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Biomedical subjects

D B Lindsay

Publications and source records attributed to D B Lindsay.

At least 19 recordsLinked to original sources
PubMed1999

Action of long(R3)-insulin-like growth factor-1 on protein metabolism in beef heifers.

Insulin-like growth factor-1 (IGF-1) is perhaps the most important endogenous factor controlling growth. Most studies to date in livestock have shown that IGF-1 has greatest efficacy when animals are in a catabolic state. We have determined the effects of an i.v. infusion of the IGF-1 analog Long(R3)-IGF-1 on protein metabolism in beef heifers that were slowly losing liveweight because of restricted feeding. There was a tendency for both whole-body protein and skeletal muscle protein to be conserved in Long(R3)-IGF-1-treated heifers. Long(R3)-IGF-1 administration markedly reduced the plasma concentrations of all amino acids measured and glucose. There was a significant change in the profile differences of endogenous plasma IGF-1 concentrations during the 8-hr infusion period, with plasma IGF-1 decreasing sharply in the test group. There was a significant difference in mean profiles for plasma IGF-2 between the test and control groups. Overall, plasma IGF-2 for the control group decreased only slightly over time (about 40 ng/ml), whereas the test group decreased dramatically (by about 140 ng/ml). Increased plasma concentrations of a 31-32-kDa IGF-binding protein (possibly IGF-binding protein-1) in the treated group was detected by radioligand blot. We found that Long(R3)-IGF-1 infusion tended to preserve whole-body and muscle protein in beef heifers on a low-quality diet, and suggest that further investigation of this treatment may provide an alternative approach to reducing weight loss during the dry season.

Amino Acids↗
PubMed1993

Ligand binding properties of putative beta 3-adrenoceptors compared in brown adipose tissue and in skeletal muscle membranes.

1. The beta-adrenoceptor population was characterized in membrane preparations from rat brown adipose tissue (BAT) and from soleus muscle by use of the radioligand [125I]-iodocyanopindolol ([125I]-ICYP). In addition, atypical binding sites for [125I]-ICYP found in both tissues were examined, and the relationship between these sites and the putative rat beta 3-adrenoceptor is discussed. 2. It was established that BAT membranes host a mixed population of beta 1- and beta 2-adrenoceptors. Of these two sites, 55% showed a high affinity for the beta 1-selective ligand CGP 20712A (pK 8.5), and 45% showed a high affinity for the beta 2-selective antagonist ICI 118551 (pK 8.6). Soleus muscle membranes were found to host a population of beta 2-adrenoceptors, characterized by a high affinity for ICI 118551 (pK 9.1), but beta 1-adrenoceptors could not be detected in this preparation. 5-Hydroxytryptamine receptors were not detected in either preparation. 3. In addition to beta 1- and beta 2-adrenoceptors, atypical binding sites were identified in both tissues using high concentrations of radioligand (0.5-0.6 nM) and in the presence of 1 microM (-)-propranolol. The atypical sites were abundant, representing 80 and 81% of the total [125I]-ICYP binding sites in BAT and soleus muscle respectively. When the pK values for 11 ligands were compared, the correlation coefficient for atypical sites in BAT and soleus muscle was 0.94. 4. The atypical binding sites showed a moderate affinity for (+/-)-cyanopindolol (pK 7.3-7.7), poor stereo selectivity for the (+)- and (-)-enantiomers of alprenolol (<10 fold), and a low affinity for B-adrenoceptor antagonists and partial agonists in the order: (+/-)-cyanopindolol>(-)-alprenolol>(-)-propranolol=(+/-)-ICI 118551>>(+/-)-CGP20712A. The affinity of these ligands for the atypical sites reflects their behaviour in functional studies of putative beta 3-adrenoceptors in rat BAT, white adipose tissue, intestine and colon.5. The atypical sites labelled by [125I]-ICYP were resistant to agonist binding, and while the order of affinity of the agonists BRL 37344> isoprenaline> noradrenaline matches their order of potency at putative beta 3-adrenoceptors, none of these compounds caused displacement of the radioligand at concentrations below 10 microM.6. It is concluded that the atypical binding sites for [125I]-ICYP found in rat BAT and soleus muscle membranes are the same, and that these sites show some relationship to the putative rat beta 3-adrenoceptor identified in functional studies using antagonists. However, under the conditions used in the present study, pK values obtained for beta 3-agonist binding are not useful.

Adipose Tissue, Brown↗
PubMed1993

Growth, nitrogen metabolism, and cardiac responses to clenbuterol and ketoclenbuterol in rats and underfed cattle.

Two beta-adrenoceptor agonists, clenbuterol and ketoclenbuterol, were examined for their effects on growth and cardiac tissue. In female rats, clenbuterol caused a 48% increase in weight gain (P < .05), with improved feed efficiency (26%; P < .1) and increased muscle mass (9%; P < .1). Ketoclenbuterol had less effect on weight gain (30%) and feed efficiency (16%) and did not increase muscle mass. Next we studied the adverse cardiovascular effects of these compounds. Neither drug increased the force of contraction of isolated rat ventricular papillary muscle. Clenbuterol was potent at causing an increase in the rate of contraction of isolated rat atria, and when fed to cattle over 2 d, the drug caused heart rate to increase by 92 to 117%. In contrast, ketoclenbuterol was not a potent stimulator of atrial rate in the rat, and in cattle it caused a smaller increase in heart rate than clenbuterol (12 to 27%). Finally, cattle that were underfed to simulate dry-season tropical pasture conditions were treated with clenbuterol or ketoclenbuterol for 35 d. Ketoclenbuterol caused no beneficial changes in N metabolism. The results obtained with clenbuterol were equivocal, and might have been confounded partly by the refusal of some treated animals to eat all the feed offered. Although clenbuterol did not cause a reduction in total urinary N output relative to control animals, marked reductions in plasma urea concentrations and in urea synthesis were observed (23 to 53%; P < .001). We conclude that ketoclenbuterol is not effective for attenuation of dry-season protein loss in cattle. Clenbuterol seems to be less effective in underfed cattle than in well-fed cattle, and further evidence is required to judge whether compounds of this nature are likely to benefit tropical cattle under harsh grazing conditions.

Adrenergic beta-Agonists↗
PubMed1992

Effects of the alpha 2-adrenoceptor agonist guanfacine on growth and thermogenesis in mice.

Guanfacine is an alpha 2-adrenoceptor agonist with antithermogenic properties. A single treatment of guanfacine caused a dose-related reduction in metabolic rate. The maximum reduction was 40%, and a dose of .5 mg/kg was close to that required to produce half this effect. It was determined whether the antithermogenic action of guanfacine would result in increased growth rate in mice. In animals treated once daily for 10 d (0, .125, .5, or 2 mg/kg), the drug caused dose-related reductions in feed intake, weight gain, and feed conversion efficiency. In a further experiment, mice were fed a restricted quantity of feed and treated for 14 d with guanfacine (.5 mg/kg twice daily). Because of repeated dosing, the antithermogenic effect of the drug was attenuated, so that metabolic rate was not lower in treated mice at the end of the experiment. Control and treated mice ate all the feed offered, but the guanfacine-treated group gained 2.9 g less weight (P < .01) than the controls. Half this difference in BW was accounted for by body water (P < .1), whereas body energy content was also reduced by the drug (P < .05). In a final experiment we sought possible sources of energy loss. Mice were treated with guanfacine (.5 mg/kg) three times over 24 h. Severe glucosuria was observed in the guanfacine-treated mice, with a tendency also toward increased output of fecal energy. We have confirmed that guanfacine has a powerful, if short-term, antithermogenic action. However, in mice, other effects of the drug on energy metabolism result in weight loss rather than growth stimulation.

Animals↗
PubMed1991

Affinity of clenbuterol analogues for beta 2-adrenoceptors in bovine skeletal muscle and the effect of these compounds on urinary nitrogen excretion in female rats.

The longissimus dorsi muscles of cattle are highly responsive to the anabolic effects of beta 2-adrenoceptor agonists, and in the present study were shown to be a rich and homogeneous source of beta 2-adrenoceptors. Structural analogues of the beta 2-adrenoceptor agonist clenbuterol were prepared in order to examine the relative importance of the benzylic hydroxyl functionality and the aromatic ring halogen substituents in determining the affinity of phenylethanolamines for beta 2-adrenoceptors in bovine muscle. It was calculated that the hydroxyl-hydrogen bonding interaction of these compounds contributes only 1-2 kcal/mol to the total binding energy. The aromatic halo-substituents contributed up to 3 kcal/mol to the total binding energy, and we suggest that the relative importance of the latter functionality has been previously underestimated. There was a poor correlation between the affinity of clenbuterol analogues for binding to beta 2-adrenoceptors, and the potency of these compounds in reducing urinary nitrogen excretion after oral administration to female rats. We suggest that beta 2-adrenoceptor agonist efficacy is reduced in phenylethanolamine compounds when iodine is present on the aromatic ring. In contrast, the increased potency of a ketone derivative might be explained by conversion in vivo to clenbuterol, with increased bioavailability of this beta 2-agonist at the site of action.

Animals↗
PubMed1991

Effects of clenbuterol, ICI118551 and sotalol on the growth of cardiac and skeletal muscle and on beta 2-adrenoceptor density in female rats.

The aim of the present study was to determine whether the anabolic effects of clenbuterol in rat skeletal muscle are mediated by beta 2-adrenoceptor stimulation. Female rats were treated with clenbuterol, alone or in combination with either the nonselective beta 1/beta 2-adrenoceptor antagonist sotalol, or the beta 2-adrenoceptor-selective antagonist ICI118551. Clenbuterol caused an increase in muscle growth, accompanied by a reduction in beta 2-adrenoceptor density in the rat hind-limb. Both actions were attenuated by sotalol. However, at the dose tested ICI118551 was the more effective antagonist of the muscle growth response, and when given alone, ICI118551 caused significant muscle atrophy. An increase in the weight of the heart was also observed in clenbuterol-treated rats, and again while this effect was attenuated by sotalol, it was reversed by ICI118551. It is concluded that beta 2-adrenoceptors mediate the anabolic effects of clenbuterol in cardiac and skeletal muscle, and that they play an important physiological role in the growth and maintenance of muscle mass in the rat hind-limb.

Adrenergic beta-Antagonists↗
PubMed1988

Protein synthesis and degradation in the mammary gland of lactating goats.

Lactating goats were given a close arterial infusion of [1-14C]leucine and [4,5-3H]4-methyl-2-oxopentanoic acid into one half of the mammary gland at 2-3 weeks and 34-39 weeks after kidding. Rates of protein synthesis, degradation and net output were determined from measurements of arteriovenous difference and blood flow using a model of leucine metabolism previously developed for muscle (Oddy & Lindsay, 1986). Protein leucine output in milk (Y mumol/min) correlated well with the difference between synthesis and degradation (X mumol/min) derived from the model: Y = 1.30 + 1.24X (r2 = 0.9; n = 9, P less than 0.01). There was substantial synthesis and degradation of protein within the mammary gland. Although only an approximate value could be obtained for the partitioning of protein synthesis and degradation between tissue and milk proteins, there was evidence of appreciable turnover of both. There was no significant difference between mammary leucine and protein metabolism in early and late lactation other than that imparted by a greater mass of mammary tissue in early lactation, although there was a tendency for greater oxidation of leucine in late lactation.

Animals↗
PubMed1987

Effects of pituitary-derived bovine growth hormone on production parameters and biokinetics of key metabolites in lactating dairy cows at peak and mid-lactation.

Changes in production parameters and metabolite biokinetics induced by treatment with pituitary-derived bovine growth hormone (bGH) were monitored at peak (c. 40 days) and mid-lactation (c. 130 days) in dairy cows. During treatment with bGH milk production increased by 6 and 14% at peak and mid-lactation respectively. At peak lactation the content of milk fat tended to increase, whereas milk protein tended to decrease and milk lactose decreased significantly. Yield of milk fat increased, but there was no change in the yield of milk protein and lactose. The content of milk fat tended to increase at mid-lactation. Milk protein decreased and there was no change in milk lactose. Yields of milk fat and lactose but not protein increased. Growth hormone exerted metabolic effects which differed with stage of lactation. At peak lactation plasma glucose concentration and its irreversible loss increased, plasma urea and acetate were unchanged and their irreversible losses tended to increase. No change was measured for plasma non-esterified fatty acids (NEFA) and the irreversible loss of NEFA decreased. At mid-lactation plasma concentrations of glucose and NEFA were increased, plasma urea decreased and acetate and 3-hydroxybutyrate tended to increase. Irreversible losses of NEFA increased, urea tended to decrease and acetate and glucose remained essentially constant. The results show that exogenous pituitary bGH exerts metabolic effects which result in the supply of increased nutrients to support milk synthesis. The metabolic effects differ with the stage of lactation, reflecting differences in physiological and/or nutritional state.

Acetates↗
PubMed1987

Effect of insulin on hind-limb and whole-body leucine and protein metabolism in fed and fasted lambs.

1. A combination of isotope-dilution and arterio-venous difference techniques was used to determine rates of leucine metabolism and protein synthesis and degradation in a hind-limb preparation (predominantly muscle) and the whole body of eight lambs fed on milk to appetite and eight lambs fasted from 24 to 48 h. 2. Compared with fed lambs, fasted lambs showed decreased rates of protein synthesis in both whole body and hind-limb, and in hind-limb muscle, elevated rates of protein degradation. 3. The effects of two rates of insulin infusion on whole-body and hind-limb-muscle leucine metabolism, and in turn on protein metabolism, were determined. Insulin had no significant effect on leucine flux or oxidation (and hence protein synthesis and degradation) in whole-body or hind-limb muscle of fed lambs. In fasted lambs insulin progressively reduced arterial leucine concentration and whole-body leucine flux and oxidation, indicating a reduction in both protein synthesis and degradation. Insulin reduced the rate of leucine efflux from hind-limb muscle, which was followed by a reduction in leucine uptake. Insulin increased hind-limb-muscle glucose uptake in both fed and fasted lambs. 4. On the basis that hind-limb muscle was representative of skeletal muscle in general, we estimated that muscle accounted for the same percentage (about 27) of whole-body protein synthesis in both fed and fasted lambs. This percentage was unaffected by infusion of insulin, although the absolute rates differed in fed and fasted lambs.

Animals↗
PubMed1986

Determination of rates of protein synthesis, gain and degradation in intact hind-limb muscle of lambs.

A model of leucine metabolism in the hind-limb muscles of the milk-fed lamb was developed which permitted simultaneous estimation of the rates of protein synthesis (Ks, days-1), degradation (Kd) and therefore gain (Kg) of muscle in vivo. The conclusions drawn from the model were: the rate of protein synthesis in muscle was related to uptake of leucine; the rate of degradation of protein was related to leucine output, as leucine, or its corresponding oxo acid, 4-methyl-2-oxopentanoic acid, or CO2. These findings support findings drawn from a wide range of studies in vitro. There was no correlation between rate of protein synthesis and rate of protein degradation, which suggests that the method can allow independent estimates of each. Estimates of protein synthesis obtained from the model (of leucine metabolism in muscle) were compared with those obtained simultaneously by constant infusion of radioisotope and analysis of incorporation into tissue. There were no significant differences between the mean values obtained for synthesis (Ks), gain (Kg) and degradation (Kd) by either method (Ks 0.051 +/- 0.002, 0.046 +/- 0.007; Kg 0.016 +/- 0.002, 0.004 +/- 0.008; Kd 0.035 +/- 0.004, 0.041 +/- 0.008 day-1, respectively, for tissue analysis and the model). However, Ks obtained from the model was significantly and positively correlated with uptake of leucine from plasma, whereas Ks obtained from tissue analysis was not.

Animals↗
PubMed1986

Metabolism of valine and the exchange of amino acids across the hind-limb muscles of fed and starved sheep.

A combination of the isotope-dilution and arterio-venous (AV) difference techniques was used to study simultaneously the metabolism of valine in the whole body and in the hind-limb muscles of fed and starved (40 h) sheep. The net exchange of gluconeogenic amino acids across hind-limb muscles was also studied. Valine entry rate was unaffected by nutritional status. There was significant extraction of valine by hind-limb muscles in both fed and starved sheep. The percentage of valine uptake decarboxylated was higher (P less than 0.05) in fed sheep but the amount of valine decarboxylated was not significantly different. The proportion of valine uptake that was transaminated was about 30 times higher in starved sheep. About 54% of valine taken up by hind-limb muscle of starved sheep was metabolized. The corresponding value for fed sheep was 21%. The contribution of CO2 from valine decarboxylation to total hind-limb muscle CO2 output was about 0.2%. The output of alanine in both fed and starved sheep was low but the output of glutamine was relatively high and roughly equivalent to the amounts of aspartate, glutamate and branched-chain amino acids that were catabolized. This study has confirmed that valine is catabolized in sheep skeletal muscle, and shown that glutamine is a major carrier of amino nitrogen out of muscle.

Amino Acids↗
PubMed1983

The metabolism of circulating non-esterified fatty acids by the whole animal, hind-limb muscle and uterus of pregnant ewes.

1. The over-all and regional metabolism of non-esterified fatty acids (NEFA) was studied using a combination of isotopic and arteriovenous-difference techniques. 2. There was a common linear relationship, whether stearic, palmitic or oleic acids were used as tracer, between the arterial NEFA concentration and the rates of entry and oxidation. 3. Assuming that the tracer used reflected the metabolism of all the NEFA, the total entry rate in fed and fasted pregnant ewes was (mean +/- SE) 0.44 +/- 0.02 and 0.55 +/- 0.07 mmol/h per kg body-weight respectively. Oxidation of NEFA contributed (mean +/- SE) 34 +/- 5 and 58 +/- 7% to the respiratory carbon dioxide in fed and fasted animals, this accounting for (mean +/- SE) 46 +/- 6 and 59 +/- 3% of the respective entry rates. 4. Hind-limb muscle both utilized and produced NEFA. The mean gross fractional extraction (calculated from isotopic uptake) was (mean +/- SE) 9 +/- 1%. Gross utilization of any NEFA and appearance of 14CO2 across the muscle were linearly related to the arterial concentration of tracer fatty acid, irrespective of whether this was oleate or stearate. The amount of 14CO2 appearing was consistent with (mean +/- SE) 54 +/- 8% of the CO2 produced by the hind-limb being derived from NEFA oxidation. 5. Infused NEFA were partly converted to ketone bodies. Uptake and oxidation in the hind-limb of ketones formed in the liver could account for approximately 20% of the 14CO2 apparently produced in muscle from NEFA. Correction for this reduces the proportion of CO2 derived from NEFA to 43%. There was some indication that ketones were also produced from NEFA in the hind-limb. 6. NEFA were not a significant energy source for the gravid uterus. 7. An over-all view of energy sources for the whole animal and for hind-limb muscle in normal and fasted pregnant sheep was presented.

Animals↗
PubMed1982

Acetate metabolism in lactating sheep.

1. The metabolism of acetate, glucose and D(-)-3-hydroxybutyrate was studied in lactating and non-lactating sheep in vivo. Special consideration was given to the utilization by hind-limb muscle in both groups of sheep and the uptake of nutrients by the lactating mammary gland was also measured. 2. The entry of acetate into the circulation (mmol/h per kg body-weight) was similar in all experimental animals at a given arterial concentration of acetate. However, normal lactation was associated with a reduced extraction of acetate by muscle and the 'spared' acetate was comparable with that removed by the udder. Feeding lactating ewes a 700 g concentrate/kg ration tended to prevent this redistribution of acetate utilization. 3. The muscles of non-lactating ewes utilized sufficient glucose, when corrected for lactate release, to account for 57% of the oxygen utilization by muscle. In lactation this fell to 32% largely because of an increased lactate production. D(-)-3-Hydroxybutyrate utilization by muscle accounted for 16-17% of the O2 consumed by the muscle in non-lactating and lactating sheep. 4. Lactating mammary gland metabolism in sheep was similar to published values for dairy cows and goats. Thus the extraction (%) of glucose, O2, acetate and D(-)-3-hydroxybutyrate was 25, 28, 62 and 53 respectively. Blood flow was 529 ml/min per kg udder and the ratio, blood flow: milk flow was 475. glucose used by the udder relative to the whole animal utilization rate may be less in sheep than in cows and goats, but the comparable proportion for acetate is as large or larger than in these species.

3-Hydroxybutyric Acid↗
PubMed1982

Metabolism of ketone bodies in pregnant sheep.

A combination of isotope-dilution and arteriovenous-difference techniques was used to determine the significance of ketones to energy homoeostasis in fasted pregnant ewes. 2. There was incomplete interconversion of D(-) 3-hydroxybutyrate (3HB) and acetoacetate (AcAc) and therefore neither entry rate nor oxidation of total ketone bodies could be estimated by assuming circulating ketone bodies represent a single metabolic compartment. Total ketone body metabolism was satisfactorily summarized using a three-compartment model. In fasted pregnant ewes the mean entry rate of total ketones was 1 mmol/h per kg body-weight and of the ketones entering the circulating 87% were promptly oxidized to carbon dioxide accounting for 30% of the total CO2 production. 3. Ketone bodies are readily utilized by hind-limb skeletal muscle such that if completely oxidized, 18 +/- 4 and 48 +/- 3% of the oxygen utilized could be accounted for in fed and fasted pregnant ewes respectively. For both 3HB and AcAc there was a hyperbolic relationship between utilization and arterial concentration. The apparent Michaelis constant (Km) values were 0.55 and 1.42 mM respectively and the maximum velocity (Vmax) 2.9 and 5.6 mmol/h per kg muscle. The arterial concentration of AcAc is always below the Km value and this limits the utilization rate. THe D(-) 3HB concentration however, may surpass that required for maximum utilization and ketoacidosis may be a consequence of this. 4. A two-compartment model was used to analyse ketone body metabolism by hind-limb skeletal muscle. The results suggested substantial interconversion and production of AcAc and 3HB. 5. The pregnant uterus utilized 3HB which if completely oxidized accounted for 12 +/- 2 (fed) and 25 +/- 4 (fasted) % of its O2 consumption. At least 64% of the net 3HB utilized was oxidized. AcAc was not utilized in significant quantitites.

Animals↗
PubMed1982

Relationships between amino acid catabolism and protein anabolism in the ruminant.

The observed relation found in sheep between the flux rate of an amino acid and the proportion found in whole-body protein suggests that the major immediate fate of an amino acid is its incorporation into tissue protein. This may be true even for dispensable amino acids. In ruminants, there is substantial utilization of several amino acids (serine, glycine, threonine, histidine, and methionine) for the synthesis of methyl groups; the use of these amino acids for gluconeogenesis is limited. There is little evidence that demands of gluconeogenesis limit the availability of amino acids for protein synthesis. Most amino acids are catabolized in the liver but there may be significant catabolism of alanine, aspartate, and glutamate in peripheral tissues, especially muscle. Normally, peripheral catabolism of branched-chain amino acids is significantly less in ruminants than other species. Nevertheless, there is some oxidation of leucine by muscle and this may be substantially increased in the diabetic state. Catabolism of leucine (and perhaps isoleucine and valine) might be inversely related to use for protein synthesis, but there is no evidence of such a relation for other amino acids.

Alanine↗
PubMed1981

On the insensitivity of sheep to the almost complete microbial destruction of dietary choline before alimentary-tract absorption.

1. Injection of [Me-14C]choline into sheep indicated that the small amount of phosphatidylcholine present in abomasal digesta was largely (69%) of non-dietary or ruminal origin. 2. Long-term feeding of [Me-3H]choline to sheep produced insignificant labelling of plasma phosphatidylcholine, indicating that more than 99% of the choline body pool was of non-dietary origin. 3. In contrast, when rats were fed with [Me-3H]choline for similar periods, 18-54% of the tissue phosphatidylcholine was derived from dietary choline. 4. The loss of [14C]choline and 32P from the plasma phosphatidylcholine after a single injection of these isotopes indicated a markedly slower turnover of choline in the sheep compared with the rat. This observation, coupled with a lack of liver glycerophosphocholine diesterase, provides an explanation for the insensitivity of the sheep to an almost complete microbial destruction of dietary choline before alimentary-tract absorption.

Abomasum↗