bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparison of the Renal and Neuroendocrine Effects of Two 5-Hydroxytryptamine Renal Prodrugs in Normal Man
Authors: Li Kam Wa T. C. , Freestone S. , Samson R. R. , Johnson N. R. , Lee M. R. 
Published: August 2015

1. The effects of 1 h intravenous infusions of equimolar amounts (45 nmol min−1 kg−1) of two putative 5-hydroxytryptamine renal prodrugs, 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan, were investigated in a randomized, placebo-controlled, cross-over study in nine healthy male subjects.
2. Cumulative urinary 5-hydroxytryptamine excretion over the 3 h observation period rose by about 370-fold after 5-hydroxy-L-tryptophan and 390-fold after γ-L-glutamyl-5-hydroxy-L-tryptophan when compared with placebo infusion. Urinary 5-hydroxy-L-tryptophan excretion was three times higher after administration of γ-L-glutamyl-5-hydroxy-L-tryptophan than after 5-hydroxy-L-tryptophan infusion. Urinary 5-hydroxyindole-3-acetic acid excretion after 5-hydroxy-L-tryptophan infusion was significantly greater than that after γ-L-glutamyl-5-hydroxy-L-tryptophan administration. Urinary dopamine excretion was not affected by either compound when compared with placebo.
3. 5-Hydroxy-L-tryptophan significantly reduced urine flow rate and urinary sodium excretion. γ-L-Glutamyl-5-hydroxy-L-tryptophan was antinatriuretic but did not affect urine output. These changes occurred without significant alterations in effective renal plasma flow and glomerular filtration rate.
4. Both 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan significantly increased plasma aldosterone concentration without a concomitant rise in plasma renin activity. The increase after γ-L-glutamyl-5-hydroxy-L-tryptophan was smaller and delayed. 5-Hydroxy-L-tryptophan, but not γ-glutamyl-5-hydroxy-L-tryptophan, increased serum growth hormone concentration.
5. There was a significant increase in diastolic blood pressure after 5-hydroxy-L-tryptophan administration, but not after γ-L-glutamyl-5-hydroxy-L-rryptophan.
6. These results show that both prodrugs generate 5-hydroxytryptamine. The antinatriuresis after both compounds is presumably mediated by intrarenally generated 5-hydroxytryptamine and this appears to be predominantly a tubular effect. The urinary metabolite data and greater extrarenal effects produced by 5-hydroxy-L-tryptophan indicate that the glutamyl derivative is relatively more selective for the kidney than 5-hydroxy-L-tryptophan.
Sulphide Impairment of Substrate Oxidation in Rat Colonocytes: A Biochemical Basis for Ulcerative Colitis?
Authors: Roediger W. E. W. , Duncan A. , Kapaniris O. , Millard S. 
Published: August 2015

1. Isolated colonic epithelial cells of the rat were incubated for 40 min with [6-14C]glucose and n-[1-14C]batyrate in the presence of 0.1-2.0 mmol/l NaHS, a concentration range found in the human colon. Metabolic products, 14CO2, acetoacetate, β-hydroxybutyrate and lactate, were measured and injury to cells was judged by diminished production of metabolites.
2. Oxidation of n-butyrate to CO2 and acetoacetate was reduced at 0.1 and 0.5 mmol/l NaHS, whereas glucose oxidation remained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxidation were dose-dependently reduced at the same rate.
3. To bypass short-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidation, ketogenesis from crotonate was measured in the presence of 1.0 mmol/l NaHS. Suppression by sulphide of ketogenesis from crotonate (−10.5 + 6.1%) compared with control conditions was not significant, whereas suppression of ketogenesis from n-butyrate (−36.00 + 5.14%) was signficant (P = &lt;0.01). Inhibition of FAD-linked oxidation was more affected by NaHS than was NAD-linked oxidation.
4. L-Methionine (5.0 mmol/l) significantly redressed the impaired β-oxidation induced by NaHS. Methionine equally improved CO2 and ketone body production, suggesting a global reversal of the action of sulphide.
5. Sulphide-induced oxidative changes closely mirror the impairment of β-oxidation observed in colonocytes of patients with ulcerative colitis. A hypothesis for the disease process of ulcerative colitis is that sulphides may form persulphides with butyryl-CoA, which would inhibit cellular short-chain acyl-CoA dehydrogenase and β-oxidation to induce an energy-deficiency state in colonocytes and mucosal inflammation.
Indomethacin Stimulates Basal Glucose Production in Humans without Changes in Concentrations of Glucoregulatory Hormones
Authors: Corssmit E. P. M. , Romijn J. A. , Endert E. , Sauerwein H. P. 
Published: August 2015

1. To investigate whether indomethacin affects basal glucose production, we measured hepatic glucose production in six healthy postabsorptive subjects on two occasions: once after administration of indomethacin (150 mg orally) and once after administration of placebo.
2. Glucose production was measured by primed, continuous infusion of [3-3H]-glucose.
3. Indomethacin administration resulted in an increase in glucose production from 10.9 (SEM 0.3) μmol min−1 kg−1 to a maximum of 16.5 (SEM 1.6) μmol min−1 kg−1 (P &lt;0.05) within ∼1 h, whereas in the control experiment glucose production declined gradually (P &lt;0.01) (P &lt;0.05 indomethacin versus control). There were no differences in plasma concentrations of insulin, C-peptide and counter-regulatory hormones between the two experiments.
4. Since indomethacin administration resulted in an increase in glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that indomethacin stimulates hepatic glucose production through other mechanisms.
Forearm Substrate Utilization during Exercise after a Meal Containing Both Fat and Carbohydrate
Authors: Griffiths A. John , Humphreys Sandy M. , Clark Mo L. , Frayn Keith N. 
Published: August 2015

1. Whilst the provision of exogenous carbohydrate has been shown to be beneficial to endurance exercise performance, little attention has been paid to the possibility of dietary manipulation of the availability of fat.
2. Ten normal subjects were studied on two occasions: after an overnight fast (postabsorptive state) and after a meal containing 80g of fat and 80g of carbohydrate (fed state). Forearm substrate exchange was studied during 60 min of isometric forearm exercise (5s contraction, 5s relaxation).
3. In the fed state concentrations of plasma triacylglycerol (1510 ± 150 versus 850 ± 80 μmol/l, P &lt; 0.01), blood ketone bodies (151 ± 21 versus 80 ± 10 μmol/l, P &lt; 0.01) and plasma insulin (17 ± 3 versus 7 ± 1 m-units/l, P &lt; 0.01) were elevated compared with the postabsorptive state; plasma glucose and non-esterified fatty acid concentrations were not significantly different.
4. Forearm blood flow and O2 consumption each increased about 6-fold during exercise, with no differences between the two nutritional states. The potential contribution of individual substrates to forearm O2 consumption (a calculation which is independent of blood flow) was assessed: for triacylglycerol it was significantly greater in the fed state (P &lt; 0.01). The sum of the potential contributions of triacylglycerol, non-esterified fatty acids, glucose and ketone bodies to forearm O2 consumption was significantly greater, both before and during exercise, in the fed than in the postabsorptive state (P &lt; 0.05), implying the sparing of endogenous (forearm) fuels.
5. These studies highlight the potential for manipulation of substrate supply during exercise by feeding meals containing both carbohydrate and fat.
Nitrogen Homoeostasis in Man: Diurnal Changes in Nitrogen Excretion, Leucine Oxidation and Whole Body Leucine Kinetics during a Reduction from a High to a Moderate Protein Intake
Authors: Quevedo Marcelo R. , Price Gill M. , Halliday David , Pacy Paul J. , Millward D. Joe 
Published: August 2015

1. The adaptation of the diurnal cycle of nitrogen (N) homoeostasis during a change in protein intake was investigated with diurnal measurements of N and leucine balance and turnover during a reduction from a high to a moderate protein intake in normal adults.
2. In experiment 1, during a 9 day period after a reduction from 1.82 to 0.77 g of protein day−1 kg−1, N excretion fell slowly at a similar rate in fed and fasted states so that the lowered intake was unable to replete any of the postabsorptive losses for 3 days. There was a marked negative N balance, which persisted throughout the study, although with a significant reduction in N losses in both fed and fasted states on day 4, balances during days 4–9 (−32.8 ± 28.3 mg of N day−1 kg−1) were less negative than during days 1–3 (−79.1 ± 60.4 mg of N day−1 kg−1).
3. In experiment 2, during a 14 day period after a reduction from 1.89 to 0.77 g of protein day−1kg−1, [1-13C]leucine oxidation and turnover were measured by primed intravenous infusion, during fasting and feeding in subjects before and on days 3, 7 and 14 after the dietary change. Leucine oxidation fell by 32% (P &lt; 0.05) on day 3 in the fed state and by 12% (P &lt; 0.05) during fasting, falling further in each case by day 7 with improved balance. N losses predicted from the leucine oxidation fell with the same time course as the measured N excretion in experiment 1, but the predicted losses were lower, so that the overall negative leucine balance on day 3 (−22 ± 17 mg of N day−1 kg−1) became positive by day 7 (+ 15 ± 21 mg of N day−1 kg−1).
4. Rates of protein synthesis and degradation calculated from leucine kinetics indicated that feeding the high protein diet resulted in a 60% inhibition of degradation and a 15% (P &lt; 0.05) stimulation of synthesis. With the moderate protein diet the improving fasting balance between days 3 and 7 was the result of a non-significant fall in degradation. Feeding the moderate protein diet abolished the stimulation of synthesis and significantly lowered the inhibition of degradation (31 ± 9%). The improving fed balance between days 3 and 7 was the result of changes in the rates of synthesis and degradation which were below the detection limits of the methods. The daily sum of fasted and fed rates of synthesis (4.33 g day−1 kg−1) did not change with the lowered intake, whereas the rate of degradation increased significantly from 3.61 to 4.26 g day−1 kg−1).
5. Thus, in response to a lower protein intake, adaptation of amino acid oxidation and N excretion occurs, with a similar pattern of gradual reductions in fed and fasted periods during the first week. Thus protein requirements are influenced by the habitual protein intake, which influences the nutritional demand for protein for repletion of fasting losses, the efficiency of such repletion and the consequent dietary need.
Gender Differences in Urinary Kallikrein Excretion in Man: Variation Throughout the Menstrual Cycle
Authors: Albano J. D. M. , Campbell S. K. , Farrer A. , Millar J. G. B. 
Published: August 2015

1. Urinary kallikrein excretion was measured in healthy male subjects and in healthy pre- and post-menopausal females.
2. Urinary kallikrein excretion was shown to be constant throughout a 24 h period. Individual male subjects showed little fluctuation in urinary kallikrein excretion; within-subject variance accounted for 1.65% of the total.
3. Female subjects with ovulatory menstrual periods excreted significantly more kallikrein than post-menopausal females and males.
4. Pre-menopausal females showed a much greater within-subject variation in urinary kallikrein excretion and this could be related to the stage of the menstrual cycle, with significantly greater urinary kallikrein excretion in the luteal phase than in the follicular phase.
5. Plasma renin activity and plasma aldosterone concentration also showed a menstrual variation, with concentrations in the luteal phase being significantly higher than those in the follicular phase.
6. The rise in urinary kallikrein excretion in the luteal phase could be abolished by oral administration of the aldosterone antagonist spironolactone.
7. Urinary kallikrein excretion in post-menopausal females was similar to the range found in males, and showed no cyclic changes over a 4 week period.
8. Gender and menstrual status should be taken into account in studies of the physiological role of tissue kallikreins.
Lipoprotein Profiles in a Family with Two Mutants of Apolipoprotein E: Possible Association with Hypertriglyceridaemia but Not with Dysbetalipoproteinaemia
Authors: Zhao Shui-Ping , Van den Maagdenberg Arn M. J. M. , Vroom Ton F. F. P. , Hooft Ferdinand M. Van't , Leuven Jan A. Gevers , Havekes Louis M. , Frants Rune R. , Van Der Laarse Arnoud , Smelt Augustinus H. M. 
Published: August 2015

1. The plasma lipoprotein profiles of eight members of a Dutch pedigree spanning three generations where two rare apolipoprotein E mutants, APOE*3(Cys-112→Arg; Arg-251→Gly) and APOE*2(Val-236 →Glu), segregate were analysed to determine whether the APOE mutants were associated with dyslipidaemia.
2. The proband, a 51-year-old Caucasian male, was a carrier of APOE*3(Cys-112→Arg; Arg-251→Gly) and his spouse was a carrier of APOE*2(Val-236→Glu). Four other family members were carriers of one or both of the mutant APOE genes.
3. The plasma cholesterol and triacylglycerol concentrations were markedly elevated in the proband and were classified as type IV hyperlipoproteinaemia. The plasma triacylglycerol concentration was moderately increased in a sister, who was a carrier of APOE*3(Cys-112→Arg; Arg-251→Gly), and in the son, who was a compound heterozygote for both mutant APOE alleles. Normal plasma lipid levels were observed in all other family members. In the plasma samples of the proband and his family members β-very-low-density lipoprotein was not detectable and the molar ratio of very-low-density lipoprotein-cholesterol to very-low-density lipoprotein-triacylglycerol was less than 0.9. The concentration of intermediate-density lipoprotein was within normal limits.
4. None of the family members carrying APOE*3-(Cys-112→Arg; Arg-251→Gly) and/or APOE*2(Val-236→Glu) exhibited lipoprotein abnormalities characteristic of familial dysbetalipoproteinaemia, although three family members carrying APOE*3-(Cys-112→Arg; Arg-251→Gly) showed hypertriglyceridaemia.
β-Adrenoceptor Subtypes Mediating the Metabolic Effects of BRL 35135 in Man
Authors: Wheeldon N. M. , McDevitt D. G. , McFarlane L. C. , Lipworth B. J. 
Published: August 2015

1. The aim of the present study was to evaluate the metabolic responses produced in man by the β-adrenoceptor agonist BRL 35135, and to determine which of these responses are β3-, rather than β1- or β2-, mediated.
2. Eight normal male subjects received single oral doses of BRL 35135 (8 mg) or the selective β2-adrenoceptor agonist salbutamol (8 mg) after pretreatment with placebo, bisoprolol (5 mg) as a selective β1-antagonist or nadolol (20 mg) to block β1-and β2-, but not β3-adrenoceptors.
3. BRL 35135 and salbutamol produced a significant fall in serum potassium concentration compared with placebo, in keeping with β2-adrenoceptor stimulation. Both drugs also produced a significant increase in serum glucose, insulin and lactate concentrations, which mirrored the hypokalaemic response, being unaffected by selective β1-blockade (bisoprolol), but completely blocked by nadolol. BRL 35135 (but not salbutamol) also produced a significant rise in serum free fatty acid and glycerol concentrations, which appeared to be β2-mediated.
4. A significant increase in basal metabolic rate occurred with both BRL 35135 and salbutamol. In the case of salbutamol, this effect appeared to be mediated solely by β2-adrenoceptors, whereas BRL 35135 produced a thermogenic response which could only be partially accounted for by a combination of β1- and β2-adrenoceptor stimulation.
5. These results infer the possibility of thermogenic β3-adrenoceptors in man, although these do not appear to be involved in the control of carbohydrate or fat metabolism.
Tumour and Host Tissue Responses to Branched-Chain Amino Acid Supplementation of Patients with Cancer
Authors: McNurlan M. A. , Heys S. D. , Park K. G. M. , Broom J. , Brown D. S. , Eremin O. , Garlick P. J. 
Published: August 2015

1 Rates of protein synthesis have been measured from the incorporation of 57 mg of l-[1-13C]leucine/kg for 90 min into muscle tissue and colorectal tumours removed at surgery from cancer patients.
2. For the 20 h preceding surgery and during the measurement of protein synthesis, the patients received intravenous saline, conventional intravenous nutrition (0.2 g of N and 103 non-protein kJ/kg body weight) or intravenous nutrition enriched with the branched-chain amino acids leucine, isoleucine and valine (0.2 g of N with 30% from branched-chain amino acids and 103 non-protein kJ/kg body weight).
3. Conventional intravenous nutrition resulted in a significant stimulation of the rate of protein synthesis in both muscle tissue (2.64 ± 0.75%/day versus 1.78 ± 0.51%/day in saline control, means ± SD) and tumour tissue (43.9 ± 10.3%/day versus 22.6 ± 5.6%/day in saline control).
4. Pre-operative nutrition enriched with branched-chain amino acids was less effective than conventional intravenous nutrition in stimulating protein synthesis in both muscle and tumour. The rates of protein synthesis were 2.12 ± 0.41%/day in muscle and 33.7 ± 5.3%/day in the tumours.
5. The expression of proliferating cell nuclear antigen in sections of the tumours showed changes with intravenous feeding of the two different amino acid mixtures that were similar to the changes in protein synthesis, and these two variables were significantly correlated. This is evidence that feeding with conventional mixtures and mixtures enriched with branched-chain amino acids stimulates tumour growth.
6. In this study the mixture enriched with branched-chain amino acids provided no clear advantage for cancer patients, since a smaller response to branched-chain amino acids was observed in both tumours and host muscle tissue.
Studies in Surgical Trauma: Oxidative Stress in Ischaemia-Reperfusion of Rat Liver
Authors: Liu P. T. , Symons A. M. , Howarth J. A. , Boulter P. S. , Parke D. V. 
Published: August 2015

1. Hypovolaemic shock associated with surgical trauma has been studied in a rat liver ischaemia-reperfusion model by determination of oxidative stress, lipid peroxidation and tissue infiltration of polymorphonuclear leucocytes.
2. Liver ischaemia alone resulted in slight liver oedema and polymorphonuclear leucocyte infiltration, a slight increase in thiobarbituric acid-reacting substances (an index of lipid peroxidation) and decreases in liver reduced glutathione and total radical-trapping antioxidant parameter, indices of oxidative stress. Ischaemia plus 30 min of reperfusion further increased liver oedema, polymorphonuclear leucocyte infiltration and thiobarbituric-acid reacting substances, and further decreased liver reduced glutathione and total radical-trapping antioxidant parameter.
3. After 60 and 90 min of reperfusion, oedema (40% increase), polymorphonuclear leucocyte infiltration (40-fold increase) and thiobarbituric-acid reacting substances (20-fold increase) were maximal, and liver reduced glutathione (75–95% decrease) and total radical-trapping antioxidant parameter (85–90% decrease) were at a minimum.
4. All parameters were exacerbated by 24 h starvation. Liver reduced glutathione closely paralleled total radical-trapping antioxidant parameter, and ischaemia alone depleted both by 30% in fed rats and 50% in fasted rats.
5. Oxidative stress and lipid peroxidation were associated more with the period of reperfusion and polymorphonuclear leucocyte infiltration. Polymorphonuclear leucocyte infiltration into lung also occurred after 90 min of liver reperfusion.
6. Possible mechanisms of hepatic ischaemia-reperfusion-induced oxidative stress are discussed.
Sympathetic Restraint of Baroreflex Control of Heart Period in Normotensive and Hypertensive Subjects
Authors: Lucini Daniela , Pagani Massimo , Mela Giuseppe Sandro , Malliani Alberto 
Published: August 2015

1. We assessed the effects of changing levels of sympathetic drive on the gain of baroreflex control of the sino-atrial node, in normotensive and hypertensive subjects.
2. Autoregressive spectral and cross-spectral analysis of R—R interval and systolic arterial pressure (non-invasive Finapres method) variabilities providing an estimate of baroreflex gain through the frequency domain index α were performed on data from 63 normotensive and 78 mild hypertensive subjects. Subjects were studied at rest and during active orthostatism, which induces sympathetic predominance. Seven control subjects and 14 hypertensive subjects were also studied after chronic atenolol treatment, to attenuate β-adrenoceptor-mediated responses.
3. In both normotensive and hypertensive subjects, the index α was reduced by active standing and increased by chronic β-adrenoceptor blockade. Furthermore, at rest, the index at was correlated with R—R variance and appeared significantly reduced with age. The age-related negative correlation of the index α was no longer evident during the standing-induced increase in sympathetic drive, in both normotensive and hypertensive subjects.
4. The index α, a non-invasive frequency domain estimate of the overall gain of baroreflex control of the sino-atrial node, which appears to be reduced in essential hypertension, is negatively modulated by physiological increases in sympathetic drive, and augmented by pharmacological blockade of β-adrenoceptors.
5. In essential hypertension the enhanced sympathetic drive present already at rest, and the simultaneous reduction of the gain of baroreflex mechanisms, are the expression of a complex alteration in neural cardiovascular control.