL), group 2 (n = 6) underwent bile duct ligation (BDL), group 3 (n = 6) was injected with 400 mg galactosamine (GAL), group 4 (n = 6) was sham-operated and pair-fed to group 2 (PF). All were killed by decapitation at day 7. Serum IGF-I, by RIA, was significantly (P < 0.05) lower in the BDL group (458 +/- 37 micrograms/l) and PF group (451 +/- 51 micrograms/l) compared with the AL group (643 +/- 77 micrograms/l) and GAL group (720 +/- 67 micrograms/l). Immunoblotting showed raised IGFBP-2 levels in all groups compared with AL (BDL, 167 +/- 14% of AL; GAL, 173 +/- 13%; PF, 149 +/- 9%). IGFBP-3 was decreased in the GAL (56 +/- 11%) and PF groups (66 +/- 5%) but increased in the BDL group (154 +/- 29%). IGFBP-4 was decreased in the GAL (76 +/- 11%) and PF groups (47 +/- 5%) but unchanged in the BDL group (90 +/- 10%). By Northern analysis, IGFBP-1 mRNA expression was increased in the GAL (321 +/- 51%) and PF groups (263 +/- 12%) but reduced in the BDL group (68 +/- 8%). IGFBP-2 expression increased in all groups (PF, 836 +/- 19%; BDL, 683 +/- 121%; GAL, 372 +/- 68%) and was highest in the BDL and PF groups. IGFBP-3 expression was reduced in all groups (BDL, 57 +/- 16%; GAL, 52 +/- 12% PF, 51 +/- 13%). IGFBP-4 expression was reduced in the GAL (30 +/- 4%) and PF (28 +/- 5%) groups but unchanged in the BDL group (76 +/- 9%). Marked changes in gene expression of IGFBPs occurred in both models of liver disease, together with serum changes, which were different from each other and from malnutrition alone.

Animals↗
PubMed1996

Alcoholic cardiomyopathy: clinical and experimental pathological changes.

In this review we survey the features of alcohol-induced lesions in the heart, in both the clinical and laboratory-animal setting. The data indicates a diverse range of lesions that contribute to the genesis of the entity alcoholic cardiomyopathy (also referred to as alcoholic heart muscle disease). Biopsies of affected patients reveal lesions similar to dilated cardiomyopathy though quantitative morphometry can distinguish between the two disorders. Biochemical analysis reveals an increase in the activities of some enzymes, though the pathogenetic nature of these alterations are unknown, but may well be adaptive. The induction of ischaemia in acute ethanol exposure may contribute to the heart muscle damage, though long term experimental studies indicate that heat shock proteins are reduced, making the heart more vulnerable to cardiac dysfunction. Changes in the rate of protein turnover induced by alcohol appear to be a central feature in animal studies and it is very likely that similar changes occur in man.

Acetaldehyde↗
PubMed1996

Alcohol and the heart: biochemical alterations.

A considerable amount of attention has focused on the cardiovascular events associated with ethanol consumption. The available evidence suggests that moderate ethanol consumption is associated with reduced risk of coronary heart disease, i.e., vessel events. In contrast, this review is primarily concerned with ethanol and heart muscle damage. Clinical features of the consequences of prolonged and excessive ethanol consumption encompass defects in myocardial contractility and derangement of cellular architecture, including disarray of the contractile elements. Although the incidence of heart muscle abnormalities in alcohol misusers is generally higher than previously considered, the mechanisms are only just being elucidated. This process has been facilitated by laboratory based studies in which animals receive either a single dose of ethanol (acute studies) or a continuous supply of ethanol in their daily diets (chronic studies). Results from these models show that acute ethanol dosage causes a marked decrease in the synthesis of contractile proteins. This occurs in the absence of overt mitochondrial abnormalities: ATP concentrations are generally unaffected. Paradoxically, the synthesis of mitochondrial proteins is reduced. Use of metabolic inhibitors suggests that the deleterious effects of acetaldehyde contribute to these reductions in protein synthesis. In chronic studies, ethanol causes a reduction in the amount of contractile proteins, and two dimensional protein profiling implicates selective loss of individual myocardial proteins. The differential activities of lysosomal proteases may contribute to this patterned response. However, in chronic ethanol feeding, adaptive mechanisms also become important, as the synthesis of the myofibrillary proteins increases. Overall, the mechanisms inherent in these biochemical responses may contribute to the genesis of a distinct disease entity, alcoholic heart muscle disease.

Animals↗
PubMed1995

Protein synthesis in the heart in vivo, its measurement and patho-physiological alterations.

Changes in cardiac protein composition occur in a variety of patho-physiological situations and are usually accompanied by modifications in protein synthesis. Although adjustments in protein synthesis during starvation may be adaptive, the alterations in protein synthesis seen in response to ethanol ingestion may be pathological and an important step in the genesis of alcoholic heart muscle disease. The alterations in heart muscle in hypertension are initially adaptive but in the long term they are deleterious, and involve both transcription and translation. While adequate methods exist for quantifying the amount of mRNA for contractile and non-contractile proteins, such studies of gene-expression provide no dynamic information on the rate at which tissue proteins are lost or accrued. This can only be determined by measuring the rate of protein turnover, i.e. either protein synthesis or protein breakdown. Techniques for directly determining the rates of protein breakdown are limited or involve surgical procedures. Methods for measuring the rate of protein synthesis are described, and are illustrated by their application to the investigation of starvation and ethanol toxicity. In particular, attention is focused on the fact that reliable rates of protein synthesis are obtained only if the specific radioactivity of the precursor at the site of protein synthesis (aminoacyl-tRNA) is assessed.

Animals↗
PubMed1995

Protein synthesis in the hypertrophied heart of spontaneously hypertensive rats and a comparison of the effects of an ACE-inhibitor and a calcium channel antagonist.

The aim of the investigation was to assess and compare the effects of a calcium channel antagonist, (i.e. amlodipine) and an ACE-inhibitor (i.e. lisinopril) in reducing chronic left ventricular hypertrophy in 15-week old spontaneously hypertensive rats (SHR). Changes in cardiac hypertrophy were assessed after 8 weeks by measuring the fractional rates of protein synthesis using a 'flooding dose' of [3H]-phenylalanine for 10 min. Blood pressure was monitored throughout the treatment period in both SHR and Wistar-Kyoto control rats (WKY). The results showed a decrease in blood pressure by amlodipine after 1 week of treatment which was further reduced at 4 to 8 weeks. Lisinopril caused immediate and sustained reductions in blood pressure (190 mmHg to 130 mmHg, P < 0.001). After 8 weeks of treatment in SHR rats, amlodipine had no significant effect on left ventricular weight (P > 0.05), whereas lisinopril caused a marked reduction. The protein content and RNA were also not changed by amlodipine. In contrast, lisinopril significantly lowered the tissue protein, RNA and DNA content (P < 0.001). The changes in the left ventricles of lisinopril-treated SHR rats were accompanied by an increase in the fractional synthesis rate of left ventricular myofibrillar proteins (+12 per cent, P < 0.025). The synthesis rate per unit RNA was also increased in right ventricular tissue of lisinopril-treated SHR rats. However, amlodipine had no effect on the fractional synthesis rates of any of the left-ventricular fractions of SHR rats (P > 0.05). The cellular efficiency in the right ventricle was also increased in amlodipine-treated SHR rats, indicating a moderate effect on protein metabolism. In conclusion, amlodipine had minimal effects in the reduction of established left ventricular hypertrophy (LVH), despite reducing the blood pressure, whereas lisinopril caused regression of LVH. These events were associated with small changes in protein synthesis rates, with the contractile protein showing an increase.

Amlodipine↗