bluuebunny/crossref_metadata_2025 huggingface dataset:
A bioenergetic explanation for the selective vulnerability of renal medullary tubules to hypoxia
Authors: Torikai Shozo
Published: August 2015

1. In order to explain the vulnerability of medullary thick ascending limb of Heme's loop (mTAL) during hypoxia, adenosine 5′-triphosphate (ATP) content was measured in isolated rat mTAL cells during control conditions and chemically induced hypoxia and compared with those in medullary collecting duct (MCD) cells.

2. Basal ATP levels in mTAL and MCD were estimated as 3.6 and 2.1 mmol/l, respectively. Antimycin A (5 μmol/l) decreased the ATP content by 41% of the control value in the mTAL cells, but failed to reduce that of the MCD cells. Administration of sodium cyanide (5 mmol/l) drastically depleted ATP in the mTAL cells within 5 min (2–3% of control). On the other hand, ATP levels in MCD cells were sustained for at least 60 min after cyanide administration (64% of control).

3. When tubules were made permeable to sodium by the addition of nystatin, the effects of chemical hypoxia on the cell ATP levels were intensified in both segments, and this was partially blocked by pretreatment with ouabain, or by lowering the sodium concentration of the medium.

4. Higher doses of nystatin in mTAL caused a reduction in ATP levels even under control conditions, but its effect was prevented in low sodium medium.

5. The present study suggests that cell ATP levels can be altered by sodium, potassium-dependent adenosine triphosphatase activity, and that due to their high sodium-transporting activity, mTAL cells are more sensitive to reductions in ATP levels during hypoxia than are MCD cells.
Calcium and magnesium in essential hypertension
Authors: Tillman D. M. , Semple P. F.
Published: August 2015

1. Because disturbances of calcium metabolism have been described in hypertension, measurements of plasma and serum concentrations of ionized calcium, total calcium, magnesium and renin were made in 38 patients with essential hypertension and age- and sex-matched control subjects. Urinary excretion of calcium, magnesium and sodium was also determined.

2. The mean serum concentration of ionized calcium was 1.23 ± 0.04 (sd) mmol/l in the hypertensive group and 1.21 ±0.03 mmol/l in controls, and results were similar after correction for pH. There was a weak positive correlation between serum ionized calcium (pH 7.4) and systolic pressure (r = 0.26, P < 0.02), but no correlation with plasma renin concentration.

3. Although the difference between serum total calcium concentration in the hypertensive (2.29 ±0.09 mmol/l) and control (2.26 ±0.07 mmol/l) subjects was not significant, there was a significant correlation between total calcium and systolic pressure (r = 0.23, P < 0.05) which was maintained after correction for other variables.

4. There were no differences in plasma concentrations of parathyroid hormone or 1,25-dihydroxycholecalciferol between hypertensive and control subjects.

5. The hypertensive group showed higher urinary excretion of calcium (5.9 ±3.0 mmol/24h) than controls (4.6 ± 1.7 mmol/24 h), but the difference was not maintained after correction for sodium excretion.

6. Serum concentrations of magnesium were similar in the two groups, but urinary excretion of magnesium was significantly lower in hypertensive (3.7 ± 1.3 mmol/24 h) than control (4.5 ±1.6 mmol/24 h) subjects and there was an inverse correlation between magnesium excretion and blood pressure (r = 0.3–0.35, P < 0.01).
Sudden onset of proteinuria in chronic serum sickness in rats
Authors: Gorfien Janet B. , Van Liew Judith B. , Gorfien Stephen , Noble Bernice
Published: August 2015

1. Daily intravenous administration of bovine serum albumin (BSA) to rats produces chronic serum sickness glomerulonephritis, an immune-complex-mediated renal disease that is eventually always fatal. We have performed a detailed study of the onset of proteinuria in chronic serum sickness in order to assess the long-term consequences of discontinuing daily BSA injections precisely at that very early and well-defined stage of disease.

2. Urine and plasma samples from rats receiving daily BSA injections were collected and analysed daily before the onset of proteinuria, at which time the rats were divided into three groups. Group 1 continued to receive daily BSA injections, in group 2 injections were stopped on the first, and in group 3 on the third, day of proteinuria. Proteinuria began suddenly and was not preceded either by microalbuminuria or abnormalities of plasma composition. The sudden expression of proteinuria was accompanied by an equally rapid development of hypoalbuminaemia and hypercholesterolaemia. Development of the characteristic glomerular histopathology of serum sickness coincided with, but did not precede, the onset of proteinuria. Despite the discontinuation of antigen injections at the onset of proteinuria, basement membrane thickening was evident 8 weeks later; proteinuria persisted and hypercholesterolaemia increased.

3. In this model of immune complex glomerulonephritis, changes in kidney function and immunopathology were abrupt and closely linked, precluding the use of those criteria to predict when proteinuria would begin. Furthermore, extremely brief periods of active immunological injury to the peripheral capillary wall were sufficient to produce persistent abnormalities of glomerular structure and function.
Luteinizing hormone in women is secreted in superimposed pulse patterns
Authors: Murdoch A. P. , Diggle P. J. , White M. C. , Harris M. , Kendall-Taylor P. , Dunlop W.
Published: August 2015

1. The pulsatile nature of luteinizing hormone (LH) secretion has recognized physiological and clinical importance, but because of the difficulties with statistical analysis of serial data the precise nature of this pulsed signal is poorly understood. Several groups have noted small-amplitude, high-frequency pulses superimposed on large slower pulses, but, using conventional methods of analysis, it is not possible to distinguish these from assay variation or to characterize them.

2. In an alternative approach we have applied the methods of time series analysis which identify the harmonic patterns within data. Twenty-four healthy women in the early follicular phase of the cycle had blood samples taken at intervals of 1, 5 or 10 min for up to 6 h.

3. We found that LH secretion consists of superimposed harmonics of varying amplitude which occur in frequency bands of about (a) 1–3 h and (b) 2–3 min. Investigations excluded a reproducible pulsatility in our LH assay, implying that the small fast pulses are physiological events.

4. We conclude that LH release is highly complex and that the methods of time series analysis permit identification and characterization of the multiple pulses.
Effects of infusion of prostacyclin on anatomical intrapulmonary right to left shunt: a useful model of human hypoxic vasoconstriction?
Authors: Bush A. , Busst C. M. , Knight W. B. , Shinebourne E. A.
Published: August 2015

1. Eleven infants and children (mean age 4.3 years, range 0.2–12 years) with pulmonary vascular disease secondary to congenital cardiac anomalies (n = 6) or bronchopulmonary dysplasia (n = 5), were studied during cardiac catheterization while ventilated on 100% oxygen.

2. All had a raised pulmonary vascular resistance (mean 11.8 units, range 4.1–26.0 units, normal value < 3 units) and a raised anatomical intrapulmonary right to left shunt (mean 22%, range 8–50%, normal value <5%). The elevated shunt was attributed to the effects of 100% oxygen and general anaesthesia causing alveolar collapse, with only partial compensation for impairment of gas exchange by compensatory local hypoxic vasoconstriction.

3. When prostacyclin was infused, pulmonary vascular resistance fell by 3.2 ± 1.8 units (mmHg litre−1 min m2), and pulmonary blood flow rose by 1.0 ± 0.7 litre min−1 m−2 (mean ± 95% confidence intervals).

4. Intrapulmonary right to left shunt fraction increased in eight of 11 patients, with a maximal rise for the group of 5.9 ± 4.6% (mean ± 95% confidence intervals). However, even at doses of prostacyclin sufficient to cause systemic vasodilatation and tachycardia, there was no evidence for a selective increase in shunt fraction.

5. We suggest that studying the effects of therapeutic interventions on intrapulmonary shunt fraction may be a useful model in vivo of human hypoxic pulmonary vasoconstriction.
Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal re-uptake in the sympathetic nervous system in vivo
Authors: Eisenhofer Graeme , Goldstein David S. , Kopin Irwin J.
Published: August 2015

1. Neuronal re-uptake is the primary means for terminating the actions of endogenously released noradrenaline. A portion of the recaptured noradrenaline is deaminated to form dihydroxyphenylglycol. The present report describes a technique using plasma dihydroxyphenylglycol for estimation of the rate of neuronal reuptake of endogenous noradrenaline in vivo.

2. Neuronal re-uptake of noradrenaline in the sympathetic nervous system of the rat was estimated from the effects of neuronal uptake blockade with desipramine on three variables: (i) the plasma clearance of intravenously infused 3H-labelled noradrenaline, (ii) the plasma concentration of endogenous dihydroxyphenylglycol, and (iii) the plasma concentration of 3H-labelled dihydroxyphenylglycol formed from infused 3H-labelled noradrenaline.

3. Desipramine decreased plasma dihydroxyphenylglycol by 36%, this representing the fraction of dihydroxyphenylglycol in plasma that was derived from recaptured noradrenaline. After desipramine, the decrease in the rate of neuronal uptake of 3H-labelled noradrenaline was 9.7 times that of the decrease in the plasma spillover of 3H-labelled dihydroxyphenylglycol. Since the appearances in plasma of dihydroxyphenylglycol from unlabelled and 3H-labelled noradrenaline were similar, the neuronal re-uptake of endogenous noradrenaline could be assumed to be 9.7 times as much as the plasma spillover of dihydroxyphenylglycol that was derived from recaptured noradrenaline (0.15 nmol min−1 kg−1).

4. The rate of neuronal re-uptake of endogenous noradrenaline was estimated to be 1.45 nmol min−1 kg−1, whereas the plasma spillover of noradrenaline was 0.127 nmol min−1 kg−1. Thus, only a small fraction (<9%) of the noradrenaline released into the synaptic cleft spills over into the circulation.
Effects of chronic hypokalaemia and adrenalectomy on potassium transport by the medullary collecting duct of the rat
Authors: Halperin M. L. , Honrath U. , Wilson D. R. , Sonnenberg H.
Published: August 2015

1. The purpose of this study was to evaluate the roles of chronic hypokalaemia and of aldosterone in K+ transport in the medullary collecting duct. Renal clearance and duct transport measurements were made before and after KCl infusion in three groups of animals: normal rats on a regular K+ diet (group I), and sham-operated (II) or adrenalectomized rats (group III), both on a low K+ diet.

2. Only the sham-operated animals on the low K+ diet became hypokalemic. They also had the lowest rate of K+ excretion at the time of study. Adrenalectomized rats were normokalaemic, and had an intermediate rate of K+ excretion. After the acute KCl infusion, kaliuresis remained significantly depressed in the rats which were previously hypokalemic. In contrast, K+ excretion rates in response to K+ infusion were high and not significantly different in both previously normokalaemic groups, independent of the presence of the adrenal glands.

3. In the medullary collecting duct, before the KCl infusion there was no net K+ transport in either normokalaemic group (I and III). However, after the KCl infusion there was significant K+ secretion in both of these groups (32% and 22% of total urinary excretion, respectively). In contrast, the sham-operated hypokalemic rats on the low K+ diet had a small absolute, but large fractional K+ reabsorption (64% of delivered load) in the medullary collecting duct. With KCl infusion in this group, K+ delivery to the medullary duct increased, but absolute reabsorption along the duct was maintained, resulting in a fractional reabsorption of 28% of delivery.

4. The results indicate that an acute K+ load can stimulate net K+ secretion in the medullary collecting duct, and that this secretion can be independent of aldosterone. Chronic hypokalaemia stimulates net K+ reabsorption in this nephron segment, a process that persists during acute hyperkalaemia.
Increased rates of hepatic cholesterogenesis and fatty acid synthesis in septic rats in vivo: evidence for the possible involvement of insulin
Authors: de Vasconcelos Paulo R. L. , Kettlewell Michael G. W. , Gibbons Geoffrey F. , Williamson Dermot H.
Published: August 2015

1. Sepsis induced by caecal ligation and puncture increased the rates of hepatic cholesterogenesis and fatty acid synthesis in vivo compared with sham-operated rats. These changes were accompanied by higher concentrations of lactate and pyruvate in blood and liver and an increase in plasma insulin.

2. The total activity of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase (EC 1.1.1.88) in liver was increased by sepsis, but there was no significant change in the expressed activity. Short-term insulin deficiency (induced by mannoheptulose or streptozotocin) decreased the rates of cholesterogenesis and fatty acid synthesis in livers of septic rats but did not alter the expressed/total activity of HMG-CoA reductase.

3. It is concluded that the increased rate of hepatic cholesterogenesis in septic rats is in part a result of the higher plasma insulin, the hormone acting to maintain the total activity of HMG-CoA reductase and to stimulate a step before the formation of HMG-CoA.

4. These changes may contribute to the hypertriacyl-glycerolaemia associated with sepsis.
Effect of chronic ethanol ingestion on tissue RNA and blood flow in skeletal muscle with comparative reference to bone and tissues of the gastrointestinal tract of the rat
Authors: Preedy V. R. , Venkatesan S. , Peters T. J. , Nott D. M. , Yates J. , Jenkins S. A.
Published: August 2015

1. The effects of feeding a diet containing ethanol as 36% of total calories for 4–5 weeks on muscle RNA content and blood flow was investigated in male rats weighing 150–250 g. Control animals were pair-fed the same diet in which ethanol was substituted by isocaloric glucose.

2. Chronic ethanol consumption reduced the capacity for type II (anaerobic, fast-twitch) fibre-rich skeletal muscles to synthesize protein as reflected by a decreased RNA/protein ratio. Type 1 (aerobic, slow-twitch) fibre-rich muscles were unaffected.

3. Ethanol feeding had no significant effect on cardiac output. Furthermore, the percentage of cardiac output to type I and type II fibre-rich muscles, bone and tissues of the gastrointestinal tract, i.e. stomach, small intestine and large intestine, was unaffected by ethanol consumption. Similarly, ethanol feeding had no effect on blood flow when it was calculated on the basis of tissue weight (ml min−1 g−1).

4. It was concluded that chronic ethanol feeding in the rat was associated with selective skeletal muscle dysfunction in the absence of changes in blood supply.
Responsiveness of superficial hand veins to adrenergic stimuli in patients with cystic fibrosis
Authors: Eichler Hans-Georg , Eichler Irmgard , Lewiston Norman , Blaschke Terrence F. , Hoffman Brian B.
Published: August 2015

1. The basic biochemical defect of cystic fibrosis (CF) remains undetermined, but impaired function of the β-adrenoceptor-mediated adenosine 3′:5′-cyclic monophosphate (cyclic AMP)-dependent regulatory pathway in secretory cells is likely to be involved in the pathophysiology of the disease.

2. We have compared responsiveness to β-adrenergic stimulation in vivo by infusing isoprenaline locally into peripheral veins of CF patients and control subjects; the dorsal hand vein technique was used to measure the vascular response to isoprenaline.

3. CF patients required significantly higher doses of isoprenaline for half-maximal dilatation of the preconstricted veins (ED50) than controls (geometric mean: 44.5 ng/min in CF patients compared with 14.8 ng/min in controls; P < 0.05). Maximal venodilatation was 74 ± 30% of baseline in CF patients compared with 94 ± 50% in controls (NS between groups).

4. The clinical score of CF patients was uncorrelated with the ED50 of isoprenaline. Thus the decreased β-adrenergic responsiveness does not seem to be related to the severity of the disease.

5. Our results indicate a defect in the cyclic-AMP-dependent pathway in vascular smooth muscle cells of CF patients. Whether this is associated with the CF gene defect itself requires further study.
Neural influences on the pulmonary vascular bed in man
Authors: Moruzzi Paolo , Sganzerla Paolo , Guazzi Maurizio D.
Published: August 2015

1. Impedance to venous return by distention of a balloon in the inferior vena cava (IVCB) was utilized in 10 patients, during diagnostic procedures, to reduce blood flow through the lungs at baseline and to buffer its changes during stimulation of the adrenergic system, which was obtained with mental arithmetic (AT) and cold pressor (CPT) tests.

2. When venous return was unimpeded, cardiac output rose by 2.06 1/min during the AT and remained steady during the CPT, and arteriolar resistance in the pulmonary circuit was significantly reduced and slightly raised, respectively.

3. During IVCB, baseline cardiac output decreased by 710 ml/min, it rose by 925 ml/min during the AT and again remained steady during the CPT; pulmonary arteriolar resistance was unchanged from before obstruction at baseline and was significantly augmented by both tests. In particular, AT became a clear vasoconstrictor stimulus, having originally produced vasodilatation.

4. These observations support the view that lung blood vessels in man are sensitive to adrenergic influences and that vasoconstriction can be elicited in circumstances in which the flow through the lungs is restrained. The physiological importance of the neural regulation of the pulmonary circulation in man remains undefined.
Enhancement of the pulmonary vasoconstriction reaction to alveolar hypoxia in systemic high blood pressure
Authors: Guazzi Maurizio D. , Berti Marco , Doria Elisabetta , Fiorentini Cesare , Galli Claudia , Pepi Mauro , Tamborini Gloria
Published: August 2015

1. In systemic hypertension the pulmonary vessels show an excessive tone at rest and hyper-react to adrenoceptor stimulation. Alterations in Ca2+ handling by the vascular smooth muscle cells seem to underlie these disorders. Alveolar hypoxia also constricts pulmonary arteries, increasing the intracellular Ca2+ availability for smooth muscle contraction. This suggests the hypothesis that hypoxic pulmonary vasoconstriction depends on similar biochemical disorders, and that the response to the hypoxic stimulus may be emphasized in high blood pressure.

2. In 21 hypertensive and 10 normotensive men, pulmonary arterial pressure and arteriolar resistance have been evaluated during air respiration and after 15 min of breathing 17, 15 and 12% oxygen in nitrogen. Curves relating changes in pulmonary arterial pressure and arteriolar resistance to the oxygen content of inspired gas had a similar configuration in the two populations, but in hypertension were steeper and significantly shifted to the left of those in normotension, reflecting a lower threshold and an enhanced vasoconstrictor reactivity.

3. This pattern was not related to differences in severity of the hypoxic stimulus, degree of hypocapnia and respiratory alkalosis induced by hypoxia, and plasma catecholamines.

4. The association of high blood pressure with enhanced pulmonary vasoreactivity to alveolar hypoxia could have clinical implications in patients who are chronically hypoxic and have systemic hypertension.
Effect of nedocromil sodium on down-regulation of pulmonary β-adrenoceptors
Authors: Kioumis I. , Ukena D. , Barnes Peter J.
Published: August 2015

1. We have studied the effect of the anti-inflammatory anti-asthma drug, nedocromil sodium, on down-regulation of pulmonary β-adrenoceptors in guinea-pig lung.

2. Incubation of minced lung with isoprenaline (10 μmol/l) resulted in a reduction in maximum binding capacity of [125I]iodocyanopindolol to lung membranes from 246 ± 4 to 169 ± 6 fmol/mg of protein (mean ± sem, P < 0.01, n = 18).

3. Nedocromil sodium, which had no direct effect on [125I]iodocyanopindolol binding, prevented isoprenaline-induced down-regulation, giving complete protection at a dose of 100 μmol/l.

4. The mechanism of this effect is not certain, but nedocromil sodium may interfere with the internalization of β-adrenoceptors in pulmonary parenchymal cells. This may have some therapeutic relevance.
Amiloride prevents the metabolic acidosis of a KCl load in nephrectomized rats
Authors: Altenberg Guillermo A. , Aristimuño Patricia C. , Amorena Carlos E. , Taquini Alberto C.
Published: August 2015

1. Counter movements of K+ and H+ across cell membranes were studied in nephrectomized KCl-loaded rats. In one group of animals, the movements of K+ and H+ were determined during and after a KCl load, and in another group, amiloride was used in order to evaluate Na+ participation in K+/H+ exchange.

2. After a KCl load at constant Pco2, 79% of infused K+ left the inulin space, half of which was in exchange for H+. As a result, blood pH fell from 7.40 ± 0.01 to 7.30 ± 0.01 (mean ± sem; P < 0.001).

3. During KCl infusion, the K+/H+ exchange ratio varied between 1.3 and 6.8, showing that the coupling ratio is not fixed.

4. Amiloride did not change blood pH and plasma [K+], but prevented the metabolic acidosis produced by the KCl load without affecting K+ entry into the non-inulin space. Therefore, K+ and H+ movements became completely dissociated.

5. The results indicate that KCl activates an amiloride-sensitive H+ extrusion from the cells. This finding is compatible with the view that Na+/H+ exchange participates in the metabolic acidosis produced by a KCl load.
Effects of Plasma, Tumour Necrosis Factor, Endotoxin and Dexamethasone on Extracellular Proteolysis by Neutrophils from Healthy Subjects and Patients with Emphysema
Authors: Burnett David , Chamba Anita , Hill Susan L. , Stockley Robert A.
Published: August 2015

1. Neutrophils from patients with chronic obstructive bronchitis and emphysema or age-matched control subjects were cultured on a substrate of 125I-fibronectin. The neutrophils from patients with lung disease digested significantly more fibronectin and released more elastase into the culture supernatant than did cells from control subjects. Preincubation of neutrophils from emphysematous patients with plasma from control subjects significantly inhibited fibronectin digestion by the patients' neutrophils by, on average, 10%. Preincubation of control subjects' neutrophils with plasma from emphysematous patients had no effect on fibronectin digestion.

2. Tumour necrosis factor increased fibronectin digestion in a dose-dependent manner when the cytokine was added to the adherent cells but not when preincubated with the polymorphonuclear leucocytes in suspension. Bacterial endotoxin in concentrations above 6 μg/ml significantly increased fibronectin digestion by neutrophils, but leukotriene B4, interferon-μ and interleukin-1α had no significant effects.

3. Dexamethasone inhibited fibronectin digestion by neutrophils in a dose-dependent manner, from 11% at 10−10 mol/l to 68% at 10−3 mol/l.
Whole Body Protein Turnover and Resting Metabolic Rate in Homozygous Sickle Cell Disease
Authors: Badaloo Asha , Jackson Alan A. , Jahoor Farook
Published: August 2015

1. Whole body protein turnover and resting metabolic rate were measured in six adults with homozygous sickle cell disease (genotype HbSS) and in six normal adults (genotype HbAA) of similar age.

2. Turnover was measured with prime/intermittent oral doses of [15N]glycine over 18 h and resting energy expenditure was measured by indirect calorimetry.

3. In HbSS, nitrogen flux (0.9 ± 0.08 g day−1 kg−1), protein synthesis (6.0 ± 0.5 g day−1 kg−1) and protein degradation (5.6 ± 0.5 g day−1 kg−1) were significantly increased compared with HbAA nitrogen (flux 0.5 ± 0.02 g day−1 kg−1, protein synthesis 3.2 ± 0.2 g day−1 kg−1 and protein degradation 2.8 ± 0.2 g day−1 kg−1).

4. Resting energy expenditure was significantly higher in HbSS compared with HbAA when expressed per unit of body weight (115 ± 3 and 94 ± 4 kJ day−1 kg−1, respectively) or weight 0.75 (317 ± 6 and 269 ± 8 kJ day−1 kg−0.75, respectively).

5. The increase in protein turnover and energy expenditure suggest that patients with HbSS exist in a hypermetabolic state that requires greater dietary energy compared with HbAA.
Vitamin D Deficiency and Muscle Strength in Male Alcoholics
Authors: Hickish T. , Colston K. W. , Bland J. M. , Maxwell J. D.
Published: August 2015

1. Chronic alcoholism may be complicated by proximal muscle weakness associated with a selective atrophy of type II skeletal muscle fibres. The histopathological findings are non-specific as identical changes are seen in proximal muscle weakness associated with various metabolic myopathies, including osteomalacia.

2. The maximum voluntary contraction (MVC) of the dominant quadriceps and plasma 25-hydroxycholecalciferol [25-(OH)D] were measured in male alcoholics and control subjects to determine whether vitamin D deficiency contributed to proximal muscle weakness.

3. In both groups MVC declined with age and was related to body build. The distribution of plasma 25-(OH)D was skewed in alcoholics, with the mean significantly lower than in control subjects. Seventeen per cent of patients (but none of the control subjects) had pronounced biochemical deficiency [plasma 25-(OH)D < 10 nmol/l].

4. Alcoholics were significantly weaker than control subjects, even after correcting for the effects of age, height and weight. The severity of associated liver disease (cirrhosis vs no cirrhosis) did not influence muscle strength. Variation in plasma 25-(OH)D and albumin made an insignificant contribution to the difference in MVC observed between patients and control subjects.

5. We conclude that proximal muscle strength is reduced in chronic alcoholism but that this is not due to associated vitamin D [25-(OH)D] deficiency or alcoholic cirrhosis.
The Antihypertensive and Renal Activities of Potassium Canrenoate are Associated with Increased Renal Prostaglandin Excretion
Authors: Castellani Sergio , Scarti Luca , Chen Ji Lin , Del Rosso Attilio , Carnovali Marino , Masotti Giulio
Published: August 2015

1. In a double-blind, randomized, cross-over study the effects of potassium canrenoate administration (100 mg twice daily for 10 days orally) on renal prostaglandin synthesis (prostaglandin E2 and prostaglandin F2α) were evaluated in 10 normotensive females and in 10 females with essential hypertension.

2. When compared with normotensive subjects, hypertensive patients in baseline conditions showed a reduced excretion of urinary prostaglandin E2 associated with an excessive prostaglandin F2α production.

3. Potassium canrenoate significantly reduced mean blood pressure in hypertensive patients [from 118.9 ± 8.7 mmHg (1.62 ± 0.12 kPa) to a peak minimum value of 104.7 ± 9.8 mmHg (1.42 ± 0.13 kPa) on the seventh day of treatment; P < 0.01 for the whole period] but not in control subjects [from 88 ± 9.4 mmHg (1.20 ± 0.13 kPa) to 84.3 ± 8.3 mmHg (1.15 ± 0.11 kPa) on the eighth day, NS] even though potassium canrenoate significantly increased sodium excretion in both groups. Renal prostaglandin excretion was affected differently in the two groups: in control subjects excretion of both prostaglandin E2 and prostaglandin F2α was increased after drug administration, whereas in hypertensive patients only prostaglandin E2 excretion was enhanced.
Cardiovascular Response to Coughing: Its Value in the Assessment of Autonomic Nervous Control
Authors: Van Lieshout E. J. , Van Lieshout J. J. , Ten Harkel A. D. J. , Wieling W.
Published: August 2015

1. The relationship between blood pressure and heart rate responses to coughing was investigated in 10 healthy subjects in three body positions and compared with the circulatory responses to commonly used autonomic function tests: forced breathing, standing up and the Valsalva manoeuvre.

2. We observed a concomitant intra-cough increase in supine heart rate and blood pressure and a sustained post-cough elevation of heart rate in the absence of arterial hypotension. These findings indicate that the sustained increase in heart rate in response to coughing is not caused by arterial hypotension and that these heart rate changes are not under arterial baroreflex control.

3. The maximal change in heart rate in response to coughing (28 ± 8 beats/min) was comparable with the response to forced breathing (29 ± 9 beats/min, P > 0.4), with a reasonable correlation (r = 0.67, P < 0.05), and smaller than the change in response to standing up (41 ± 9 beats/min, P < 0.01) and to the Valsalva manoeuvre (39 ± 13 beats/min, P < 0.01).

4. Quantifying the initial heart rate response to coughing offers no advantage in measuring cardiac acceleratory capacity; standing up and the Valsalva manoeuvre are superior to coughing in evaluating arterial baroreflex cardiovascular function.
Effect of Almitrine on Hypoxic Ventilatory Drive Measured by Transient and Progressive Isocapnic Hypoxia in Normal Men
Authors: Airlie M. A. A. , Flenley D. C. , Warren P. M.
Published: August 2015

1. In a double-blind placebo-controlled study, we have investigated the effect of the peripheral chemoreceptor stimulant drug almitrine bismesylate on hypoxic ventilatory drive (expressed as the slope of the minute ventilation/arterial oxygen saturation relationship in litres min−1 %−1) as measured by both progressive isocapnic hypoxia at rest and transient hypoxia (three breaths of 100% N2) during moderate exercise, in seven normal men, to determine if the ventilatory response to the transient hypoxic stimulus is a more specific measure of peripheral chemoreceptor sensitivity to hypoxia.

2. Hypoxic ventilatory drive measured using progressive isocapnic hypoxia ranged from −0.13 to −2.65 litres min−1 % −1 after placebo and from − 0.20 to − 6.48 litres min−1 %−1 after almitrine. The response was greater after almitrine in six of the seven subjects, and the difference was significant for the whole group (P < 0.05).

3. Hypoxic ventilatory drive measured using transient hypoxia ranged from −0.19 to −1.59 litres min−1 %−1 after placebo and from −0.09 to −1.62 litres min−1 %−1 after almitrine. The response was not consistently greater after almitrine, and the difference was not significant for the group.

4. Difficulties in accurately quantifying a brief rise in minute ventilation after transient hypoxia, particularly in subjects with a low hypoxic ventilatory drive, may have masked small changes in the slope of the minute ventilation/arterial oxygen saturation relationship with this method. However, the significant increase in the response to progressive isocapnic hypoxia after almitrine suggests that the failure to demonstrate an effect using transient hypoxic stimuli was not solely due to between-day variation in hypoxic ventilatory drive or the small numbers of subjects studied.

5. We conclude that, although transient hypoxia avoids any central depression of ventilation that might result from the prolonged hypoxia used in the conventional steady state or progressive isocapnic methods (thereby leading to underestimation of the hypoxic ventilatory drive), the ventilatory response to such transient stimuli is also affected by factors other than peripheral chemoreceptor activity.
Effect of Vasopressin on Bronchial Reactivity to Histamine
Authors: Knox Alan J. , Britton John R. , Tattersfield Anne E.
Published: August 2015

1. Recent evidence suggests that a high salt diet increases bronchial reactivity, but the underlying mechanism is unclear.

2. To determine whether alterations in circulating vasopressin might be responsible, we have studied the effect of an infusion of vasopressin on the airways of six normal and eight asthmatic subjects measuring the response as expiratory flow at 30% of vital capacity (V̇30P) in the normal subjects and as forced expiratory volume in 1s (FEV1) in the asthmatic subjects, in a double-blind, placebo-controlled, cross-over study.

3. Vasopressin, given as an infusion at a rate of 2 i.u./h for 1 h, followed by 4 i.u./h for a further hour, produced plasma concentrations of 12.8 and 17 ng/l, respectively, compared with 2.0 and 2.0 ng/l on placebo.

4. Airway reactivity to histamine was measured after 1 and 2 h as the provocative doses of histamine causing a 40% reduction in V̇30P (PD40V̇30P) in the normal subjects and a 20% reduction in FEV1 (PD20FEV1) in the asthmatic subjects.

5. There was a small increase in PD40V̇30P after both vasopressin and placebo in normal subjects (refractoriness) but no change in PD20FEV1 in the asthmatic subjects.

6. There was no significant difference between vasopressin and placebo in V̇30P or PD40 V̇30P over the 2 h after the drug in the normal subjects or in FEV1 or PD20FEV1 over the 2 h after the drug in the asthmatic subjects.

7. We conclude that alterations in circulating vasopressin are unlikely to be responsible for the increase in bronchial reactivity when dietary salt intake is increased.
Protoporphyrin IX-Induced Impairment of Biliary Lipid Secretion in the Rat
Authors: Perez-Barriocanal F. , Redondo-Torres J. G. , Villanueva G. R. , Arteche E. , Berenson M. M. , Marin J. J. G.
Published: August 2015

1. In order to gain information on the effect of protoporphyrin IX on changes in the properties of the canalicular plasma membrane, we studied the release of canalicular membrane constituents, namely phospholipids, cholesterol and 5′-nucleotidase, into bile in anaesthetized rats receiving saline or taurocholate (0.5 μmol min−1 100 g−1 body weight) with or without protoporphyrin IX infusion (10 or 20 μg min−1 100 g−1 body weight).

2. Protoporphyrin IX induced an impairment of spontaneous bile flow and of biliary secretion of cholesterol, phospholipids and bile acids. The taurocholate-induced increase in bile acid output was not significantly reduced by protoporphyrin IX at either of the doses used. However, when a cholestatic dose of protoporphyrin IX was infused, the taurocholate-induced bile flow and secretion of lecithin and cholesterol were significantly reduced.

3. Biliary output of phospholipid species other than lecithin did not counterbalance the protoporphyrin IX-induced reduction in biliary lecithin secretion. Biliary outputs of both total phospholipid and lecithin were inhibited by protoporphyrin IX to similar extents.

4. Protoporphyrin IX alone had no effect on the biliary release of 5′-nucleotidase, whereas when it was given with taurocholate, it increased the bile acid-induced biliary output of this enzyme markedly.

5. In summary, these results indicate that protoporphyrin IX impairs the biliary secretion of phospholipids and cholesterol but not that of bile acid. The release of canalicular membrane constituents other than lipids was also modified by protoporphyrin IX.
The Antinatriuretic Effect of Dopaminergic Blockade during Volume Expansion is Independent of Circulating Atrial Natriuretic Factor
Authors: Coruzzi Paolo , Novarini Almerico , Musiari Luisa , Ravanetti Carlo , Ghielmi Salvatore , Rodella Anna , Montanari Alberto
Published: August 2015

1. Ten normal subjects were subjected to 2 h water immersion with and without pharmacological dopaminergic blockade with either metoclopramide (group I) or domperidone (group II).

2. In group I, urinary sodium excretion showed a marked increase during water immersion alone, whereas it was blunted during water immersion plus dopaminergic blockade with metoclopramide (P < 0.05 vs water immersion alone, n = 5). Plasma aldosterone was significantly suppressed by water immersion alone (P < 0.05), but remained unchanged during water immersion plus metoclopramide. Plasma atrial natriuretic factor showed similar augmentation during water immersion alone and during water immersion plus metoclopramide.

3. Another five subjects (group II) were studied during water immersion alone and during water immersion plus dopaminergic blockade with domperidone. In this group the increase in urinary sodium excretion was similarly blunted by dopaminergic blockade. Plasma atrial natriuretic factor was equally elevated during water immersion alone and during water immersion plus domperidone, but aldosterone was suppressed by both water immersion alone and water immersion plus domperidone.

4. Our findings suggest that water immersion-induced atrial natriuretic factor release is independent of dopaminergic activity. Dopamine blockade is able to blunt significantly both water immersion-induced natriuresis and plasma aldosterone suppression, independently of the marked elevation of circulating atrial natriuretic factor, via a mechanism involving type 2 dopaminergic receptors.
Cardiac Secretion and Renal Clearance of Atrial Natriuretic Peptide in Normal Man: Effect of Salt Restriction
Authors: Sudhir Krishnankutty , Friberg Peter , Meredith Ian T. , Woods Robyn L. , Esler Murray D. , Jennings Garry L.
Published: August 2015

1. Previous studies of endogenous atrial natriuretic peptide (ANP) in humans have examined changes in plasma levels, rather than regional secretion and clearance of the peptide. Using arterial and selective venous catheterization and sampling, and measurement of regional organ flow, we measured haemodynamics, cardiac secretion of ANP and renal clearance of ANP in six healthy volunteers at rest, on a normal sodium diet

2. Salt restriction decreases plasma concentrations of ANP. We assessed the contribution of the heart and kidney to this decrease, by measuring cardiac secretion and renal clearance of ANP at the termination of a low salt diet

3. Twenty-four hour urinary sodium excretion fell on the low salt diet from 163 to 29 mmol/day [standard error of the difference (sed) ± 14, P < 0.001]. Body weight decreased on salt restriction from 76.4 to 75.4 kg (sed ± 0.33, P < 0.05). Brachial mean arterial pressure fell by 6% (P < 0.05), but right atrial pressure was unchanged. Renal vein plasma renin activity increased by 56% with sodium restriction (P < 0.01), whereas arterial ANP concentrations fell by 39% (P < 0.05)

4. Coronary sinus ANP levels fell from 417 to 268 pg/ml (sed ± 74, P < 0.05), whereas renal vein concentrations were unaltered. There was a 47% decrease in cardiac secretion of ANP in the low salt state (P < 0.05). Net extraction of ANP across the kidney (about two-thirds) and renal clearance of ANP were unchanged on the low salt diet. Thus decreased plasma ANP with sodium restriction is due to reduced cardiac secretion.
Clinical Science in the 1990s
Authors: Brown M. J.
Published: August 2015

From this issue, Clinical Science will increase its page numbers from an average of 112 to 128 per monthly issue. This welcome change — equivalent to at least two manuscripts — has been ‘forced’ on us by the increasing pressure on space; this has led to an undesirable increase in the delay between acceptance and publication, and to a fall in the proportion of submitted manuscripts we have been able to accept. The change in page numbers will instead permit us now to return to our exceptionally short interval between acceptance and publication of 3–4 months; and at the same time we shall be able not only to accept (as now) those papers requiring little or no revision, but also to offer hope to some of those papers which have raised our interest but come to grief in review because of a major but remediable problem. Our view, doubtless unoriginal, has been that the review process, which is unusually thorough for Clinical Science, involving a specialist editor and two external referees, is most constructive when it helps the evolution of a good paper from an interesting piece of research.

Traditionally, the papers in Clinical Science have represented some areas of research more than others. However, this has reflected entirely the pattern of papers submitted to us, rather than any selective interest of the Editorial Board, which numbers up to 35 scientists covering most areas of medical research. Arguably, after the explosion during the last decade of specialist journals, the general journal can look forward to a renaissance in the 1990s, as scientists in apparently different specialities discover that they are interested in the same substances, asking similar questions and developing techniques of mutual benefit to answer these questions. This situation arises from the trend, even among clinical scientists, to recognize the power of research based at the cellular and molecular level to achieve real progress, and at this level the concept of organ-based specialism breaks down. It is perhaps ironic that this journal, for a short while at the end of the 1970s, adopted — and then discarded — the name of Clinical Science and Molecular Medicine, since this title perfectly represents the direction in which clinical science, and therefore Clinical Science, is now progressing.
Acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells
Authors: Ireland A. , Priddle J. D. , Jewell D. P.
Published: August 2015

1. This study investigates the acetylation of 5′-aminosalicylic acid by isolated human colonic epithelial cells.

2. After incubation of intact cells with 0.1 mmol/l 5-aminosalicylic acid, N-acetyl-5-aminosalicylic acid was detected in a concentration of 141 (± 23.8 sem) nmol/g dry weight in the incubation medium, and 34.8 (± 5.5 sem) nmol/g dry weight intracellularly. No unchanged 5-aminosalicylic acid was detected inside the cell.

3. Acetylation of 5-aminosalicylic acid by a cell homogenate was very poor, but the addition of 1 mmol/l acetyl-CoA resulted in complete conversion of 0.1 mmol/l 5-aminosalicylic acid to N-acetyl-5-aminosalicylic acid.

4. N-Acetyltransferase activity was detected in the cytosol, with a mean of 3.3 nmol min−1 mg−1 of protein. There was no N-acetyltransferase activity in the brush border. There was no difference in enzyme activity between epithelial cells derived from normal, Crohn's disease or ulcerative colitis patients.

5. Preliminary characterization of the N-acetyltransferase enzyme suggests a molecular weight of 150 000.
Response to dynamic exercise in cardiac transplant recipients: implications for control of the sodium regulatory hormone atrial natriuretic peptide
Authors: Singer D. R. J. , Banner N. R. , Cox A. , Patel N. , Burdon M. , Buckley M. G. , MacGregor G. A. , Yacoub M. H.
Published: August 2015

1. To study the importance of cardiac innervation in the regulation of atrial natriuretic peptide, plasma atrial natriuretic peptide levels were measured during symptom-limited, graded exercise on a cycle ergometer in seven male orthotopic cardiac transplant recipients.

2. Resting plasma atrial natriuretic peptide was significantly higher in the transplant recipients than in two control groups, one matched to the transplant recipients (group 1) and the other to the age of the donor heart (group II).

3. The response to exercise of the cardiac transplant recipients was compared with the response of control group II. Mean maximal work load achieved with exercise was around 40% lower in the cardiac transplant recipients. During exercise, plasma atrial natriuretic peptide levels increased in both the cardiac transplant recipients and the control subjects. The increase in plasma atrial natriuretic peptide with exercise was greater in absolute, but less in percentage, terms in transplant recipients than in the control subjects.

4. The increase in mean arterial pressure with exercise was similar in patients and in control subjects; however, heart rate increased in the patients by only 33% compared with a rise of 151% in the control group.

5. These results provide insight into the control of the sodium regulatory hormone atrial natriuretic peptide. First, factors other than a change in heart rate appear of importance in the regulation of atrial natriuretic peptide. Secondly, these findings suggest that cardiac innervation is not of dominant importance in the modulation of atrial natriuretic peptide secretion.
Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats
Authors: Madeddu Paolo , Glorioso Nicola , Soro Aldo , Manunta Paolo , Troffa Chiara , Tonolo Giancarlo , Melis Maria Grazia , Pazzola Antonio
Published: August 2015

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet.

2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2.

3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake.

4. The kallikrein–kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.
Mucolysis of the colonic mucus barrier by faecal proteinases: Inhibition by interacting polyacrylate
Authors: Hutton D. A. , Pearson J. P. , Allen A. , Foster S. N. E.
Published: August 2015

1. Mucolytic (mucus solubilizing) activity in human faeces has been characterized with both purified human and pig colonic mucin and shown to be mediated by proteolysis.

2. Mucolytic activity was demonstrated by: (i) a drop in mucin viscosity; (ii) a substantial reduction in mucin size, from polymer to degraded subunit, as assessed by Sepharose CL-2B gel filtration; (iii) formation of new N-terminal peptides.

3. Mucolytic activity was also followed in faecal extracts by its proteolytic activity using standard succinyl albumin substrate. Proteolysis extended over the pH range 4.5–11.0. Proteolysis was inhibited at pH 7.5 by soybean trypsin inhibitor and phenylmethanesulphonyl fluoride, suggesting the presence of serine proteinases.

4. The polyacrylate carbomer (934P) inhibited both mucolysis of pig colonic mucin and proteolysis of succinyl albumin.

5. Interaction between the polyacrylate (carbomer 934P) and purified human and pig colonic mucin was demonstrated by a marked synergistic increase in solution viscosity (360% above control).

6. The results demonstrate the presence of a mucolytic activity in the human colonic lumen that has the potential to degrade the mucus barrier, and that polyacrylates inhibit this mucolysis and interact to strengthen the colonic mucus barrier. Polyacrylates may therefore have therapeutic potential in inflammatory bowel disease where luminal proteolytic activity can be raised.
Lack of effect of an inspiratory threshold load on plasma atrial natriuretic peptide levels
Authors: Warley A. R. H. , Fontes F. , Wilson M. , Raine A. E. G. , Stradling J. R.
Published: August 2015

1. After a run-in period, six healthy, recumbent, water-loaded male subjects breathed through an inspiratory threshold load for 90 min. To correct for prolonged recumbency, a similar protocol was followed on a separate control day, but without an inspiratory load.

2. A negative intrathoracic pressure of at least 30 cmH2O was required to overcome the threshold load.

3. Urine was collected every 30 min and analysed for sodium concentration.

4. Plasma samples were collected every 30 min and analysed for atrial natriuretic peptide concentration.

5. The inspiratory load had no effect on urine volume, urinary sodium excretion or plasma atrial natriuretic peptide levels.