bluuebunny/crossref_metadata_2025 huggingface dataset:
Domperidone, a DA2-specific dopamine antagonist, has no effect on the renal or haemodynamic response to atrial natriuretic peptide in man
Authors: Allen M. J. , Ang V. T. Y. , Bennett E. D.
Published: August 2015

1. Animal experiments have suggested that the renal effects of atrial natriuretic peptide (ANP) are dependent on dopaminergic activation, predominantly of the DA1-receptor. In man, there is evidence of dependence on the DA2-receptor for the natriuresis produced by central blood volume expansion.

2. Six normal volunteers underwent infusions of α-human ANP preceded by domperidone (a DA2-antagonist) or placebo. Eight volunteers underwent a 3 h period of 10° head-down tilt also preceded by domperidone or placebo.

3. Both the ANP infusion and head-down tilt produced a significant diuresis and natriuresis, neither of which was antagonized by the presence of domperidone.

4. The ANP infusion significantly reduced diastolic blood pressure and produced significant increases in the Doppler-measured aortic blood velocity variables of peak velocity and maximal acceleration. Domperidone had an independent effect of increasing blood pressure but did not appear to have a specific interaction with the haemodynamic effects of ANP.

5. Head-down tilt reduced mean arterial pressure and heart rate and increased maximal acceleration. Again, an independent effect of domperidone was seen on blood pressure. Heart rate and maximal acceleration showed similar changes in the presence of domperidone.

6. Domperidone does not antagonize the renal or haemodynamic effects of ANP and if dopaminergic activation is necessary for the renal action of ANP it is unlikely to be mediated by the DA2-receptor.
Erythrocytes alter the pattern of renal hypoxic injury: predominance of proximal tubular injury with moderate hypoxia
Authors: Endre Zoltan H. , Ratcliffe Peter J. , Tange John D. , Ferguson David J. P. , Radda George K. , Ledingham John G. G.
Published: August 2015

1. The distribution of morphological injury was assessed qualitatively and quantitatively in the perfused rat kidney in vitro at controlled rates of oxygen delivery in the presence of low concentrations of erythrocytes.

2. In control kidneys (total oxygen delivery approximately 32 μmol/min per kidney) no injury was seen in the medullary thick ascending limb of Henle's loop (MTAL) whilst 11 ± 5 (sd)% of proximal tubules sustained damage.

3. Mild hypoxia (total oxygen delivery approximately 28 μmol/min per kidney) produced little or no injury to MTAL, namely 6 ± 4(sd)% and 3 ± 3% of tubules damaged, respectively. In contrast, both groups sustained extensive damage to proximal tubules, averaging 46 ± 13% (P < 0.01 vs control) and 84 ± 14% (P < 0.001 vs control), respectively. This damage was equally distributed between the superficial and deep cortex.

4. Comparison with morphometric data obtained previously from cell-free-perfused rat kidneys [P. J. Ratcliffe, Z. H. Endre, S. J. Scheinman, J. D. Tange, J. G. G. Ledingham & G. K. Radda (1988) Clinical Science74, 437–448] showed that (a) erythrocytes prevent hypoxic damage to the MTAL at mild and moderate levels of hypoxia; (b) when oxygen delivery rates are matched between cell-free- and erythrocyte-perfused kidneys, proximal tubular injury is greater in the presence of erythrocytes; (c) when arterial partial pressure of oxygen is matched between cell-free- and erythrocyte-perfused kidneys, the degree of proximal tubular injury is similar.

5. The data suggest that the proximal tubule and not the MTAL is the nephron segment most at risk of hypoxic injury in vitro.
Maternal zinc during oral iron supplementation in pregnancy: a preliminary study
Authors: Bloxam David L. , Williams Norman R. , Waskett Rosie J. D. , Pattinson-Green Patricia M. , Morarji Yogini , Stewart Simon G.
Published: August 2015

1. To investigate the possible effect of iron ingestion on maternal zinc status, one group of women was given 94 mg of iron per day as ferrous sulphate with multivitamins during the second and third trimesters of their pregnancies and another, control, group was given a placebo of multivitamins without iron.

2. The subjects given iron developed significantly lower plasma zinc concentrations than those in the control group. This effect on zinc was maximal by 6 weeks, whilst that on maternal iron status was slower.

3. There was no parallel decrease of zinc concentration in maternal mixed leucocytes, or of plasma heat-labile alkaline phosphatase activity, suggesting that there was a redistribution of zinc between plasma and tissues.

4. The results indicate that iron supplementation during pregnancy alters the disposition of zinc in the mother.
Extrarenal potassium adaptation: the role of aldosterone
Authors: Spital Aaron , Sterns Richard H.
Published: August 2015

1. Prior adaptation to a high potassium (HK) diet reduces the increment in plasma potassium after nephrectomy and acute potassium loading. Previous work has suggested that this ‘extrarenal potassium adaptation’ is due to direct stimulation of cellular potassium uptake by chronic hyperaldosteronism.

2. In contrast, we have shown that when dietary potassium is withdrawn from HK rats, large urinary potassium losses persist, resulting in ‘paradoxical potassium depletion’. This potassium depletion facilitates cellular potassium uptake and is, at least in part, responsible for extrarenal potassium adaptation.

3. To try to reconcile these observations, we explored further the role of aldosterone in extrarenal potassium adaptation. When dietary potassium was withdrawn from chronically adrenalectomized HK rats, paradoxical potassium depletion was markedly blunted and extrarenal potassium adaptation could not be demonstrated. Similarly, urinary potassium losses and potassium depletion were reduced when acute adrenalectomy was performed concomitantly with dietary potassium withdrawal.

4. We were unable to confirm previous studies showing extrarenal potassium adaptation in the absence of potassium depletion. Thus, extrarenal potassium adaptation did not occur after pretreatment with chronic high-dose mineralocorticoid, after prior adaptation to a sodium-free diet, or after prior adaptation to an extremely HK diet in the absence of dietary potassium withdrawal.

5. We conclude that chronic hyperaldosteronism is important in extrarenal potassium adaptation, but probably not via direct enhancement of cellular potassium uptake. Rather, in HK animals, hyperaldosteronism magnifies urinary potassium losses during fasting and thus promotes potassium depletion, which in turn facilitates the uptake of an acute potassium load.
Effect of postural change and thermoregulatory stress on the capillary microcirculation of the human toe
Authors: Flynn M. D. , Hassan A. A. K. , Tooke J. E.
Published: August 2015

1. We have applied the technique of television capillary microscopy to make direct measurements of nutritional capillary flow in the toe nailfold (i) at heart level and (ii) in a near standing position, with the foot 96 cm below heart level. By indirect heating we have examined the relationship between posture-related changes and thermoregulation in the capillary circulation of the toe.

2. Capillary blood flow in 14 male subjects with their feet at heart level showed a positive correlation with increasing skin temperature.

3. On quiet standing, capillary blood flow decreased to 11.3% of supine values, achieved both by a reduction in capillary blood velocity and the duration of flow.

4. Indirect heating of the trunk led to a partial release of sympathetic tone and induced a significant increase in capillary blood flow in both the supine and dependent positions. However during heating, the percentage fall in capillary blood flow associated with dependency remained unchanged.

5. In conclusion, it appears that in the dependent foot, compensatory mechanisms exist to limit nutritional capillary blood flow by regulating both erythrocyte velocity and the duration of flow. These mechanisms fulfil a physiological requirement to limit the rate of oedema formation. The preservation of this response during the partial sympathetic release induced by indirect heating suggests a mechanism independent of that controlling flow through arteriovenous shunts. Our results are compatible with the hypothesis that a local vasoconstrictor mechanism is operative in the vascular resistance elements in closest relation with the capillary bed, and distal to that regulating arteriovenous shunt flow.
Effect of aminophylline on plasma and urinary catecholamine levels during heavy leg exercise in healthy young men
Authors: Wennmalm Å. , Karwatowska-Prokopczuk E. , Wennmalm M.
Published: August 2015

1. Methylxanthines have been shown to elevate the basal plasma level and/or urinary excretion of noradrenaline (NA) and adrenaline (ADR) in healthy subjects. The present study addressed the hypothesis that the methylxanthine aminophylline also augments plasma and urinary catecholamines during increased sympathoadrenal activity.

2. Eleven healthy young men performed a maximal 2 h bicycle exercise twice, after double-blind intravenous administration of placebo or aminophylline. Femoral venous plasma and urinary concentrations of NA and ADR were analysed in samples representing basal state, exercise and recovery, using liquid chromatography with electrochemical detection.

3. Leg exercise induced eight- and six-fold increases in the plasma concentrations of NA and ADR, respectively, and seven- and four-fold increases in the urinary concentrations of NA and ADR, respectively, indicating that sympathoadrenal activity was considerably elevated.

4. After aminophylline (mean plasma concentration 20–35 μmol/l), the plasma concentrations of NA (P < 0.001) and ADR (P < 0.05) were independently higher at rest, during exercise and during recovery, in comparison to after placebo; the mean exercise plasma level of NA was increased by the drug from 13 ± 1 to 21 ± 2 nmol/l and the corresponding level of ADR from 2.1 ± 0.4 to 2.9 ± 0.5 nmol/l. Also urinary NA (P < 0.01) and ADR (P < 0.05) were elevated by aminophylline; the exercise concentrations of NA in the urine were 75 ± 8 and 97 ± 10 μmol/mol of creatinine after placebo and aminophylline, respectively, and the corresponding levels of ADR were 12 ± 3 and 16 ± 3 μmol/mol of creatinine, respectively.

5. These data indicate that the facilitating effect of methylxanthines on plasma and urinary NA and ADR is present also when the sympathoadrenal activity is elevated by physical exercise.
Measurement of cation transport in vivo in healthy volunteers after the oral administration of lithium carbonate
Authors: Wood A. J. , Viswalingam A. , Glue P. , Aronson J. K. , Grahame-Smith D. G.
Published: August 2015

1. We have measured cation transport in vivo in seven healthy volunteers under control conditions and after they had taken lithium carbonate for 21 days in doses which maintained the serum lithium concentration in the range 0.6–0.8 mmol/l.

2. We have measured cation transport in vivo after the administration of an oral load of rubidium chloride, and have found that, although intra-erythrocytic concentrations of rubidium were significantly lower 1 h after the administration of rubidium when the subjects were taking lithium, there was a significant increase in the rate of uptake of rubidium into the erythrocytes over the subsequent period of the test, suggesting a direct stimulation of sodium, potassium-activated adenosine triphosphatase by lithium.

3. Lithium administration did not affect the plasma concentration versus time profile of rubidium after the rubidium load, implying that the lithium-stimulated uptake of rubidium which occurs in erythrocytes does not necessarily occur in other cell types.

4. These results suggest that previous studies of cation transport using peripheral cells and assay systems in vitro do not necessarily reflect changes in cation transport in vivo in excitable tissues.
Increase in anterior tibialis muscle protein synthesis in healthy man during mixed amino acid infusion: studies of incorporation of [1−13C]leucine
Authors: Bennet W. M. , Connacher A. A. , Scrimgeour C. M. , Smith K. , Rennie M. J.
Published: August 2015

1. Anterior tibial muscle protein synthesis in seven healthy postabsorptive men was determined from increases in muscle protein bound leucine enrichment during a primed continuous infusion of l-[1−13C]leucine. Biopsies were taken 30 min after the beginning of leucine infusion (when plasma 13C enrichment was steady), 240 min later during continued fasting and again after 240 min of infusion of a mixed amino acid solution which increased plasma total amino acid concentrations by 37%. The mean enrichment of 13C in plasma α-ketoisocaproate was used as an index of the enrichment of the precursor pool for leucine metabolism.

2. Anterior tibial muscle mixed protein synthetic rate during fasting was 0.055 (sd 0.008) %/h and this increased by an average of 35% during infusion of mixed amino acid to 0.074 (sd 0.021) %/h (P < 0.05).

3. Whole-body protein breakdown (expressed as the rate of endogenous leucine appearance in plasma) was 121 (sd 8) μmol h−1 kg−1 during fasting and decreased (P < 0.01) by an average of 12% during amino acid infusion. Leucine oxidation was 18 (sd 3) μmol h−1 kg−1 during fasting and increased (P < 0.001) by 89% during amino acid infusion. Whole-body protein synthesis (non-oxidative leucine disappearance) was 104 (sd 6) μmol h−1 kg−1 during fasting and rose by 13% (P < 0.001) during mixed amino acid infusion.

4. 13C enrichment of muscle free leucine was only 61 (sd 19) % of that in plasma α-ketoisocaproate and this increased to 74 (sd 16) % (P < 0.02) during mixed amino acid infusion.

5. The results suggest that increased availability of amino acids reverses whole-body protein balance from negative to positive and a major component of this is the increase in muscle protein synthesis.
The thyroid hormone analogue SKF L-94901: nuclear occupancy and serum binding studies
Authors: Barlow John W. , Raggatt Lorna E. , Lim Chen-Fee , Munro Sharon L. , Topliss Duncan J. , Stockigt Jan R.
Published: August 2015

1. We studied a brominated thyroid hormone analogue, SKF L-94901, which has the potential to lower serum cholesterol without adverse cardiovascular effects. This compound is about 50% as active as tri-iodothyronine (T3) in liver nuclear receptor binding in vivo but only 1% as active in vitro and has nearly 200 times more enzyme-inducing activity in liver than in heart. Our aim was to examine the interaction of SKF L-94901 with [125I]T3 binding to the intact nuclei in whole cells, isolated nuclei and nuclear extracts of human HeLa cells and to investigate the binding of this compound to human serum.

2. Relative to thyroxine (T4), the affinity of this compound for T4-binding globulin was 0.0035%, for transthyretin 1.66% and for albumin 1.26%. Low affinity for serum proteins, with a relatively high circulating free fraction, could explain why SKF L-94901 is more potent in vivo than in vitro.

3. Human HeLa cell nuclei, isolated after whole-cell incubations, bound [125I]T3 with high affinity (Kd = 78 ± 8 pmol/l, mean ± sem), which was displaceable by T3 analogues in the order Triac {[4-(4-hydroxy-3-iodophenoxy)-3,5-di-iodophenyl]acetic acid} > T3 > T4 ≫ reverse T3. Similar high-affinity (Kd = 58 ± 6 pmol/l, mean ± sem) and identical specificity was observed in high-salt (0.4 mol/l KCl) nuclear extracts. In nuclei of whole cells incubated with [125I]T3 and SKF L-94901, the analogue was 0.8% as potent as T3, whereas in experiments with nuclear extract, the analogue was 7.7% as potent as T3. Results from incubation of T3 with isolated nuclei were virtually identical to those obtained with nuclear extracts.

4. These results suggest an extranuclear component may be involved in restricting access of SKF L-94901 to the nucleus. Whether such mechanisms account for observed differences in its effects on different tissues with reduced influence of SKF L-94901 on cardiac tissue remains to be established.

5. We conclude that SKF L-94901 is weakly bound in serum and shows less potent competition for T3 nuclear binding after incubation of whole cells than after incubation with nuclear extracts or isolated nuclei. This compound may allow further analysis of intracellular mechanisms of thyroid hormone transport and action.
Pitfalls in the assessment of cardiovascular reflexes in patients with sympathetic failure but intact vagal control
Authors: van Lieshout J. J. , Wieling W. , Wesseling K. H. , Karemaker J. M.
Published: August 2015

1. Two patients are described who presented with orthostatic hypotension as the main symptom. The diagnosis was sympathetic failure with intact vagal control.

2. Unusual test result's were obtained. Assessment of the integrity of the total baroreflex arc by the Valsalva manoeuvre measuring only heart rate changes proved impossible, since the magnitude and time course of the heart rate response were normal notwithstanding the presence of a blood pressure response typical of sympathetic failure.

3. Sustained handgrip, cold pressor test and mental stress test all could induce a rise in blood pressure, despite the presence of sympathetic vasomotor lesions, but only when accompanied by a rise in heart rate. Efferent parasympathetic blockade by atropine, resulting in an increase in heart rate, was also accompanied by a substantial rise in blood pressure. These findings seem to result from a heart rate rise dependent increase in cardiac output unopposed by reflex vasodilatation.

4. In these patients the only baroreflex way to control blood pressure is by varying heart rate. This condition can be evaluated only if blood pressure and heart rate are measured on a beat-by-beat basis.
High-molecular-mass proteins in haemodialysis-associated amyloidosis
Authors: Argiles A. , Mourad G. , Axelrud-Cavadore C. , Watrin A. , Mion C. , Cavadore J. C.
Published: August 2015

1. Protein constituents were determined in eight amyloid deposits from eight patients (five male and three female), 53 ± 4 years of age, treated by haemodialysis for 9-20 years using only cuprophane membranes and operated for carpal tunnel syndrome.

2. Soluble proteins were removed by solubilization in phosphate-buffered saline after osmotic lysis. The proteins of the insoluble fibrils were characterized by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and two-dimensional gel electrophoresis, and immunologically identified by Western blotting.

3. In addition to β2-microglobulin, α2-macroglobulin was identified in the fibrillar material. The presence of these two proteins in amyloid deposits was confirmed by immunofluorescent microscopic studies.

4. Our data confirm the presence of β2-microglobulin in haemodialysis-associated amyloidosis, and also suggest a possible role for α2-microglobulin: it may protect β2-microglobulin from proteolytic digestion, leading to its accumulation in intact form and to amyloid fibril formation.
Single-breath breath-holding estimate of pulmonary blood flow in man: comparison with direct Fick cardiac output
Authors: Kendrick A. H. , Rozkovec A. , Papouchado M. , West J. , Laszlo G.
Published: August 2015

1. Resting pulmonary blood flow (Q.), using the uptake of the soluble inert gas Freon-22 and an indirect estimate of lung tissue volume, has been estimated during breath-holding (Q.c) and compared with direct Fick cardiac output (Q.f) in 16 patients with various cardiac disorders.

2. The effect of breath-hold time was investigated by comparing Q.c estimated using 6 and 10 s of breath-holding in 17 patients. Repeatability was assessed by duplicate measurements of Q.c in the patients and in six normal subjects.

3. Q.c tended to overestimate Q.f, the bias and error being 0.09 l/min and 0.59, respectively. The coefficient of repeatability for Q.c in the patients was 0.75 l/min and in the normal subjects was 0.66 1/min. For Q.f it was 0.72 l/min. There was no significant difference in Q.c measured at the two breath-hold times.

4. The technique is simple to perform, and provides a rapid estimate of Q., monitoring acute and chronic changes in cardiac output in normal subjects and patients with cardiac disease.
Exercise-Mediated Peripheral Tissue and Whole-Body Amino Acid Metabolism during Intravenous Feeding in Normal Man
Authors: Albert James D. , Matthews Dwight E. , Legaspi Adrian , Tracey Kevin J. , Jeevanandam Malayappa , Brennan Murray F. , Lowry Stephen F.
Published: August 2015

1. The effect of a daily submaximal exercise regimen on whole-body and peripheral tissue amino acid metabolism during weight-stable intravenous feeding (IVF) was evaluated in 11 normal volunteers. Five of the subjects performed 1 h of daily bicycle exercise at 75 W during IVF, while the remaining six subjects received IVF without daily exercise. Body nitrogen balance, leg and forearm plasma amino acid flux and whole-body kinetics were measured before and on day 10 of IVF using a [1-13C]leucine and [15N]glycine tracer.

2. At the end of the IVF period, exercised subjects demonstrated leg uptake of total amino acids (237 ± 103 nmol min−1 100 ml−1 of tissue, mean ± sem) which was significantly (P < 0.05) different than in non-exercised subjects (− 1101 ± 253 nmol min−1 100 ml−1 of tissue).

3. In the non-exercised forearm, a significant (P < 0.05) decrease in total amino acid flux was observed in exercised subjects (− 162 ± 88 nmol min−1 100 ml−1 of tissue) compared with non-exercised subjects (−460 ± 105 nmol min−1 100 ml−1 of tissue) on day 10 of IVF.

4. Efflux of 3-methylhistidine significantly (P < 0.05) decreased from the leg in those subjects who performed daily exercise (−0.29 ± 0.12 nmol min−1 100 ml−1 of tissue) compared with those subjects receiving IVF without daily exercise (− 1.46 ± 0.35 nmol min−1 100 ml−1 of tissue).

5. Although IVF increased whole-body leucine turnover in both exercised and non-exercised subjects, only exercised subjects demonstrated a significant (P < 0.05) increase in leucine oxidation which was proportionate to an increased muscle uptake of leucine. Whole-body protein breakdown, as assessed by [15N]glycine, was significantly (P < 0.05) decreased in exercised subjects compared with non-exercised subjects during IVF.

6. These data demonstrate that daily submaximal exercise produced a systemic as well as limb-specific enhancement of amino acid balance in muscle, providing an anti-catabolic response under conditions of partial immobility induced by hospitalization.
Protective Effect of p-Chlorophenylalanine in Glycerol-Induced Acute Renal Failure in Rats
Authors: Barrett Richard J. , Taylor David R. , Wright Kathryn F.
Published: August 2015

1. Studies were conducted to test the hypothesis that glycerol-induced acute renal failure in rats may be mediated by 5-hydroxytryptamine.

2. The tryptophan hydroxylase inhibitor, β-chlorophenylalanine, or saline was administered for 4 days before performance of 24 h clearance studies after glycerol administration.

3. p-Chlorophenylalanine significantly reduced the nephrotoxic effect of glycerol, as evidenced by improved glomerular filtration rate, urine volume excretion and absolute sodium excretion, and reduced plasma creatinine concentration.

4. These results suggest that glycerol-induced acute renal failure may be mediated by the renovascular and/or tubular actions of 5-hydroxytryptamine.
Evidence for a Decreased Noradrenaline Sensitivity in Mesenteric Resistance Vessels from Rats with Chemical Renal Medullectomy
Authors: Bund S. J. , Heagerty A. M. , Fletcher A. , Swales J. D.
Published: August 2015

1. Chemical renal medullectomy was performed in Wistar rats by intraperitoneal injection of 2-bromoethylamine hydrobromide (200 mg/kg body weight). The effect of this treatment upon blood pressure and mesenteric vascular reactivity and morphology was studied 3 weeks after treatment.

2. Blood pressure was significantly raised in medull-ectomized rats. The indirect systolic pressures (means ± sem) were 112 ± 2.4 mmHg (14.9 ± 0.32 kPa) and 123 ± 3.5 mmHg (16.4 ± 0.5 kPa) (P < 0.02) for control (n = 12) and medullectomized (n = 12) rats, respectively. However, there were no significant changes in the morphology of the mesenteric resistance vessels.

3. Maximum pressor responses and Ca2+ sensitivities were unchanged in these vessels compared with controls, but the sensitivity to noradrenaline was significantly reduced. Noradrenaline pD2 (= −log ED50) values (means ± sem) were 5.87 ± 0.03 and 5.69 ± 0.08 (P < 0.05) for control (n = 12) and medullectomized (n = 12) rats, respectively.

4. This study demonstrates that in this model of hypertension the noradrenaline sensitivity is reduced in mesenteric resistance vessels, but there are no detectable morphological changes associated with the rise in blood pressure.
Platelet Cytosolic Free Calcium in Essential Hypertension: Responses to Vasopressin
Authors: Dominiczak A. F. , Morton J. J. , Murray G. , Semple P. F.
Published: August 2015

1. Resting and stimulated free calcium concentrations have been measured in platelets loaded with the fluorescent probe quin2 from 30 patients with essential hypertension and from 30 age-matched controls.

2. Cytosolic free calcium concentrations were 94.6 ± 2.7 (mean ± sem) in the hypertensive group and 91.7 ± 2.8 nmol/l in the normotensive group, the difference was not significant.

3. Arginine vasopressin caused a transient increase in platelet free calcium concentration in all subjects. In the presence of extracellular calcium the increase was significantly higher in the control subjects than in the hypertensive patients (P = 0.005). In the absence of extracellular calcium, arginine vasopressin caused much smaller increases, and there was then no difference between the responses of the two groups.

4. Platelet free calcium concentrations were measured again in 13 patients after 8 weeks treatment with either verapamil (n = 6) or atenolol (n = 7). The reductions in systolic pressure after drug treatment were correlated with the changes in cytosolic free calcium concentrations (r = 0.75, P < 0.01).
Expression of the Caeruloplasmin Gene in the Adult and Neonatal Rat Liver
Authors: Barrow L. , Tanner M. S. , Critchley D. R.
Published: August 2015

1. It has been suggested that low levels of serum caeruloplasmin in Wilson's disease result from the failure to switch from a fetal to an adult mode of caeruloplasmin gene expression. To investigate postnatal expression of the caeruloplasmin gene, steady-state levels of caeruloplasmin messenger RNA in adult and neonatal rat liver were measured.

2. Copper parameters observed in neonatal rats were similar to those seen in Wilson's disease: hepatic copper concentration was significantly elevated (neonatal 164 ± 35 μg/g, adults 50 ± 8 μg/g, P < .001) and serum copper and caeruloplasmin levels were low (neonatal 0.5 ± 0.1 μg/ml, adults 1.3 ± 0.2 μg/ml, P < .001; neonatal 0.20 ± 0.04 arbitrary units, adults 0.69 ± 0.16 arbitrary units, P < .001), respectively.

3. Caeruloplasmin messenger RNA levels were analysed by Northern and dot blotting using a 12P-labelled caeruloplasmin complementary DNA probe. A caeruloplasmin messenger RNA of approximately 4.4 kilobases was detected in both adult and neonatal rat liver, with no significant difference observed in steady-state levels.

4. A step subsequent to caeruloplasmin gene transcription must therefore be impaired in neonatal rats.
Inhibitory Role of Ca2+ in the Control of Renin Secretion: A Study Using Supervised Dispersed Rat Renal Cortical Cells
Authors: Pardy Karen , Williams B. C. , Noble A. R.
Published: August 2015

1. The role of Ca2+ in the control of renin release was investigated using a collagenase-dispersed rat kidney cortex cell preparation.

2. Superfusion with a series of low [Ca2+] buffers in either ascending or descending order of concentration increased renin release. Exposure to 0.06 mmol/l Ca2+ increased release by 120% (P < 0.001) when presented as the first buffer in ascending order of concentration and by 79% (P < 0.001) when presented as the fourth and last in a series of descending order.

3. The Ca2+ entry blocking drug diltiazem in a range of concentrations increased renin release and at 10−5 mol/l diltiazem the mean stimulation was 35% (P < 0.01).

4. 8-(N,N-Diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) reduces the release of Ca2+ from intracellular stores and, studied over a range of concentrations, this compound increased renin release. At 10−5 mol/l TMB-8 the mean increase was 44% (P < 0.001).

5. None of these experimental manipulations, low [Ca2+], diltiazem or TMB-8, had any effect on the release of adenosine 3′:5′-cyclic monophosphate into the cell superfusate, indicating that a decrease in intracellular [Ca2+] increases renin release by a mechanism which is independent of changes in adenosine 3′:5′-cyclic monophosphate production.

6. Effects of low [Ca2+], diltiazem and TMB-8 on renin secretion were all shown to be reversible when superfusion with control buffer was resumed.
Atrial Natriuretic Factor: Comparability of Venous and Arterial Plasma Measurements in Man at Rest and during Exercise
Authors: Kanstrup I. L. , Høilund-Carlsen P. F. , Nielsen M. Damkjær , Marving J. , Gadsbøsll N.
Published: August 2015

1. Simultaneously obtained arterial and venous plasma atrial natriuretic factor (ANF) concentrations were compared at supine rest and during graded dynamic leg exercise in 10 healthy male subjects (aged 33–51 years).

2. Arterial ANF concentrations ranged between 12 and 179 pg/ml and venous concentrations between 9 and 177 pg/ml.

3. A positive correlation between arterial and venous concentrations was found (r = 0.984).

4. Arterial ANF concentrations were higher than venous concentrations in all pairs of samples (n = 31), but the difference was small and changed little with exercise: the mean difference was 5 pg/ml at rest, 12 pg/ml during submaximal exercise and 6 pg/ml during maximal exercise.

5. The extraction ratios for ANF varied greatly, but were in general lower (P < 0.05) during maximal exercise (median 0.07, range 0.01–0.32) than at rest (median 0.22, range 0.05–0.33).

6. It was concluded that the plasma ANF concentration in a peripheral arm vein is a good indicator of the systemic peptide concentration at rest as well as during dynamic leg exercise.
Erythrocyte Sodium/Lithium Countertransport and Renal Lithium Clearance in a Random Sample of Untreated Middle-Aged Men
Authors: Strazzullo Pasquale , Cappuccio Francesco P. , Trevisan Maurizio , Iacoviello Licia , Iacone Roberto , Jossa Fabrizio , Giorgione Nicola , Farinaro Eduardo , Mancini Mario
Published: August 2015

1. It has been proposed that the enhanced erythrocyte Na+/Li+ countertransport observed in many patients with essential hypertension could be a marker of abnormal renal proximal tubular function. We thus investigated the relationship of blood pressure and Na+/Li+ countertransport to an index of proximal tubular function such as renal Li+ clearance.

2. The study was carried out in a sample of 299 untreated male subjects (aged 21–59 years) randomly selected from a population at work. Na+/Li+ counter-transport was measured in a representative sub-group of 176 men.

3. We did not detect statistically significant correlation of either blood pressure or Na+/Li+ countertransport (Vmax) with fractional excretion of Li+, while confirming the existence of a significant continuous association of blood pressure and body mass index with Na+/Li+ countertransport (P < 0.01).

4. A sub-sample of 57 participants belonging to the lowest or the highest quintiles of Na+/Li+ counter-transport distribution repeated the Li+ clearance study after moderate Na+ restriction.

5. Although fractional excretions of Na+ and Li+ were reduced on the low Na+ diet (both P < 0.001), they did not differ significantly between groups.

6. Our results are at variance with the findings of a recent case-control study in a young age group and suggest that further studies are necessary before a conclusion can be drawn as to the suitability of Na+/Li+ countertransport as a marker of Na+ reabsorption in the renal proximal tubule.
Muscle Enzyme Adaptation in Patients with Peripheral Arterial Insufficiency: Spontaneous Adaptation, Effect of Different Treatments and Consequences on Walking Performance
Authors: Lundgren Fredrik , Dahllöf A.-G. , Scherstén T. , Bylund-Fellenius A.-C.
Published: August 2015

1. The activities of phosphofructokinase (PFK), citrate synthetase (CS), lactate dehydrogenase (LDH), 3-hydroxyacyl-CoA dehydrogenase (ACDH) and cytochrome-c oxidase (Cyt-ox) in the calf muscle tissue were compared in subjects with intermittent claudication (n = 38) and controls (n = 20). The activities of CS, ACDH and Cyt-ox were increased and the activity of Cyt-ox was positively correlated to the maximal walking distance (MWD) in the patients.

2. Thirty-three patients with intermittent claudication were randomized to three treatment groups: (1) operative surgery, (2) operative surgery supplemented with physical training and (3) physical training alone. Before and after 6–12 months of treatment, symptom-free walking distance (SFWD), MWD, ankle-brachial blood pressure quotient (ankle index), maximal plethysmographic calf blood flow (MPBF) and the activities of PFK, CS, LDH, ACDH and Cyt-ox were measured.

3. SFWD and MWD increased in all three groups. Ankle index and MPBF increased in groups 1 and 2, but were unchanged in group 3. The activities of Cyt-ox and CS decreased with operation, but the activity of Cyt-ox was further augmented with training in group 3. Overall, the change in ankle index explained 80–90% of the variability in walking performance. In a separate analysis, the increased activity of Cyt-ox in group 3 was positively correlated to, and explained 31% of the variability in, the improvement in SFWD.

4. These findings indicate that both physical activity and a reduced calf blood flow are necessary conditions for the enzymatic adaptation to take place. A causal relationship betweeen metabolic adaptation in the muscle tissue and walking performance is suggested. The possible importance of other factors as determinants of walking ability is also discussed.
Reduced Selenium Status of Patients with Asthma
Authors: Stone J. , Hinks L. J. , Beasley R. , Holgate S. T. , Clayton B. A.
Published: August 2015

1. Selenium is an essential component of glutathione peroxidase (GSH-Px, EC 1.11.1.9), an enzyme which helps protect cells against damage caused by free radicals and hydroperoxides.

2. We report the plasma, whole blood and platelet concentrations of selenium, and whole blood and platelet activities of GSH-Px, in 49 patients with asthma, 23 of whom had coexisting eczema, and 76 healthy control subjects.

3. The asthmatic patients had significantly lower concentrations of selenium measured in plasma (P < 0.01) and whole blood (P < 0.001), but not in platelets. When the data were summarized as odds ratios there was a highly significant 3.54- and 5.08-fold increased probability of asthma observed for the lower range of plasma and whole blood selenium concentrations, respectively.

4. No overall decrease in platelet or whole blood GSH-Px activity was found when the asthmatic and control groups were compared.

5. Although patients with symptomatic asthma have a reduced selenium status, this does not appear to influence the antioxidant capacity of their circulating blood cells.
Sympathetic Vasoconstriction as a Mechanism of Action of Ouabain in Forearm Arterioles of Hypertensive Patients
Authors: Pedrinelli Roberto , Taddei Stefano , Salvetti Antonio
Published: August 2015

1. The interaction of ouabain, a Na+/K+ adenosine 5′-triphosphatase inhibitor, with sympathetic mechanisms of vasoconstriction, as well as its possible site(s) of action, were investigated in forearm arterioles of patients with uncomplicated hypertension.

2. Intra-arterial infusion of ouabain per se decreased forearm blood flow without changes in systemic arterial pressure or contralateral flow. However, the vasoconstrictor effect of the glycoside was abolished after local pre-treatment with either phentolamine, a competitive α-adrenoceptor antagonist, or bretylium tosylate, a neurotransmitter blocker.

3. To exclude a non-specific effect due to the vasodilatation, a similar protocol was performed using histamine, which acts independently of sympathetic mechanisms. The vascular effect of ouabain was maintained in spite of histamine-induced increases in forearm blood flow even greater than those obtained from either blocker.

4. To discriminate between pre- and post-synaptic site(s) of action of ouabain, exogenous noradrenaline was infused intra-arterially after inactivation of local neurotransmitter release by bretylium, thus causing direct postsynaptic vascular α-adrenoceptor stimulation. Under these conditions, noradrenaline decreased forearm blood flow irrespective of the presence or absence of ouabain.

5. Thus, local sympatholysis by drugs acting on different levels of the sympathetic neuroeffector junction abolished the effect of ouabain, whereas histamine did not influence it. The data provide positive evidence for an effect of ouabain on sympathetically mediated vasoconstriction. This action is apparently not exerted at a postsynaptic site but possibly by enhancing neurotransmitter release.

6. If a circulating endogenous ouabain-like Na+/K+ adenosine 5′-triphosphatase inhibitor is relevant to the development of hypertension in man, it might act through a similar mechanism.
Stimulation of Erythrocyte and Renal Na+, K+-Adenosine Triphosphatase Activity by Antidigoxin Antibody in Normal Rats
Authors: Wagener Osvaldo E. , Mujais Salim K. , Del Greco Francesco , Quintanilla Antonio P.
Published: August 2015

1. A circulating ouabain-like factor which inhibits the Na+, K+-pump has been implicated in volume-expanded states. To assess the role of this putative factor in normovolaemic rats, we measured erythrocyte and renal Na+, K+-adenosine triphosphatase activity after the infusion of a mixture of high-affinity digoxin-binding Fab fragments (Digibind) capable of removing digoxin from pump sites.

2. Compared with either saline (vehicle) or sheep immunoglobin G, infusion of the antidigoxin antibody caused a moderate increase of Na+, K+-adenosine triphosphatase activity in the erythrocyte (saline 348 ± 12; immunoglobulin G 339 ± 16; antidigoxin antibody 432 ± 22 nmol h−1 mg−1; P < 0.005 by analysis of variance) and a larger increase in the renal cortex (saline 9.7 ± 0.9; immunoglobulin G 9 ± 1.4; antidigoxin antibody 24.3 ± 1.8 μmol h−1 mg−1; P < 0.0005 by analysis of variance) without a change in blood pressure

3. These results are consistent with the presence of a digoxin-like inhibitor of the Na+, K+ -pump in normal rats.
A Widespread Abnormality of Renin Gene Expression in the Spontaneously Hypertensive Rat: Modulation in Some Tissues with the Development of Hypertension
Authors: Samani Nilesh J. , Swales John D. , Brammar William J.
Published: August 2015

1. Renin messenger RNA (mRNA) levels were compared in the kidneys, livers, brains, adrenals, aortae and hearts of spontaneously hypertensive (SHR) and Wistar—Kyoto (WKY) rats at 5 and 12 weeks of age using a ribonuclease-protection technique

2. Relative levels of renin mRNA were increased in the kidney, liver, brain, adrenal and heart of the young SHR compared with the WKY. In the aorta, levels were similar in the two strains at 5 weeks

3. In 12-week-old animals, while increased levels persisted in the liver, brain and adrenal of the SHR, the level in the kidney was now the same in the two strains and the levels in the heart and aorta were lower in the SHR compared with the WKY

4. Renin mRNA levels in the kidneys of SHR and WKY were also compared by Northern blotting and confirmed the observations made with the ribonuclease-protection technique

5. The findings indicate a widespread abnormality of renin gene expression in the SHR which is modulated in some tissues by the development of hypertension

6. While the mechanism(s) for the abnormality remains to be determined, the increased renin mRNA levels in the SHR in several tissues concerned with blood pressure regulation suggests an important role for the renin-angiotensin system in the development and maintenance of hypertension

7. However, the finding of increased renin mRNA in the liver also suggests abnormalities in other, as yet unknown, functions of the renin—angiotensin system in the SHR.
Effect of α-Human Atrial Natriuretic Peptide on Proteinuria in Patients with Primary Glomerular Diseases
Authors: Ishii Masao , Hirata Yasunobu , Sugimoto Tokuichiro , Matsuoka Hiroaki , Kimura Kenjiro , Ishimitsu Toshihiko , Fukui Kazushige , Sugimoto Tsuneaki , Kurosawa Yuko , Kiyose Hiroshi , Kangawa Kenji , Matsuo Hisayuki
Published: August 2015

1. The effects of synthetic α-human atrial natriuretic peptide (α-hANP) on urinary protein excretion were examined in nine healthy subjects and 20 patients with primary glomerular diseases who had proteinuria of 1.0 g or more per day. Synthetic α-hANP was intravenously infused into supine subjects at a rate of 8.3 pmol min−1 kg−1 for 40 min

2. Before α-hANP infusion, the plasma concentration of immunoreactive α-hANP was significantly higher in the patients with glomerulonephritis than in the normal subjects (44.3 ± 8.7 vs 19.4 ± 3.0 pmol/l, mean ± sem, P < 0.01) and it showed a positive correlation with mean arterial pressure (rs = 0.84, P < 0.001) and a negative correlation with creatinine clearance (rs = −0.50, P < 0.01)

3. During infusion of α-hANP, although the urinary excretion of protein did not change significantly in the normal subjects, it increased from 0.6 ± 0.2 to 3.0 ± 0.8 mg min−1 m−2 (P < 0.001) in the patients with glomerulonephritis. The urinary protein/creatinine ratio did not change significantly in the former (from 0.18 ± 0.05 to 0.22 ± 0.06; NS), whereas it rose from 3.25 ± 0.94 to 7.62 ± 1.31 (P < 0.001) in the latter

4. The urinary excretions of albumin and of α1-, α2-, β- and γ-globulins, which were electrophoretically analysed, all increased in eight nephrotic patients during or immediately after infusion of α-hANP

5. The α-hANP infusion increased urinary volume, urinary excretion of sodium and creatinine clearance in the glomerulonephritic patients, whereas the changes in urinary volume and creatinine clearance were not significant in the normal subjects. Renal blood flow did not show any significant changes in either group. Packed cell volume increased slightly, but significantly, in the two groups, whereas plasma renin activity did not show any significant changes in either group

6. These results suggest that α-hANP increases the transglomerular permeability to plasma protein in damaged glomeruli, most likely affecting the steric hindrance.
Sodium Handling in the Isolated Perfused Kidney of the Cirrhotic Rat
Authors: Firth John D. , Gove Christopher , Panos Marios Z. , Raine Anthony E. G. , Williams Roger , Ledingham John G. G.
Published: August 2015

1. In cirrhosis the kidney tends to retain salt and water abnormally. Two theories have been proposed to account for this: the ‘underfilling’ theory, in which sodium retention is thought to occur secondary to perceived underfilling of the circulation, and the ‘overflow’ theory, in which sodium retention is considered to be due to a primary renal defect

2. Using the model of cirrhosis produced by carbon tetrachloride administration in the rat, the ability of the kidney to excrete sodium has been examined in vivo and during isolated perfusion

3. Cirrhotic animals demonstrated a reduced ability to excrete an acute sodium load: 6 h after 2 mmol of sodium was given by gavage, 27.5 ± 10.5% had been excreted by the cirrhotic rats and 62.5 ± 7.0% by control rats (P < 0.025)

4. In contrast, during isolated perfusion, kidneys from cirrhotic animals excreted the same amount of sodium as control animals over a range of perfusion pressures from 90 to 150 mmHg (12 to 20 kPa)

5. The data are consistent with the view that in cirrhosis the kidney retains sodium in response to immediate external factors.
A study of patients with alcoholic liver disease by 31P nuclear magnetic resonance spectroscopy
Authors: Angus Peter W. , Dixon Ruth M. , Rajagopalan Bheeshma , Ryley Nicholas G. , Simpson Kenneth J. , Peters Timothy J. , Jewell Derek P. , Radda George K.
Published: August 2015

1. Patients with a history of alcohol abuse were studied by 31P n.m.r. spectroscopy of the liver in vivo, and the results were related to the pattern of disease assessed by standard biochemical and histological techniques.

2. The ratios of metabolites measured from the 31P n.m.r. spectra were abnormal in patients with alcoholic hepatatis but not in those with fatty change or cirrhosis in the absence of hepatitis. In particular, the levels of phosphomonoesters were raised, with respect either to Pi, or to adenosine 5′-triphosphate. The level of phosphomonoesters showed a significant positive correlation with the severity of alcoholic hepatitis, assessed by histology.

3. The ratio of Pi to adenosine 5′-triphosphate was used as a measure of the energy status of the hepatocytes, and was unchanged between patients and controls.
Age-independent forearm vasodilatation by acetylcholine and adenosine 5′-triphosphate in humans
Authors: Imaizumi Tsutomu , Takeshita Akira , Suzuki Satoshi , Yoshida Megumu , Ando Shinichi , Nakamura Motoomi
Published: August 2015

1. Forearm vasodilator responses to acetylcholine, ATP and sodium nitroprusside were examined in healthy young (20 ± 1 years, n = 9), middle-aged (46 ± 2 years, n = 6) and old (57 ± 1 years, n = 6) subjects.

2. A brachial artery was cannulated with a 20-gauge cannula through which drugs at graded doses were locally infused for 2 min at each dose. During drug infusions, forearm blood flow was continuously measured at 15 s intervals using a plethysmograph. Forearm vascular resistance was calculated from forearm blood flow and mean blood pressure obtained in the opposite arm. Basal forearm blood flow and forearm vascular resistance did not differ between the three groups.

3. Acetylcholine and ATP were used to examine endothelium-dependent vasodilatation, and sodium nitroprusside was used to examine endothelium-independent vasodilatation. All three drugs caused dose-dependent increases in forearm blood flow (P < 0.01) and decreases in forearm vascular resistance (P < 0.01). The increases in forearm blood flow or decreases in forearm vascular resistance in response to infusions of the three drugs did not differ between the three groups.

4. These results suggest that endothelium-dependent and endothelium-independent vasodilatation in forearm resistance arteries do not alter with ageing in humans.