bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in the Gene Coding for Cholesteryl Ester Transfer Protein are Related to Plasma High-Density Lipoprotein Cholesterol and Transfer Protein Activity
Authors: Freeman Dilys J. , Packard Christopher J. , Shepherd James , Gaffney Dairena
Published: August 2015

1. Cholesteryl ester transfer protein activity may have a physiological effect on high-density lipoprotein levels.

2. We examined restriction fragment length polymorphisms associated with the cholesteryl ester transfer protein gene and the apolipoprotein AI gene in a group of 60 unrelated subjects selected from an initial survey of 5000 subjects on the basis of their high-density lipoprotein levels being high or low at the extremes of the distribution. The activities of cholesteryl ester transfer protein and lectithin:cholesterol acyltransferase (phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) were also determined. Analysis by selection of those with a low high-density lipoprotein cholesterol level (≤ 1.1 for males, ≤ 1.2 for females) gave 32 individuals with 24% B2 alleles. Selection of subjects with a high-density lipoprotein cholesterol level (≥ 2 mmol/l) gave 17 with 62% B2 alleles.

3. The group with low levels of high-density lipoprotein cholesterol had higher activity of cholesteryl ester transfer protein and significantly elevated triacylglycerol levels when compared with the group with high levels of high-density lipoprotein cholesterol.

4. A further significant finding was the correlation of the Msp1 restriction fragment length polymorphism detected by the apolipoprotein AI gene with lecithin:cholesterol acyltransferase activity.
Effect of Polycations on the Function of the Isolated Perfused Rat Kidney
Authors: Firth J. D.
Published: August 2015

1. In minimal change nephrotic syndrome the occurrence of heavy proteinuria can be explained on the basis of a reduction in charge selectivity of the glomerular filtration barrier, and it has been proposed that this might be caused by the neutralization of anionic groups by a circulating polycationic factor.

2. The effects of two polycations, protamine and poly-l-lysine, on the function of the isolated perfused rat kidney have been examined.

3. Poly-l-lysine polymers of relatively high molecular weight (8800 and 17800) induced heavy proteinuria, while simultaneously causing a marked increase in renal vascular resistance and a fall in filtration rate. Protamine (approximate molecular weight 7000) at relatively high concentration induced modest proteinuria in the absence of effects on vascular resistance or filtration rate.

4. A poly-l-lysine polymer of lower molecular weight (3800) did not induce proteinuria. Protamine at a concentration of 40 μg/ml and below did not affect protein excretion either. Both provoked substantial natriuresis. This appeared to be largely due to an effect on the tubular handling of sodium since the filtration rate remained steady while fractional sodium excretion rose markedly.

5. The natriuretic effect of protamine was blocked by heparin, but not by indomethacin or verapamil, suggesting that the mechanism of natriuresis did not depend upon either prostaglandin production or entry of calcium through verapamil-sensitive channels.
Dynamic Association between Artery Shear flow Condition and Platelet Cytosolic Free Ca2+ Concentration in Human Hypertension
Authors: Levenson Jaime , Devynck Marie-Aude , Pithois-Merli Isabelle , Le Quan Sang Kim Hanh , Filitti Vincenzo , Simon Alain
Published: August 2015

1. Blood cells and vascular endothelial cells are subjected to a wide range of haemodynamically generated shear stress forces. In vitro, membrane stretching or shear stress have been observed to activate ion channels and cell metabolism and to facilitate erythrocyte and platelet aggregation.

2. The present study was designed to evaluate the participation of shear stresses in the control of apparent platelet cytosolic free Ca2+ concentration in hypertensive patients.

3. Shear conditions and platelet cytosolic free Ca2+ concentration in vitro were studied after a dynamic perturbation induced by 3 months of double-blind treatment with one of two β-antagonists, carteolol and atenolol. Brachial artery wall shear rate and stress were estimated by means of a pulsed Doppler velocimeter, and blood viscosity was measured by a co-axial viscometer at a shear rate of 96 s−1. Platelet cytosolic free Ca2+ concentration was simultaneously measured by using the Quin-2 fluorescent chelator. The direct effect of atenolol and carteolol on platelet cytosolic free Ca2+ concentration in vitro was also measured after addition of the β-blockers to plateletrich plasma.

4. Atenolol and carteolol decreased blood pressure similarly but their effects on shear rate (P < 0.02), shear stress (P < 0.01) and platelet cytosolic free Ca2+ concentration (P < 0.05) differed after 3 months of therapy. In contrast, neither of the drugs significantly altered platelet cytosolic free Ca2+ concentration, in vitro per se.

5. In the overall population, strong positive correlations existed not only between changes in platelet cytosolic free Ca2+ concentration and those in shear rate (r = 0.81, P < 0.001) and shear stress (r = 0.83, P < 0.001), but also between their absolute values, suggesting a possible haemodynamic shear-dependent modulation of transmembrane Ca2+ transport.
Cardiovascular reflex responses in Bangladeshi and European subjects
Authors: Rahman M. A. , Farquhar I. , Bennett T.
Published: August 2015

1. Cardiovascular responses to three different interventions, namely the Valsalva manoeuvre, deep breathing and a cold stimulus on the face, were studied in two ethnic groups (European and Bangladeshi) that have been shown to differ in the prevalence of hypertensive-vascular disease. The data obtained consisted of systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate measured by using a beat-by-beat non-invasive blood pressure monitor (the Finapres), forearm blood flow determined by venous occlusion plethysmography, and calculated forearm vascular resistance.

2. The resting haemodynamic status was similar in European and Bangladeshi subjects. However, Bangladeshi subjects showed a greater increase in heart rate, but only after 20 s into the Valsalva manoeuvre, and greater overshoots in mean blood pressure after the manoeuvre than the European subjects. Furthermore, after cold face stimulation the fall in forearm vascular resistance to baseline levels was delayed in Bangladeshi subjects relative to that in the European subjects.

3. There were no inter-group differences in the reflex bradycardia relative to mean blood pressure or in the cardiac baroreflex sensitivity estimated from systolic blood pressure and pulse interval after the Valsalva manoeuvre. In addition, values for the mean difference between maximum and minimum pulse intervals during deep breathing did not differ in Bangladeshi and European subjects.

4. These findings together suggest that, although cardiac vagal reflex responses appear similar in the two groups, sympatho-adrenal influences on the heart and vasculature may be greater in Bangladeshi subjects than in European subjects.
Abnormal renal glucose handling in X-linked hypophosphataemic mice
Authors: Mühlbauer R. C. , Fleisch H.
Published: August 2015

1. The renal handling of glucose was determined in male X-linked hypophosphataemic (Hyp/Y) mice and in control littermates (+/Y) aged 4 months. Plasma glucose concentration and urinary glucose excretion were measured before and during stepwise increase in glycaemia induced by an acute infusion of glucose. The relationship between plasma glucose concentration and urinary glucose excretion was monitored per ml of glomerular filtrate in mice fed high and low phosphate diets.

2. Hyp/Y mice fed the high phosphate diet showed a significantly higher glucosuria compared with +/Y littermates. When glycaemia was increased, Hyp/Y mice developed frank glucosuria earlier than +/Y animals. In Hyp/Y mice we could not find a threshold below which virtually no glucose was excreted in the urine, whereas this was clearly visible in +/Y mice. These differences persisted in animals fed the low phosphate diet.

3. Using the acute response to the glucoregulatory hormones, glucagon and insulin, administered exogenously, we found that the regulation of plasma glucose concentration did not differ between Hyp/Y and +/Y mice.

4. The significantly lower plasma glucose concentration observed in Hyp/Y as compared with +/Y mice decreased further during fasting.

5. We conclude that the renal reabsorptive capacity for glucose is defective in Hyp/Y mice and their low plasma glucose concentration may be explained by the renal leak. Therefore the X-linked phosphataemic mouse appears not only to be characterized by a defect in renal phosphate and calcium reabsorption but also by an altered glucose reabsorption.
Abnormal erythrocyte choline transport in patients with chronic renal failure
Authors: Fervenza F. C. , Meredith D. , Ellory J. C. , Hendry B. M.
Published: August 2015

1. Erythrocyte choline transport has been studied in nine patients on maintenance haemodialysis for chronic renal failure, six patients on continuous ambulatory peritoneal dialysis, 31 patients with renal transplants and in nine normal control subjects.

2. The mean maximum rate of choline influx (Vmax., measured at an extracellular choline concentration of 250 μmol/l) was 66.7 (sd 14.1) μmol h−1 l−1 cells in patients on haemodialysis, 87.8 (sd 18.5) μmol h−1 l−1 cells in patients on continuous ambulatory peritoneal dialysis and 30.5 (sd 4.9) μmol h−1 l−1 cells in control subjects. The increase in choline flux in patients on haemodialysis and patients on continuous ambulatory peritoneal dialysis compared with control subjects was highly significant (P < 0.001).

3. Renal transplant patients showed variable values for the Vmax. of choline influx (range 17.7-71.7 μmol h−1 l−1 cells). The values showed a signifcant negative correlation with creatinine clearance and this correlation correctly extrapolated to the maximum choline flux in normal subjects and in patients on dialysis.

4. The kinetics of choline transport have been studied in erythrocytes of patients on haemodialysis and control subjects in ‘zero-trans’ conditions after depletion of intracellular choline. The mean Vmax. in these conditions was 38.4 (sd 4.6) μmol h−1 l−1 cells in patients on haemodialysis compared with 14.2 (sd 3.7) μmol h−1 l−1 cells in control subjects. The mean Km under ‘zero-trans’ conditions was 19.4 (sd 2.4) μmol/l in patients on haemodialysis and 7.4 (sd 1.4) μmol/l in control subjects. These differences were significant (P < 0.001).
Oral carbidopa has no effect on the renal response to angiotensin II in normal man
Authors: Eadington D. W. , Swainson C. P. , Lee M. R.
Published: August 2015

1. The effect of inhibition of intrarenal dopamine synthesis by carbidopa on the renal response to angiotensin II infusion was studied in six healthy salt-loaded volunteers.

2. Subjects received an infusion of angiotensin II at two doses (0.5 and 1.0 ng min−1 kg−1) on two occasions. Before one study they took a single dose of carbidopa (100 mg) by mouth.

3. The plasma concentrations of angiotensin II produced by the infusion were similar on both study days. Angiotensin II infusion reduced urinary dopamine excretion on the control day. Urinary dopamine excretion was undetectable at all times after carbidopa, but carbidopa did not change the basal excretion rate of sodium. Despite inhibition of renal dopamine synthesis, the reductions in both absolute and fractional sodium excretion during the angiotensin II infusion were not different from those seen in the control study.

4. The reductions in glomerular filtration rate and effective renal plasma flow which occurred during angiotensin II infusion were not modified by pretreatment with carbidopa.

5. The renal response to angiotensin II is not modulated either wholly or in part by endogenous intrarenal dopamine levels. The fall in urinary dopamine excretion which occurs during angiotensin II infusion is consistent with a modulatory role for tubular reabsorptive capacity in the regulation of proximal tubular dopamine synthesis.
Indocyanine Green elimination in patients with liver disease and in normal subjects
Authors: Burns E. , Triger D. R. , Tucker G. T. , Bax N. D. S.
Published: August 2015

1. The validity of a two-compartment pharmacokinetic model for the estimation of the hepatic extraction ratio of Indocyanine Green was tested in six patients with cirrhosis of the liver.

2. No agreement was found between the value of the hepatic extraction ratio measured directly and that calculated using the two-compartment model.

3. To investigate the reasons for the failure of the model, an extended sampling period was used to define the time course of Indocyanine Green in plasma in six healthy subjects and in six patients with cirrhosis of the liver after a bolus injection of the dye.

4. Indocyanine Green was measurable in the plasma for up to 10 h after injection in healthy subjects, and up to 48 h after injection in the patients. The plasma elimination curve in both groups was best described by a triexponential function.

5. The clearance of Indocyanine Green calculated using data collected in the first 20 min after injection overestimated that calculated using data collected for as long as Indocyanine Green was measurable in the plasma. In the patients with cirrhosis the mean overestimate was 87%.

6. Thus, a two-compartment pharmacokinetic model was inappropriate for the description of the disposition of Indocyanine Green and estimates of the hepatic extraction ratio obtained using this model in patients with cirrhosis were inaccurate.
Neuronal Re-Uptake of Noradrenaline by Sympathetic Nerves in Humans
Authors: Eisenhofer Graeme , Esler Murray D. , Meredith Ian T. , Ferrier Claudia , Lambert Gavin , Jennings Garry
Published: August 2015

1. Plasma concentrations of [3H]dihydroxyphenylglycol, the intraneuronal metabolite of noradrenaline, were examined during intravenous infusion of [3H]noradrenaline in 43 subjects, to assess the nature of its formation. Noradrenaline re-uptake by sympathetic nerves was estimated in 11 subjects from the effects of neuronal uptake blockade with desipramine on noradrenaline clearance and plasma concentrations of [3H]dihydroxyphenylglycol and endogenous dihydroxyphenylglycol. In seven subjects noradrenaline re-uptake and spillover into plasma were examined before and during mental arithmetic or handgrip exercise.

2. During infusion of [3H]noradrenaline, plasma [3H]dihydroxyphenylglycol increased progressively, indicating its formation from previously stored [3H]noradrenaline leaking from vesicles as well as from [3H]noradrenaline metabolism immediately after removal into sympathetic nerves. Thus, to estimate noradrenaline reuptake, the amount of [3H]dihydroxyphenylglycol derived from [3H]noradrenaline metabolized immediately after removal into the sympathetic axoplasm must be isolated from that derived from [3H]noradrenaline sequestered into vesicles.

3. At rest in the supine position the rate of noradrenaline re-uptake was 474 ± 122 pmol min−1 kg−1, 9.5-fold higher than the rate of spillover of noradrenaline into plasma (49.6 ± 6.4 pmol min−1 kg−1). Noradrenaline reuptake and spillover into plasma were both increased during mental arithmetic and isometric handgrip exercise.
Inhibition of Neutral Endopeptidase (EC 3.4.24.11) Leads to An Atrial Natriuretic Factor-Mediated Natriuretic, Diuretic and Antihypertensive Response in Rodents
Authors: Shepperson N. B. , Barclay P. L. , Bennett J. A. , Samuels G. M. R.
Published: August 2015

1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor.

2. (±)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (±)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum.

3. (±)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum.

4. These data demonstrate that the neutral endopeptidase inhibitor (±)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.
How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man?
Authors: Singer D. R. J. , Shirley D. G. , Markandu N. D. , Miller M. A. , Buckley M. G. , Sugden A. L. , Sagnella G. A. , MacGregor G. A.
Published: August 2015

1. Aldosterone is suppressed by sodium loading. We studied the contribution of this decrease in plasma aldosterone to the natriuresis after acute sodium loading in healthy volunteers.

2. Two litres of saline [0.9% (w/v) NaCl] were infused during the second hour of a 6 h infusion of aldosterone (3 pmol min−1 kg−1) or placebo in eight healthy young men. On the placebo day, plasma aldosterone decreased by 30 min after the start of saline infusion and remained suppressed. During aldosterone infusion, plasma aldosterone was maintained at around 400 pmol/l.

3. Urinary sodium excretion, lithium clearance and plasma atrial natriuretic peptide increased and plasma renin activity decreased after saline infusion, whether or not aldosterone was infused. However, from 60 to 240 min after saline infusion, natriuresis was significantly less during aldosterone infusion than on the placebo day. In addition, saline loading led to a progressive increase in the ratio of sodium clearance to lithium clearance, used as an index of the fractional distal tubular rejection of sodium, and in the ratio of urinary sodium to potassium. These increases were prevented by the infusion of aldosterone.

4. This study suggests that there are differences in the mechanisms determining the early and the later responses to an acute sodium load. Suppression of aldosterone may explain much of the later increase in natriuresis after saline infusion. In addition, the results are consistent with a role for atrial natriuretic peptide in the immediate increase in sodium excretion after saline loading.
Triacylglycerol in the human erythrocyte: quantification and fatty acyl turnover in normal subjects and chronic alcoholics
Authors: Lerique Brice , Gastaldi Marguerite , Boyer Jean
Published: August 2015

1. Triacylglycerol in erythrocytes from normal human subjects was estimated to average 2.7 ± 0.7 nmol/1010 cells, equivalent to 0.07% of total lipids or 0.3% of neutral lipids.

2. The specific activity of triacylglycerol labelling attained by incubating intact erythrocytes with [3H]oleic acid was 10 nmol/μmol, a value 20-fold higher than that of the highest labelled phospholipid, sphingomyelin; as isolated by ultracentrifugation over a density gradient, the youngest erythrocytes exhibited a labelling rate 10-fold higher than that of older cells.

3. The triacylglycerol content was not modified in erythrocytes from chronic alcoholics, whereas the mean rate of triacylglycerol labelling was 31% (P <0.05) higher than that of control subjects, and did not normalize 4 weeks after alcohol withdrawal.

4. These results indicate that triacylglycerol, although a quantitatively minor component, is one of the most active metabolites in the lipid matrix of the human erythrocyte membrane and appears to be implicated in the membrane response to antagonistic agents.
Renal and extra-renal levels of renin mRNA in experimental hypertension
Authors: Samani Nilesh J. , Brammar William J. , Swales John D.
Published: August 2015

1. Using a ribonuclease-protection assay, renin mRNA levels were compared in the kidneys, livers, brains, hearts and adrenal glands of two-kidney, one-clip Goldblatt hypertensive rats with those of age-matched control rats at 4 weeks (‘early’) and 20 weeks (‘chronic’) after clipping, and in the kidneys and adrenal glands of rats treated for 3 weeks with deoxycorticosterone and salt (deoxycorticosterone-salt hypertension) with those of control rats.

2. While marked changes were observed in kidney renin mRNA levels in all three experimental groups compared with their respective controls, in most of the extrarenal tissue studied minimal, if any, difference was seen in renin mRNA levels between the hypertensive and control rats.

3. The findings suggest that in these extra-renal tissues renin gene expression is differently regulated from that in the kidney, and particularly that it is not profoundly affected by changes in the level of circulating angiotensin II.

4. An increase in renin mRNA was observed in the adrenal glands of the ‘chronic’ Goldblatt rats, which may be of relevance to the maintenance of hypertension in this model.
Doxepin therapy for postprandial symptomatic hypoglycaemic patients: neurochemical, hormonal and metabolic disturbances
Authors: Lechin Fuad , van der Dijs Bertha , Lechin Alex , Lechin Marcel , Coll-García Eduardo , Jara Héctor , Cabrera Alejandra , Jiménez Vladimir , Gómez Francisco , Tovar Duilia , Rada Isaís , Arocha Luis
Published: August 2015

1. Three oral glucose tolerance tests were performed in each of 32 symptomatic postprandial hypoglycaemic patients (before placebo, before doxepin therapy and after doxepin therapy). Plasma neurotransmitters were determined in parallel with assays of plasma insulin and glucose levels.

2. Three different types of patients were distinguished. Type I showed a low noradrenaline/adrenaline ratio, high dopamine levels and low platelet 5-hydroxytryptamine (serotonin) levels during basal periods. After a glucose load, late peaks of dopamine and free 5-hydroxytryptamine, which coincided with the symptoms but not with the nadir of plasma glucose, were observed. Type II showed a low basal plasma noradrenaline/adrenaline ratio. After a glucose load, progressive increases in adrenaline and decreases in glucose were seen. Adrenergic symptoms coincided with the nadir of glucose. Although type III patients showed hyperinsulinaemia after a glucose load similar to the other types of patient, they did not show hyperglycaemia, but rather exhibited a sustained and progressive reduction in plasma glucose. These patients were characterized by a high basal plasma noradrenaline/adrenaline ratio, high basal plasma levels of 4-hydroxy-3-methoxyphenylethyleneglycol and high basal levels of platelet 5-hydroxytryptamine, all of which increased after a glucose load. Systolic and diastolic blood pressure decreases paralleled reductions in heart rate and glucose. The nadir of plasma glucose occurred simultaneously with the appearance of symptoms (weakness, heartburn, oppressive chest pain, tension headache, abdominal cramps, dizziness, etc.). Therapy with doxepin led to disappearance of the symptoms within 3–4 weeks. Normalization of all other disordered variables (cardiovascular, metabolic and neurochemical, and the clonidine test) paralleled the disappearance of the symptoms.

3. Symptoms varied in the three types of patients and we conclude that they are related to hypoglycaemia-induced disorders of plasma neurotransmitters, rather than to hypoglycaemia per se. We postulate that an uncoping stress situation (type I and II patients) and depression (type III patients) underlie the physiopathological mechanisms.
Differential stimulation by oxygen-free-radical-altered immunoglobulin G of the production of superoxide and hydrogen peroxide by human polymorphonuclear leucocytes
Authors: Kleinveld H. A. , Sluiter W. , Boonman A. M. C. , Swaak A. J. G. , Hack C. E. , Koster J. F.
Published: August 2015

1. The effect of free-radical-altered IgG (monomer and polymer u.v.-irradiated IgG), compared with that of native and heat-aggregated IgG, on the production rate of superoxide anion and hydrogen peroxide by granulocytes (polymorphonuclear leucocytes) from normal blood and granulocytes obtained from the blood and synovial fluid of patients with rheumatoid arthritis was studied.

2. Similar rates of superoxide production by granulocytes from normal blood at rest and in the presence of any form of IgG were found. In contrast, the rate of hydrogen peroxide production could be stimulated in a dose-dependent fashion by monomer or polymer u.v.-irradiated IgG.

3. The stimulatory effect of free-radical-altered IgG on the rate of hydrogen peroxide production did not occur in the presence of 2-deoxyglucose, which deprives the NADPH:O2 oxidoreductase of its substrate NADPH by inhibition of glycolysis and the pentose phosphate pathway. This points to a stimulatory effect on the direct divalent reduction of oxygen without intermediate superoxide production by this enzyme complex.

4. Granulocytes obtained from the blood and synovial fluid of patients with rheumatoid arthritis reacted differently to polymer u.v.-irradiated IgG. In the presence of this stimulus the rate of release of both superoxide and hydrogen peroxide was increased. Furthermore, these granulocytes synthesized superoxide and hydrogen peroxide at a higher rate than did granulocytes from normal blood in the presence of serum-treated zymosan but not in the presence of phorbol myristate acetate.

5. Taken together, these results indicate that the rate of superoxide and hydrogen peroxide production by the granulocyte NADPH:O2 oxidoreductase depends on the pathological condition of the donor and the type of stimulus used.
Urinary excretion of nitrogenous and non-nitrogenous compounds in the chronic ethanol-fed rat
Authors: Preedy Victor R. , Hammond Barry , Iles Richard A. , Davies SiâN E. C. , Gandy Joan D. , Chalmers Ronald A. , Peters Timothy J.
Published: August 2015

1. The metabolic consequences of chronic ethanol feeding was investigated by assay of urinary metabolites. Male Wistar rats were fed a liquid diet containing 35% of total energy as ethanol or isovolumetric, isocaloric and isonitrogenous amounts of the same diet in which ethanol was substituted by isocaloric glucose (controls).

2. At 6 weeks the entire skeletal muscle mass was reduced by approximately 20%. The urinary excretion of nitrogen, urea and uric acid increased by between 23 and 128%. Urinary creatinine excretion was not significantly altered.

3. Urinary excretion of magnesium was significantly increased by 43%. Urinary excretion of sodium, potassium, calcium and phosphate was increased slightly (i.e. 5–22%), but this change was not statistically significant.

4. Proton n.m.r. spectroscopic analysis showed that ethanol feeding reduced the urinary excretion of citrate and 2-oxoglutarate (by approximately 50%), suggesting decreased citric acid cycle activity. There was an increased excretion of alanine (44%), but excretion of succinate and acetate was not significantly altered. Ethanol in the urine of ethanol-fed rats comprised approximately 2% of total ethanol intake and less than 1% of total energy intake.

5. Lactose was detectable in urine of ethanol-fed rats, but not in control rats, reflecting the reported decreased intestinal lactase activity and increased gut permeability in alcoholics. Urinary galactose excretion decreased by 41%, but relatively large increases in lactate excretion (50%) did not achieve statistical significance.

6. It was concluded that chronic ethanol feeding causes disturbances in whole-body nitrogen homoeostasis and alterations in intermediary metabolism.
Evidence for altered Na+/H+ antiport activity in cultured skeletal muscle cells and vascular smooth muscle cells from the spontaneously hypertensive rat
Authors: Davies J. E. , Ng L. L. , Ameen M. , Syme P. D. , Aronson J. K.
Published: August 2015

1. Intracellular pH and Na+/H+ antiport activity were determined by a fluorimetric method in cultured skeletal muscle cells (myoblasts) and aortic vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats.

2. The intracellular pH was significantly more alkaline at three different extracellular pH values in both myoblasts and vascular smooth muscle cells from the spontaneously hypertensive rats than in those from the normotensive control rats.

3. A kinetic analysis of the Na+/H+ antiport activity in these cells showed that the raised activity in the spontaneously hypertensive rats was due to an increased maximal transport capacity in vascular smooth muscle cells and to an increase in the affinity of the antiport for internal H+ in the myoblasts.

4. When the extracellular pH was reduced in the skeletal muscle cells of both types of rat, the intracellular pH fell. However, in vascular smooth muscle cells, a reduction in the extracellular pH was not associated with a fall in the intracellular pH. This resistance of the intracellular pH to changes in the extracellular pH differentiates vascular smooth muscle cells from other cells that have been studied in this way.
Effects of acute insulin-induced hypoglycaemia on haemostasis, fibrinolysis and haemorheology in insulin-dependent diabetic patients and control subjects
Authors: Fisher B. M. , Quin J. D. , Rumley A. , Lennie S. E. , Small M. , MacCuish A. C. , Lowe G. D. O.
Published: August 2015

1. The effects of acute hypoglycaemia on haemostasis, fibrinolysis, blood viscosity and erythrocyte aggregation were examined after acute insulin-induced hypoglycaemia in six normal male subjects and in six male patients with poorly controlled insulin-dependent diabetes. In the control subjects hypoglycaemia caused a significant increase in the concentration of von Willebrand factor, with no change in the concentrations of fibrinogen and cross-linked fibrin degradation products. Fibrinolysis was enhanced, as indicated by significant increases in tissue plasminogen activator concentration and the fibrin plate lysis area, with a fall in plasminogen-activator inhibitor activity, suggesting complex formation. Whole-blood and plasma viscosity increased significantly after hypoglycaemia, but there was no significant change in erythrocyte aggregation tendency.

2. In diabetic patients the increase in the concentration of von Willebrand factor was significantly greater than in the control group (analysis of variance, P < 0.02). The basal concentration of tissue plasminogen activator was reduced at 3.7 ± 0.7 mg/l (mean ± sem) in the diabetic group compared with 8.5 ± 1.3 mg/l in the control group (Student's t-test, P < 0.01), but thereafter the increase in response to hypoglycaemia was similar. The changes in the other variables were not significantly different from the changes in the control group.

3. During acute hypoglycaemia in poorly controlled diabetic patients there is promotion of haemostasis with a greater increase in the concentration of von Willebrand factor, which, in association with the increase in viscosity, might reduce perfusion in diabetic microangiopathy, leading to aggravation of the microvascular complications of diabetes.
Energy expenditure and substrate metabolism measured by 24 h whole-body calorimetry in patients receiving cyclic and continuous total parenteral nutrition
Authors: Pullicino E. , Goldberg G. R. , Elia M.
Published: August 2015

1. Twenty-four hour energy expenditure and its components, i.e. ‘basal metabolic rate', activity energy expenditure and diet-induced thermogenesis were measured, using continuous whole-body indirect calorimetry, in patients receiving total parenteral nutrition while in remission from Crohn's disease (weight 51.9 ± 9.9 kg, body mass index 19.2 ± 2.0 kg/m2).

2. Total parenteral nutrition was infused continuously over 24 h in four subjects and cyclically, between 22.00 and 10.00 hours, in eight subjects. Twenty-four hour energy expenditure (6.83 ± 1.10 MJ/24 h) was lower than total energy intake (10.09 ± 1.63 MJ/24 h), resulting in a positive energy balance (3.26 ± 1.42 MJ) in all subjects. Repeated measurements of resting energy expenditure in the continuously fed subjects (5.82 ± 1.11 MJ/24 h) did not change significantly at different times of day (coefficient of variation 2.2–6.6%). In contrast, in cyclically fed subjects, resting energy expenditure was 24.2 ± 9.0% higher towards the end of the 12 h feeding period than the ‘basal metabolic rate', which was measured just before the start of the feeding period.

3. Diet-induced thermogenesis, calculated as the increment in resting energy expenditure above ‘basal metabolic rate’ over the 24 h period (adjusted for the reduction in energy expenditure during sleep), was found to be 0.60 ± 0.29 MJ or 6.1 ± 3.1% of the energy intake.

4. The energy cost of activity (activity energy expenditure) in the continuously fed patients, calculated as the difference between 24 h energy expenditure and the integrated 24 h measurements of resting energy expenditure, was 0.88 ± 0.53 MJ, i.e. 12.9 ± 5.9% of the 24 h energy expenditure.

5. The non-protein nonglycerol respiratory quotient exceeded 1.0 for varying periods of time (0.5–17 h) in 11 subjects, indicating net lipogenesis from carbohydrate.

6. The results demonstrate favourable rates of deposition, during intravenous feeding, of both energy and nitrogen over a 24 h period in patients recovering from an episode of Crohn's disease. The efficacy of these commonly used total parenteral nutrition regimens in these patients is related to three features that are absent in normal healthy individuals, namely a low basal metabolic rate, a low activity-related energy expenditure and prolonged periods of lipogenesis from carbohydrate.
Increased symptoms of hypoglycaemia in the standing position in insulin-dependent diabetes mellitus
Authors: Hirsch Irl B. , Heller Simon R. , Cryer Philip E.
Published: August 2015

1. To test the hypothesis that patients with insulin-dependent diabetes mellitus perceive the symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position, we assessed symptoms of hypoglycaemia, as well as heart rate and plasma noradrenaline and adrenaline concentrations, in both positions during hyperinsulinaemic glucose clamps on three occasions in seven patients.

2. Plasma glucose concentrations were clamped at 5.0 mmol/l (90 mg/dl) and 5.0 mmol/l on one occasion, at 5.0 mmol/l and 3.9 mmol/l (70 mg/dl) on another occasion, and at 5.0 mmol/l and 2.8 mmol/l (50 mg/dl) on yet another occasion.

3. During euglycaemia there was no effect of position on the symptom panels used to assess the symptomatic response to hypoglycaemia. However, at the plasma glucose concentration of 2.8 mmol/l, total (P< 0.003) and neurogenic (P< 0.005), but not neuroglycopenic, hypoglycaemic symptom scores were higher with the patients in the standing than in the lying position. Increments in total hypoglycaemic symptom scores, over those during the corresponding euglycaemic phase, were 5 ± 2 in the lying position and 11 ± 2 in the standing position (means ± sem, P < 0.01).

4. Thus patients with insulin-dependent diabetes mellitus perceive symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position because of enhanced neurogenic symptoms.
Measurement of tumour protein synthesis in vivo in human colorectal and breast cancer and its variability in separate biopsies from the same tumour
Authors: Heys S. D. , Park K. G. M. , McNurlan M. A. , Calder A. G. , Buchan V. , Blessing K. , Eremin O. , Garlick P. J.
Published: August 2015

1. A method is described for measuring the rates of protein synthesis in vivo in human colorectal and breast tumours by the intravenous injection of l-[1-13C]leucine as a ‘flooding dose'.

2. The incorporation of isotope into colorectal tumour protein was measured in six patients, whose tumours were biopsied after the injection. Fractional rates of protein synthesis were calculated from the enrichment of leucine in protein and the average free leucine enrichment in plasma. The range of rates obtained was 17.2–33.9%/day, with a mean rate (± sem) of 22.5 ± 2.6%/day.

3. Tumour protein synthesis rates were also measured in 15 patients with breast cancer. The range of rates obtained was 5.3–15.9%/day, with a mean rate (± sem) of 10.3 ± 0.8%/day. These rates are significantly lower than those obtained with colorectal tumours (P < 0.001).

4. In 9 of the breast cancer patients, protein synthesis was measured in multiple random biopsies taken from the same tumour. The mean (± sem) difference between the highest and lowest rates in biopsies from the same tumour was only 1.1 ± 0.3%/day. Only 13% of the variation in protein synthesis between separate tumours could be explained by sampling error because of variation within the tumour itself, the remainder being genuine variation between individual tumours.
Na+,K+-ATPase activity and hormones in single nephron segments from nephrotic rats
Authors: Vogt B. , Favre H.
Published: August 2015

1. In the nephrotic syndrome the kidneys retain salt and water, which leads to oedema formation. The site of this sodium retention has been localized in the cortical collecting tubule by micropuncture studies. Whether or not this phenomenon is an intrinsic renal problem or is the consequence of changes in hormonal activities is still a matter of discussion.

2. Using the model of puromycin aminonucleoside-induced nephrotic syndrome in the rat, we measured Na+,K+-ATPase activity in nephron segments from control and nephrotic rats and investigated the regulatory role of aldosterone and endogenous-ouabain-displacing factor.

3. Nephrotic animals had a twofold increase in Na+,K+-ATPase activity in the cortical collecting tubule only (control versus nephrotic: 1065 ± 68 versus 2081 ± 274 pmol h−1 mm−1, P = 0.036), which was not modified by adrenalectomy and was independent of the kidney content of endogenous ouabain-displacing factor. Na+,K+-ATPase activity in the cortical collecting tubule correlated with the sodium balance in both control and nephrotic rats.

4. The data are consistent with the view that sodium retention in this model of the nephrotic syndrome is a primary event, i.e. an increase in sodium transport throughout the cortical collecting tubule expressed as a twofold increase in Na+,K+-ATPase activity which is no longer under hormonal regulation (aldosterone and endogenous ouabain-displacing factor).
Twenty-four hour intragastric acidity and plasma gastrin concentration profiles in female and male subjects
Authors: Prewett E. J. , Smith J. T. L. , Nwokolo C. U. , Sawyerr A. M. , Pounder R. E.
Published: August 2015

1. Simultaneous 24 h intragastric acidity and plasma gastrin concentration profiles were determined in 35 healthy young women and 96 healthy young men.

2. The females had a consistently lower median hourly intragastric acidity, and a higher median hourly plasma gastrin concentration, throughout the 24 h.

3. The 24 h integrated intragastric acidity was significantly lower in the female group (females, 485 mmol · h · l−1; males, 842 mmol · h · l−1; P < 0.001). The 24 h integrated plasma gastrin concentration was significantly higher in the female group (females, 407 pmol · h · l−1; males, 185 pmol · h · l−1; P < 0.001).
Haemodynamic responses to psychosocial stress during the menstrual cycle
Authors: Manhem Karin , Jern Christina , Pilhall Martin , Shanks Guy , Jern Sverker
Published: August 2015

1. The haemodynamic effects of hormonal changes during the menstrual cycle were examined in 11 normotensive women (age 20–46 years). The subjects were studied on days 2–8 (follicular phase) and days 18–26 (luteal phase) in a randomized order. A standardized mental stress test and a 24 h recording of ambulatory blood pressure and heart rate were performed.

2. Pre-stress resting levels of heart rate and blood pressure were similar during the two phases of the menstrual cycle.

3. During mental stress, the heart rate response was significantly greater during the luteal phase than during the follicular phase (14.7 versus 9.7 beats/min; P < 0.05).

4. Blood pressure, plasma catecholamine concentrations and subjective stress experience increased significantly in response to stress, without any significant differences between the two phases.

5. During 24 h ambulatory monitoring, higher levels of systolic blood pressure and heart rate were observed in the luteal phase than in the follicular phase (P < 0.005 and P < 0.0001, respectively).

6. These data indicate that cyclic variations in female sex hormones not only affect systolic blood pressure and heart rate, but also alter the haemodynamic responses to psychosocial stress.
Intracellular pH in rat resistance arteries during the development of experimental hypertension
Authors: Izzard Ashley S. , MacIver David H. , Cragoe Edward J. , Heagerty Anthony M.
Published: August 2015

1. In order to examine the effects of experimental hypertension on intracellular pH in mesenteric resistance arteries, intracellular pH was measured in mesenteric resistance arteries from rats with coarctation 72 h, 9 days and 28 days after the aorta was partially constricted between the origins of the renal arteries. Carotid arterial pressure was significantly raised at all time points.

2. Second-order mesenteric resistance arteries were mounted in a myograph and were loaded with the acetoxymethyl ester of the pH-sensitive dye 2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein. Morphological measurements demonstrated that arteries from rats with coarctation had an increased media volume at 9 days and at 28 days compared with vessels from sham-operated control animals, but this was only statistically significant at 28 days.

3. Resting intracellular pH was not significantly different at any time point in arteries from rats with coarctation compared with control animals, although there was a rise in intracellular pH in both groups of rats between 72 h and 9 days. The application of 4,4-di-isothiocyanatostilbene-2,2′-disulphonic acid produced a fall in intracellular pH which was significantly greater in the sham-operated rats at 9 days; this difference was not found at 28 days. Blockade of Na+/H+ exchange with 60 μmol/l ethylisopropylamiloride led to a similar fall in intracellular pH in both groups of rats at 9 days but a significantly greater fall in intracellular pH in arteries of rats with coarctation at 28 days. Activation with noradrenaline (10 μmol/l) induced acid changes in intracellular pH that were similar in both groups of rats.

4. It is concluded that induction of coarctation of the aorta was associated with the development of significant growth in mesenteric resistance arteries, but that this structural change was not associated with an intracellular pH that was significantly different from that seen in sham-operated control rats at any time. Increased regulation of intracellular pH by Na+/H+ exchange was observed only at 28 days, after medial growth had occurred, which argues against a fundamental role of this exchange system as a mediator of cell growth.
Comparison of the electrical properties of arterial smooth muscle in normotensive rats and rats with deoxycorticosterone acetate-salt-induced hypertension: Possible involvement of (Na+-K+-Cl−) co-transport
Authors: Davis J. P. L. , Chipperfield A. R. , Harper A. A.
Published: August 2015

1. Hypertension was induced in male Sprague-Dawley rats by left unilateral nephrectomy and deoxycorticosterone acetate-salt administration. After 5 weeks, arterial systolic blood pressure was significantly elevated in these animals (191.5 ± 6.0 mmHg, mean ± sd, n = 17) compared with age-matched, unoperated control animals (134.0 ± 4.2 mmHg, n = 8, P < 0.001).

2. The membrane potential of femoral artery vascular smooth muscle measured in vitro was −55.1 ± 6.3 mV (mean ± sd, n = 154) for normotensive and −50.8 ± 5.7 mV (n = 82) for hypertensive animals. The difference in membrane potential was significant (P < 0.001).

3. The relationship between the log of the extracellular K+ concentration and membrane potential was nonlinear over the extracellular K+ concentration range 2.5–20 mmol/l, and showed a small positive shift with hypertension.

4. Tenfold reductions in the extracellular concentrations of Na+ or Cl− resulted in a membrane potential hyperpolarization in vascular smooth muscle from normotensive animals (4.9 ± 2.0 mV, n = 13 and 12.1 ± 1.3 mV, mean ± sd, n = 14, respectively). In vascular smooth muscle from hypertensive animals, the hyperpolarization in low-Na+ media was significantly increased to 12.2 ± 2.6 mV (mean ± sd, n = 5), but that in low-Cl− media was unaffected (2.7 ± 1.6 mV, n = 6).

5. The loop diuretic, bumetanide (10 μmol/l), hyperpolarized the membrane potential in vascular smooth muscle from both normotensive and hypertensive rats, but not in low-Na+ or low-Cl− media. This effect was significantly increased in hypertension, from 1.8 ± 0.7 mV (mean ± sd, n = 8) to 4.0 ± 1.0 mV (n = 5).

6. These results suggest that in these cells, K+ permeability ≫ Na+ permeability > Cl− permeabilty, and that the membrane potential is determined principally by the K+ permeability. In deoxycorticosterone acetate-salt hypertension, the membrane potential is depolarized, Na+ permeability is substantially increased, and there appears to be an increase in the activity of the (Na+-K+-Cl−) co-transporter.
Oral sodium regulates extrahepatic metabolism of vasoactive intestinal peptide
Authors: Hawley C. M. , Duggan K. A. , MacDonald G. J. , Shelley S.
Published: August 2015

1. Gastric sodium loading causes release of vasoactive intestinal peptide from the gastrointestinal tract and, in rabbits on a low-sodium diet, an apparent decrease in metabolism of vasoactive intestinal peptide by the liver. Other workers have shown that decreased hepatic metabolism of vasoactive intestinal peptide is accompanied by an increase in pulmonary metabolism of vasoactive intestinal peptide. To determine whether oral sodium loading also regulates non-hepatic metabolism of vasoactive intestinal peptide, metabolic clearance studies of intravenously infused vasoactive intestinal peptide were performed. These studies were performed in male New Zealand White rabbits equilibrated on normal- and low-sodium diets before and after an acute gastric sodium load of 1.5 mmol/kg.

2. The metabolic clearance rate of vasoactive intestinal peptide was significantly greater in rabbits on the low-sodium diet than in rabbits on the normal-sodium diet both before (P < 0.025) and after (P < 0.05) a gastric sodium load. Significant decreases in metabolic clearance rate were observed in response to the sodium load in both dietary groups (normal-sodium diet, P < 0.05; low-sodium diet, P < 0.025). The theoretical secretion rate of vasoactive intestinal peptide also fell after the gastric sodium load in rabbits on the low-sodium diet (P < 0.05) and the half-life of vasoactive intestinal peptide increased (P < 0.01).

3. We conclude that the non-hepatic metabolism of vasoactive intestinal peptide appears to be responsive to both chronic dietary sodium intake and acute gastric sodium loading.