bluuebunny/crossref_metadata_2025 huggingface dataset:
Erythrocyte Membrane Calcium Adenosine 5′-Triphosphatase Activity in the Spontaneously Hypertensive Rat
Authors: Adeoya Abimbola S. , Norman Robert I. , Bing Robert F.
Published: August 2015

1. Ca2+-adenosine 5′-triphosphatase (Ca2+ −Mg2+ – ATPase) activity was studied simultaneously in calmodulin-deficient erythrocyte ghost membranes and inside-out vesicles (IOVs) from 12-week-old female spontaneously hypertensive rats (SHR) and their matched controls: [Wistar-Kyoto normotensive rats (WKY)], and in detergent extracts of ghost membranes.

2. Both adenosine 5′-triphosphate (ATP)-dependent Ca2+ uptake by IOVs and Ca2+-dependent ATP hydrolysis activity of ghost membranes were reduced significantly in the SHR compared with WKY, when either the calmodulin-independent or calmodulin-stimulated activities were compared.

3. The ratios between Ca2+ uptake and ATP hydrolysis activities in the SHR remained approximately 1.0, showing a proportional reduction in both activities.

4. No difference in affinity for calmodulin was observed between SHR and WKY.

5. No significant difference in Ca2+-dependent ATP hydrolysis activity was observed between SHR and WKY after detergent solubilization of erythrocyte ghost membranes.

6. These results suggest that the number of Ca2+-Mg2+-ATPase units are similar in SHR and WKY and that the reduced activity in the intact SHR membrane is due to altered membrane environment.
Effect of a High Protein Diet in Patients with the Nephrotic Syndrome
Authors: Mansy H. , Goodship T. H. J. , Tapson J. S. , Hartley G. H. , Keavey Pauline , Wilkinson R.
Published: August 2015

1. Twelve patients with the nephrotic syndrome were prescribed for 4 week periods a normal protein diet (NPD) containing 1 g of protein/kg ideal body weight. They were then prescribed for further 4 week periods in random order diets with high (HPD) and low (LPD) protein contents, respectively 2.0 and 0.5 g/kg ideal body weight.

2. Compliance was confirmed by dietary history and measurement of urinary urea excretion.

3. Serum albumin was the same on all diets. Twenty-four hour urinary protein excretion increased progressively with increasing dietary protein (LPD 6.1 g, NPD 8.2 g, HPD 9.2 g). Recumbent plasma renin activity and serum phosphate were significantly increased on HPD (plasma renin activity: LPD 5.7, NPD 4.6, HPD 8.2 pmol of angiotensin I min−1 I−1; serum phosphate: LPD 1.27, NPD 1.26, HPD 1.41 mmol/l).

4. There was no evidence of protein-induced hyperfiltration or hyperperfusion: 51Cr-ethylenediaminetetraacetate and [125I]iodohippurate clearances were similar on all three diets.

5. Since proteinuria, increased plasma renin levels and hyperphosphataemia may contribute to progression of renal failure and because HPD did not improve hypoalbuminaemia, the use of HPD in the nephrotic syndrome should be abandoned.

6. Until it can be established that LPD, which is accompanied by the least proteinuria, does not, with long-term feeding, lead to malnutrition, NPD should be used in the treatment of the nephrotic syndrome.
Cardiovascular Reflex Responses in Patients with Unexplained Syncope
Authors: Wahbha M. M. A. E. , Morley C. A. , Al-Shamma Y. M. H. , Hainsworth R.
Published: August 2015

1. This study was undertaken to determine whether, in a group of patients complaining of recurrent syncopal attacks but with no apparent cause, there was evidence of abnormal cardiovascular reflex control.

2. The steady-state responses of blood pressure, heart rate and cardiac output to head-up tilting were determined in 67 patients using entirely ‘non-invasive’ methods. In some patients we also studied the immediate response of pulse interval to carotid baroreceptor stimulation by neck suction.

3. Two of the patients developed vasovagal attacks during the 20 min test period of head-up tilting. Eighteen others showed postural hypotension, defined as a fall in blood pressure to outside the limits of two sds from the mean values of age-related control subjects.

4. Patients who showed postural hypotension had a mean fall in cardiac output significantly larger than that in age-related control subjects. Responses in the non-hypotensive patients did not differ significantly from controls.

5. Stimulation of carotid baroreceptors resulted in significantly smaller responses of pulse interval in the patients defined as having postural hypotension compared with the non-hypotensive patients and with the age-related control subjects.

6. In some of the patients who did not show postural hypotension during the standard test, the duration of tilt was prolonged for up to 1 h. Five out of 26 patients developed vasovagal attacks. All the vasovagal patients showed an initial tachycardia and the response of pulse interval to neck suction was significantly larger than in the controls.

7. This study has shown that simple non-invasive tests of cardiovascular reflex function can divide patients with poor orthostatic tolerance into two groups: those with evidence of small reflex responses, associated with abnormally large falls in cardiac output during tilting, and those with evidence of overactive reflexes associated with the tendency to develop vasovagal syncope.
Effects of Endothelin on Systemic and Renal Haemodynamics and Neuroendocrine Hormones in Conscious Dogs
Authors: Nakamoto Hidetomo , Suzuki Hiromichi , Murakami Marohito , Kageyama Yo , Ohishi Akira , Fukuda Keiichi , Hori Shingo , Saruta Takao
Published: August 2015

1. The effects of endothelin on systemic and renal haemodynamics and plasma concentrations of neuroendocrine hormones including plasma renin activity, aldosterone, adrenocorticotropic hormone, Cortisol, catecholamines and arginine vasopressin were investigated in 18 conscious dogs.

2. Bolus injection of 4 pmol of endothelin/kg did not cause any significant changes in haemodynamics. Mean arterial pressure was elevated by both doses of 40 pmol/kg [91 ± 2 to 99 ± 2 mmHg (12.1 ± 0.3 to 13.2 ± 0.3 kPa), P < 0.05] or 200 pmol/kg [93 ± 2 to 107 ± 3 mmHg (12.4 ± 0.3 to 14.3± 0.4 kPa), P < 0.01], the latter dose increasing cardiac output (14%, P < 0.05) and heart rate (9%, P < 0.05), and the former reducing these parameters (14% and 8%, P < 0.05, respectively).

3. In contrast with the various changes in systemic haemodynamics, renal blood flow transiently increased immediately after bolus injection in a dose-dependent manner (28%, P < 0.05, 50%, P < 0.01 and 110%, P < 0.01 with 4, 40 and 200 pmol of endothelin/kg, respectively). This transient elevation of renal blood flow was followed by a gradual decrease (16%, P < 0.05; 31%, P < 0.01 and 36%, P < 0.01) at 10 min.

4. All neurohormones were elevated in a dose-dependent manner.

5. Among these hormones, arginine vasopressin and plasma renin activity reached a peak level at 5 min (from 2.21 ± 0.45 to 6.37 ± 0.60 pmol/l, P < 0.01, and from 0.65 ± 0.08 to 1.09 ± 0.10 pmol of angiotensin 1 h−1 ml−1P < 0.01, respectively) after bolus injection of 200 pmol of endothelin/kg, whereas adrenocorticotropic hormone and Cortisol reached a peak level at 15 min (from 6.0 ± 0.7 to 18.2 ± 1.5 pmol/l, P < 0.01, and from 4.4 ± 0.9 to 16.5 ± 2.7 × 10−2 μmol/l, P < 0.01, respectively).

6. These results suggest that endothelin is a potent vasoconstrictive peptide in vivo with a marked effect on the renal vascular system, and that it induces elevation of vasoactive hormones directly and/or through central effects.
Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11β-hydroxysteroid dehydrogenase activity in man
Authors: Stewart P. M. , Wallace A. M. , Atherden S. M. , Shearing C. H. , Edwards C. R. W.
Published: August 2015

1. 11β-Hydroxysteroid dehydrogenase is an enzyme complex consisting of 11β-dehydrogenase and 11-oxoreductase responsible for the interconversion of cortisol to cortisone in man. Inhibition of 11β-dehydrogenase (e.g. after liquorice ingestion) results in cortisol acting as a potent mineralocorticoid. We have evaluated the effect of the synthetic liquorice derivative, carbenoxolone, on this enzyme complex.

2. Carbenoxolone given to six volunteers in metabolic balance produced sodium retention with suppression of the renin-angiotensin-aldosterone system. Plasma potassium fell, although there was no kaliuresis. This was associated with inhibition of 11β-dehydrogenase (as measured by a rise in the plasma half-life of [11α-3H]-cortisol). Unlike liquorice, however, carbenoxolone also inhibited 11-oxoreductase (as measured by the generation of cortisol after oral cortisone acetate).

3. The mineralocorticoid activity of carbenoxolone, like liquorice, is mediated via cortisol by inhibition of 11β-dehydrogenase. Carbenoxolone, however, also inhibits 11-oxoreductase activity and this may relate to its effect on renal potassium excretion.
Blood pressure, left ventricular mass and intracellular calcium in primary hyperparathyroidism
Authors: Dominiczak Anna F. , Lyall Fiona , Morton James J. , Dargie Henry J. , Boyle Iain T. , Tune Tan T. , Murray Gordon , Semple Peter F.
Published: August 2015

1. Blood pressure, left ventricular mass and platelet cytosolic free calcium concentrations were measured in 23 patients with untreated primary hyperparathyroidism, 30 normotensive control subjects and 23 control subjects matched for age, sex and blood pressure. In 12 patients measurements were repeated after parathyroidectomy.

2. Patients with primary hyperparathyroidism had significantly elevated blood pressures (139 ± 6/86 ± 3 mmHg, mean ± sem) compared with control subjects (125 ± 2/78 ± 1 mmHg), but high values persisted after hypercalcaemia was corrected.

3. Despite chronic extracellular hypercalcaemia, intracellular free calcium levels were lower in patients with hyperparathyroidism than in controls matched for age, sex and blood pressure (median concentrations 81.5 nmol/l vs 93 nmol/l, 95% confidence interval 0.1 to 20.1; P < 0.05) and values tended to increase after parathyroidectomy.

4. Left ventricular mass index was increased in the primary hyperparathyroid group as compared with control subjects matched for age, sex and blood pressure (123 g/m2 vs 100 g/m2, 95% confidence interval −36.1 to −3.1; P = 0.03). Parathyroidectomy resulted in a small reduction of the left ventricular mass index (123.5 g/m2 vs 104 g/m2, 95% confidence interval 46.5 to 2.5; P = 0.1) but no change in blood pressure.

5. Hypertension and left ventricular hypertrophy in primary hyperparathyroidism are associated with relatively low levels of free calcium in platelets.
Influence of prior ventilatory experience on the estimation of breathlessness during exercise
Authors: Wilson Rachel C. , Jones P. W.
Published: August 2015

1. The intensity of breathlessness was measured during exercise in nine normal subjects using a modified Borg scale to examine the effect of prior experience of breathlessness on subsequent estimates of breathlessness.

2. Each subject performed four exercise tests, each of which consisted of two identical runs of workload incrementation (run 1 and run 2). An inspiratory resistive load of 3.8 cmH2O s−1 l−1 was applied during the appropriate run of the exercise test to examine the effect of (a) prior experience of ‘loaded’ breathing on breathlessness estimation during ‘unloaded’ breathing, and (b) prior experience of ‘unloaded’ breathing on breathlessness estimation during ‘loaded’ breathing. Run 1 was the conditioning run; run 2 was the run in which the effect of conditioning was measured.

3. There was a good correlation between breathlessness and minute ventilation during both unloaded’ breathing (median r = 0.93) and ‘loaded’ breathing (median r = 0.95).

4. The slope of the Borg score/minute ventilation relationship was greater during ‘loaded’ breathing than during ‘unloaded’ breathing (P < 0.01). There was no difference in mean Borg score between ‘unloaded’ and ‘loaded’ breathing.

5. After a period of ‘loaded’ breathing during run 1, estimated breathlessness was significantly reduced during ensuing ‘unloaded’ breathing in run 2 (P < 0.01) compared with the exercise test in which ‘unloaded’ breathing was experienced throughout both run 1 and run 2.

6. After a period of ‘unloaded’ breathing in run 1, estimated breathlessness was significantly increased during ensuing ‘loaded’ breathing in run 2 (P < 0.01) compared with the exercise test in which the inspiratory load had already been experienced in run 1.

7. Changes in the pattern of breathing (inspiratory time, expiratory time, total breath duration, inspiration time/total breath duration ratio and tidal volume) were not consistent with the changes in breathlessness.

8. We suggest that perception of breathlessness may be influenced by a subject's immediate prior experience of an altered relationship between breathlessness and ventilation.
Free fatty acids stimulate mucin hypersecretion by rabbit gall-bladder epithelium in vitro
Authors: Mingrone G. , Greco A. V. , Mastromattei E. Arcieri
Published: August 2015

1. Mucin, a high-molecular-weight glycoprotein secreted by the gall-bladder and biliary duct epithelium, is a well-known nucleation-prompting factor in experimental and human gall-stone disease.

2. Free fatty acids when incubated in vitro (micellar suspension with 1 mmol/l Tween 40) with rabbit gallbladders can promote abundant mucus secretion.

3. The hexosamine content of rabbit gall-bladder walls, measured by gas-liquid chromatography, was significantly higher in gall-bladders incubated with fatty acids than in control tissues.

4. The biochemical data were supported by ultra-structural findings showing numerous droplets with a translucent content in the perinuclear cytoplasm. Exocytosis was also seen in treated gall-bladders, confirming the secretory nature of the vesicles.

5. These results suggest that free fatty acids, which appear in high amounts when bile lecithins are hydrolysed by phospholipase, play an active role in the gall-stone formation.
Broadband ultrasound attenuation in the os calcis: relationship to bone mineral at other skeletal sites
Authors: McCloskey E. V. , Murray S. A. , Miller C. , Charlesworth D. , Tindale W. , O'Doherty D. P. , Bickerstaff D. R. , Hamdy N. A. T. , Kanis J. A.
Published: August 2015

1. We have examined the relationship between broadband ultrasound attenuation in the os calcis and measurements of bone mineral in the distal forearm and lumbar spine of normal and postmenopausal osteoporotic women.

2. Values of broadband ultrasound attenuation in postmenopausal women with vertebral osteoporotic fractures were significantly lower (35%) than in normal pre-and peri-menopausal women (55.4 ± 3.8 and 79.6 ± 0.8 dB/MHz, respectively).

3. Broadband ultrasound attenuation correlated significantly with bone mineral content measured in the distal forearm by single-photon absorptiometry (r = 0.77, P < 0.0001) and with bone mineral content (r = 0.66, P < 0.0001) and bone mineral density (r = 0.72, P < 0.0001) measured in the lumbar spine by dual-photon absorptiometry.

4. Although significant, these correlations are not sufficiently close to be predictive. However, the accuracy of broadband ultrasound attenuation in discriminating between normal subjects and patients with vertebral fracture compared very favourably with direct measurements in the spine by dual-photon absorptiometry.

5. Broadband ultrasound attenuation, but not the other measurements, correlated significantly with age in the osteoporotic patients (r = 0.50, P < 0.05).

6. These findings may reflect the partial dependence of broadband ultrasound attenuation on the intrinsic trabecular architecture of cancellous bone, the disruption of which contributes to an increase in fracture risk.
A sensitive radioimmunoassay measuring endothelin-like immunoreactivity in human plasma: Comparison of levels in patients with essential hypertension and normotensive control subjects
Authors: Davenport Anthony P. , Ashby Michael J. , Easton Patricia , Ella Sarah , Bedford Joy , Dickerson Claire , Nunez Derek J. , Capper Stephen J. , Brown Morris J.
Published: August 2015

1. A radioimmunoassay has been developed for measuring endothelin-like immunoreactivity in human plasma using an antibody raised against endothelin-1 which also cross-reacts with big endothelin-1 and endothelin-2 but not endothelin-3.

2. The sensitivity of the assay was 1 fmol/tube with inter- and intra-assay coefficients of variation of 13% and 9%, respectively. Cross-reactivity with endothelin-3 and non-endothelin peptides was less than 1%.

3. Endothelin-like immunoreactivity was present in the plasma of hypertensive patients (n = 25) at a concentration of 5.7 ± 0.5 pmol/l (mean ± sem), which was not significantly different from that of age-matched control subjects (5. ± 10.5 pmol/l). At these levels, endothelin-1 is unlikely to function as a circulating hormone.

4. Within the normotensive group, the concentration of endothelin-like immunoreactivity in plasma was positively correlated with mean arterial blood pressure, but in hypertensive patients it showed a significant negative correlation.
Effects of glucose on nitrogen balance during high nitrogen intake in malnourished patients
Authors: Forse R. Armor , Elwyn David H. , Askanazi Jeffrey , Iles Mary , Schwarz Yvonne , Kinney John M.
Published: August 2015

1. The effects of increasing glucose intake on nitrogen balance, energy expenditure and fuel utilization were measured in 12 malnourished adult patients receiving parenteral nutrition with constant, very high nitrogen intake (500 mg of N/kg), high (105 kJ/kg) or low (30 kJ/kg) glucose intake and constant fat intake (7 kJ/kg). Each patient received each diet for 8-day periods in random order.

2. Energy balance and nitrogen balance were determined daily. Blood samples, taken at admission, during 5% (w/v) dextrose (D-glucose) infusion and at the end of days 7 and 8 of each diet, were analysed for urea, glucose, lactate, triacylglycerols, fatty acids, glycerol, 3-hydroxybutyrate, insulin and glucagon.

3. The effect of increasing glucose intake was to increase nitrogen balance by 0.60 ± 0.25 (sem) mg/kJ. At zero energy balance, nitrogen balance was 48 mg day−1 kg−1. This confirms findings of previous studies: that the effects of glucose on nitrogen balance are greater at high than at low nitrogen intakes, and that, in malnourished patients, unlike in normal adults, markedly positive nitrogen balance can be achieved at zero or negative energy balances.

4. Changes in nitrogen balance were due almost entirely to changes in urea excretion.

5. The high nitrogen intake markedly increased plasma insulin and glucagon concentrations and reduced glycerol, fatty acid and 3-hydroxybutyrate concentrations, independent of any glucose effect. Glucagon concentrations were significantly decreased by added glucose intake, an effect not previously seen at low nitrogen intakes. At this high nitrogen intake, the effects of added glucose appear to be mediated by both insulin and glucagon.

6. Unlike the effects at low nitrogen intakes, added glucose caused no increase in energy expenditure (thermogenesis) or creatinine excretion, and almost no increase in glycogen stores.
A non-invasive method of measuring concentrations of rubidium in rat skeletal muscle in vivo by 87Rb nuclear magnetic resonance spectroscopy: implications for the measurement of cation transport activity in vivo
Authors: Syme P. D. , Dixon R. M. , Allis J. L. , Aronson J. K. , Grahame-Smith D. G. , Radda G. K.
Published: August 2015

1. We have used n.m.r. spectroscopy to measure rubidium concentrations in the skeletal muscle of live intact rats. Using a 1.9 T superconducting magnet and an ear-phone coil tuned to both protons (1H) and rubidium (87Rb), it was possible to make measurements of both tissue rubidium content and water content, and from these measurements to obtain the rubidium concentration.

2. The n.m.r. estimate of rubidium concentration in muscle in vivo was found to be a constant 31% (sem 4%) of that estimated by flame atomic absorption spectroscopy in an extract of excised muscle. This is close to the predicted theoretical n.m.r. visibility of 33%. The visibility was constant for muscle rubidium concentrations ranging between 10 and 34 mmol/l.

3. Rubidium concentration measurement by this method is unaffected by variations in sample geometry, sample volume, tissue conductivity, coil tuning and amplifier gain.

4. By using this method to measure changes in tissue rubidium concentration with time in the same animal, it should now be possible to assess the activity of ion transport systems, such as sodium- and potassium-activated adenosine triphosphatase in vivo, by measuring the rates of change of tissue rubidium concentrations during the administration of rubidium salts.

5. This method could also be used to measure the absolute concentration of any n.m.r.-visible nucleus and could be applied to man.
Is hydrochlorothiazide-induced hypocalciuria due to inhibition of prostaglandin E2 synthesis?
Authors: Caló Lorenzo , Cantaro Salvatore , Marchini Francesco , Giannini Sandro , Castrignano Rocco , Gambaro Giovanni , Antonello Augusto , Baggio Bruno , D'Angelo Angela , Williams Hibbard , Borsatti Arturo
Published: August 2015

1. Since prostaglandin E2 could play a role in idiopathic hypercalciuria, and considering the well-established hypocalciuric action of hydrochlorothiazide, we have evaluated the effect of 15 days' treatment with hydrochlorothiazide in 10 hypercalciuric male stone-formers on urinary Ca2+ and prostaglandin E2, as well as on plasma bicyclo-prostaglandin E2, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone.

2. In addition to lowering urinary Ca2+ (P <0.001), hydrochlorothiazide also promoted a significant fall in urinary prostaglandin E2 (P <0.001), plasma bicyclo-prostaglandin E2 (P <0.001) and 1,25-dihydroxyvitamin D (P <0.01), and an increase in plasma parathyroid hormone (P <0.025), whereas plasma 25-hydroxyvitamin D was unchanged.

3. A positive correlation between urinary Ca2+ and prostaglandin E2 was present before (P <0.00005), but not after, hydrochlorothiazide. Plasma bicyclo-prostaglandin E2 and plasma 1,25-dihydroxyvitamin D were positively correlated both before (P <0.005) and after (P <0.005) hydrochlorothiazide, as was also the percentage change in each induced by the drug (P <0.05). Furthermore, the changes in plasma 25-hydroxyvitamin D and plasma 1,25-dihydroxyvitamin D after hydrochlorothiazide were negatively correlated (P <0.05).

4. It is suggested that a block of prostaglandin E2 synthesis plays a role in the effect of hydrochlorothiazide on Ca2+ metabolism, most probably through an inhibition of 1α-hydroxylase activity.
Synthesis and secretion of atrial natriuretic factor during chronic hypoxia: A study in the conscious instrumented rat
Authors: Raffestin Bernadette , Adnot Serge , Mercadier Jean Jacques , Levame Micheline , Duc Philippe , Braquet Pierre , Viossat Isabelle , Chabrier Pierre Etienne
Published: August 2015

1. To investigate the mechanisms leading to enhanced synthesis and release of atrial natriuretic factor during chronic hypoxia, we measured immunoreactive plasma atrial natriuretic factor, blood gases, packed cell volume, pulmonary artery pressure and systemic artery pressure in male Sprague–Dawley rats exposed to 1, 2 or 3 weeks of normobaric hypoxia. Rats were implanted with pulmonary and carotid artery catheters and studied conscious, 23 h after return to hypoxia.

2. The concentration of atrial natriuretic factor messenger RNA was measured in the right and left ventricular free walls of rats exposed to 3 weeks of hypoxia and in normoxic control rats.

3. There was a trend for plasma atrial natriuretic factor to increase with the duration of exposure to hypoxia but only the 3-week hypoxic rats had a significantly higher level (1080 ± 193 pg/ml) than the normoxic control rats (318 ± 46 pg/ml, P <0.05, mean ± sem). When all the data from normoxic and hypoxic rats were considered together, plasma atrial natriuretic factor was positively correlated with packed cell volume (r = 0.66, P <0.001), pulmonary artery pressure (r = 0.68, P <0.002), and the index of right ventricular hypertrophy (r = 0.54, P <0.01), but after analysis of partial correlation, packed cell volume was the only independent contributing factor to the variance in the level of plasma atrial natriuretic factor (r2 = 0.24).

4. Three weeks exposure to hypoxia produced a 3.4-and a 2.9-fold increase in atrial natriuretic factor messenger RNA concentration in the right and left ventricles, respectively, suggesting that the increase in pulmonary artery pressure and the resulting right ventricular hypertrophy may not be the only trigger for the increase in atrial natriuretic factor synthesis and that both ventricles may contribute to the increase in plasma atrial natriuretic factor.
Rapid Communication: Response of the Human Brain to a Hypercapnic Acid Load in Vivo
Authors: Cadoux-Hudson T. A. D. , Rajagopalan B. , Ledingham J. G. G. , Radda G. K.
Published: August 2015

1. The aim of this investigation was to measure the change in intracellular pH of human brain in vivo in response to hypercapnia.

2. Five healthy male subjects inspired air for 20 min and then 5% CO2/95% O2 for 30 min, of which the first 10 min was used to achieve a steady-state end-tidal CO2 measurement.

3. 31P nuclear magnetic resonance spectroscopy was used to measure intracellular pH while breathing air and during hypercapnia. Simultaneous localization between superficial and deep brain was achieved by using the phase-modulated rotating frame imaging technique. One subject volunteered to breath air for a further phase-modulated rotating frame imaging study while recovering from hypercapnia.

4. End-tidal CO2 increased when breathing 5% CO2/95% O2 (on air, 5.57 ± 0.21%; on 5% CO2/95% O2, 6.41 ± 0.16%; rise = +0.84 ± 0.09%; means ± sem) causing a reduction in brain intracellular pH, which was more pronounced in deep brain (5 cm = mainly white matter, from 7.02 ± 0.006 pH units to 6.96 ± 0.001 pH units, mean ± sem) than in superficial brain (2 cm = mainly grey matter, from 7.02 ± 0.006 pH units to 7.00 ± 0.006 pH units, mean ± sem).

5. The white matter responded to hypercapnia with a greater fall in intracellular pH than the grey matter. This could either be due to differences in blood flow between grey and white matter in response to hypercapnia or to differences in intracellular pH regulation/buffering between these two tissues.
Effects of Chronic Administration of an Angiotensin-Converting Enzyme Inhibitor on Angiotensin-Converting Enzyme Activity in the Pars Recta of Rabbits
Authors: Praddaude Françoise , Tran-Van Tuan , Marchetti Jeannine , Girolami Jean-Pierre , Ader Jean-Louis
Published: August 2015

1. To determine whether chronic angiotensin-converting enzyme inhibition induces a decrease in proximal tubular angiotensin-converting enzyme activity, urine and blood samples were collected in conscious New Zealand rabbits before and after 16 days administration in drinking water of low doses of captopril (2.6 ± 0.6 mg 24 h−1 kg−1), high doses of captopril (7.6 ± 0.9 mg 24 h−1 kg−1) or no captopril (controls). The kidneys were then removed and angiotensin-converting enzyme activity was determined in isolated pars recta of microdissected nephrons as pmol of tritiated hippurylglycylglycine substrate hydrolysed min−1 of incubation and mm−1 of tubule.

2. Both low and high doses of captopril significantly decreased plasma angiotensin-converting enzyme activity and increased plasma renin activity, thus indicating an effective inhibition of circulating angiotensin-converting enzyme. Both low and high doses of captopril also significantly decreased mean arterial pressure and increased water intake and urine flow rate. Neither dose modified creatinine clearance and absolute and fractional sodium excretion.

3. None of the doses altered urinary kallikrein excretion. Urinary excretion of kinins was increased by 98.7% compared with control rabbits by the high dose of captopril (402 ± 152 vs 251 ± 104 ng/24 h, P < 0.01) but was unchanged by the low dose of captopril.

4. Angiotensin-converting enzyme activity in the pars recta was lower in rabbits given the high dose of captopril than in control rabbits (17.6 ± 7.2 vs 37.3 ± 9.0 pmol min−1 mm−1, P < 0.01) but was not decreased in rabbits given the low dose of captopril (40.4 ± 5.0 pmol min−1 mm−1).

5. Our results indicate that only high doses of captopril are able to inhibit tubular angiotensin-converting enzyme activity in rabbit kidneys. Changes in arterial pressure and water handling are not related to tubular angiotensin-converting enzyme inhibition. The increase in urinary kinins with no change in kallikrein excretion could be the result of a reduction in proximal kininase activity induced by the higher dose.
Direct Vascular Effects in the Rat of the Vehicles Used for the Intravenous and Oral Administration of Cyclosporin A
Authors: Amorena C. , Castro A. , Müller A. , Villamil M. F.
Published: August 2015

1. The contraction and relaxation responses to the polyoxyethylated vehicles currently used for the intravenous and oral administration of cyclosporin A in allograft recipients were studied in isolated rat aorta. The results were compared with those obtained with commercially available cyclosporin A for intravenous administration.

2. None of these compounds affected resting tension, noradrenaline-induced contraction or endothelium-independent relaxation produced by sodium nitroprusside or bumetanide. However, they all reversed the relaxation induced by acetylcholine, carbamylcholine or adenosine 5′-triphosphate, by a factor of approximately 66%.

3. This reversal of relaxation was unaffected by indomethacin and did not require the presence of cyclosporin A in the vehicles, and was completely abolished by l-arginine (3 × 10−-5 mol/l).

4. It is concluded that vehicles used for commercial preparations of cyclosporin A interfere with the synthesis of endothelium-derived relaxing factor at an early stage during which l-arginine is made available for enzymatic degradation.
Physiological Levels of Plasma Non-Esterified Fatty Acids Impair Forearm Glucose Uptake in Normal Man
Authors: Walker M. , Fulcher G. R. , Catalano C. , Petranyi G. , Orskov H. , Alberti K. G. M. M.
Published: August 2015

1. The purpose of the present study was to maintain physiological plasma non-esterified fatty acid levels and to (i) examine their effect on skeletal muscle insulin-stimulated glucose uptake and metabolite exchange using the forearm technique, and (ii) evaluate their effect on whole-body glucose uptake and fuel oxidation.

2. Intralipid (10%) and heparin (Lipid) or saline (Control) was administered to eight healthy male subjects on separate occasions for 210 min. Insulin, glucagon and somatostatin were administered from 60 to 210 min in each study and euglycaemia was maintained.

3. Plasma non-esterified fatty acid levels plateaued at 420 ±50 μmol/l with the Lipid infusion but were completely suppressed during the Control clamp. Forearm non-esterified fatty acid uptake increased with the Lipid infusion (+ 50±10 nmol min−1 100 ml−1 of forearm) and was accompanied by a significant decrease in forearm glucose uptake (+ 3.23 ± 0.25 versus + 3.65 ± 0.35 μmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05) and alanine release (–84±12 versus −113 ± 15 nmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05).

4. Whole-body glucose uptake showed a comparable decrease with the Lipid infusion (6.36 ±0.81 versus 6.85±0.66 mg min−1 kg−1; P < 0.05) and was accompanied by an increase in lipid oxidation (0.33 ±0.08 versus 0.16 ±0.05 mg min−1 kg−1; P < 0.02) and a decrease in glucose oxidation (2.93 ±0.23 versus 3.30±0.20 mg min−1 kg−1; P < 0.05).

5. We conclude that the maintenance of physiological plasma non-esterified fatty acid levels is associated with a decrease in forearm and whole-body insulin-stimulated glucose uptake. The changes in substrate oxidation and forearm alanine exchange provide support for the operation of the glucose—fatty acid cycle.
Errors Inherent in the Primed Infusion Method for the Measurement of the Rate of Glucose Appearance in Man when Uptake is not Forced by Glucose or Insulin Infusion
Authors: Heath D. F.
Published: August 2015

1. My aim was to investigate, by mathematical simulation, the errors inherent in the measurement by the primed infusion method of the rate of appearance of glucose in man when turnover was as low or lower than in overnight-fasted normal subjects (control subjects). The simulations were based on published data for means and variances of turnover rates and concentrations in non-diabetic subjects and diabetic patients.

2. Systematic errors (bias) were shown to be considerable whether or not the Steele equation was used, unless run-times were longer than is customary. Errors were greater the lower the turnover rate, and were greatest in patients with diabetes, owing to insulin resistance. Studies of, for example, control subjects, age, obesity, exercise, sepsis and injury, are, however, all likely to be affected.

3. Estimates of variance, within-group means, between-group differences and slopes of rate—concentration relationships were all biased. Entirely spurious results appeared statistically significant.

4. When the Steele equation was not used, run-times had to exceed 3 h in control subjects and 10 h in some diabetic patients to reduce bias to acceptable levels. The nature of the bias depended on how the priming dose/infusion rate ratio was chosen. Each choice implies a particular hypothesis about the values of the rate of appearance of glucose, their variance, and how they are related to concentration. The bias was always such as to favour that hypothesis.

5. When the Steele equation was used, the accessible glucose space (pool fraction × distribution volume) had to be correct to 20–30 ml to avoid unacceptable bias in some patients in runs 4 h long. The space is not known this accurately. Theoretically, in the near-steady metabolic states considered, the pool fraction should be near 1.00, i.e. the accessible space should be near the glucose distribution volume of 200–300 mg/kg. There is some confirmatory experimental evidence.

6. Large random errors from variance of specific (radio)activity measurements when the Steele equation is used can be reduced by a suitable choice of protocols.

7. The propagation of errors is too complex to permit correction of results. It is essential to choose protocols that can be shown to give results that are acceptably bias-free. Ways of doing this are discussed.
Effect of Sodium-Transport Inhibitors on Airway Smooth Muscle Contractility in Vitro
Authors: Knox Alan J. , Ajao Paul , Britton John R. , Tattersfield Anne E.
Published: August 2015

1. To determine whether alterations in membrane sodium transport in airway smooth muscle can alter its contractility, we studied the effect of ouabain (a Na+/K+-adenosine triphosphatase inhibitor) and amiloride on contractile responses in bovine trachea and human bronchial rings in a series of studies.

2. Ouabain (10−6–10−4 mol/l) caused concentration-related contraction of bovine trachea with a maximum effect at 30 min; the mean increases in tension with 10−6, 10−5 and 10−4 mol/l ouabain were 19, 27, and 32%, respectively, of the maximum response seen with 10−3 mol/l histamine (n = 6). In human bronchial rings, ouabain (10−5 mol/l) caused a mean contraction which was 40% of the maximum response to methacholine (n = 8).

3. Calcium-free fluid (plus ethylenediaminetetra-acetic acid) and nifedipine (10−5 mol/l) inhibited ouabain-induced contractions, suggesting that contraction was mediated in part by calcium entry via voltage-dependent calcium channels. Phentolamine (10−5 mol/l) was without effect.

4. Ouabain (10−5 mol/l) did not alter histamine responsiveness in bovine trachea or methacholine responsiveness in human bronchial rings.

5. Amiloride did not affect resting tone in bovine trachea but caused a concentration-dependent relaxation of bovine tracheal strips preconstricted with carbachol, 10−3 mol/l amiloride relaxing strips completely over 15 minutes (n = 8). Pretreatment with amiloride significantly inhibited contraction produced by both histamine and carbachol in a dose-related manner, 10−5, 10−4 and 10−3 mol/l amiloride shifting the concentration of histamine producing 50% maximal contraction by 3-, 8- and 35-fold (n = 10) and that of carbachol by 1.4-, 6- and 86-fold (n = 8), respectively.

6. Amiloride also reduced the contraction produced by 10−4 mol/l ouabain from 32% (control) to 7% of the maximum histamine response.

7. Our results suggest that alterations in cell membrane sodium transport modify the contractile properties of airway smooth muscle.
Studies of the Porcine Intestinal Calcitriol Receptor in Pseudo-Vitamin D Deficiency Rickets Type I
Authors: Schröder B. , Kaune R. , Harmeyer J.
Published: August 2015

1. Calcitriol (1,25-dihydroxyvitamin D3) concentrations in plasma of humans and pigs with pseudo-vitamin D deficiency rickets type I (PVDRI) have been reported to be significantly lower than in normal subjects and animals. Sometimes, however, calcitriol concentrations are relatively high in these subjects and animals (50–80 pmol/l) and nevertheless clinical symptoms of rickets develop. We have studied whether or not the development of rachitic lesions in piglets with PVDRI is due to altered binding properties of the intestinal calcitriol receptor in addition to the defective renal production of calcitriol. PVDRI piglets with clinical and biochemical symptoms of rickets (hypocalcaemia, increased activity of alkaline phosphatase) and with calcitriol concentrations in plasma of 83.7 ± 4.2 pmol/l (n = 7) were used. They were compared with unaffected piglets with normal calcitriol concentrations (178.0 ± 17.7 pmol/l, n = 9).

2. The equilibrium dissociation constant (Kd) of the receptor in the PVDRI piglets (0.31 ± 0.05 nmol/l) and in control piglets (0.33 ± 0.05 nmol/l) and the maximum binding capacity (Bmax.) (674 ± 103 and 719 ± 122 fmol/mg of protein, respectively) were not different (n = 9).

3. The association rate constant (kass) at 4°C [0.15 × 107 and 0.24 × 107 (mol/l)−1 min−1] and the dissociation rate constant (kdiss) (0.40 × 10−3 and 0.48 × 10−3 min−1; half-life of dissociation = 24.1 and 28.9 h, respectively) were also not different between diseased and control piglets.

4. No differences between PVDRI and control piglets were also found for the relative molecular mass (47 500 and 47700, respectively) and the Stokes' radius (3.04 and 3.05 nm, respectively) of the calcitriol receptor.

5. It is concluded that the intestinal calcitriol receptor of this animal model functions normally and that changes in binding properties and concentration of the intestinal calcitriol receptor do not contribute to the development of rachitic lesions in PVDRI piglets.
Stimulation of Active Renin Release in Normal and Hypertensive Pregnancy
Authors: Brown Mark A. , Zammit Vivienne C. , Adsett Delma
Published: August 2015

1. Active plasma renin concentration but not total renin concentration is reduced in women with pregnancy-induced hypertension compared with normotensive pregnant women. This study was conducted to determine whether women with pregnancy-induced hypertension are able to stimulate release of active renin.

2. Active plasma renin concentration was measured as the generation of angiotensin I at physiological pH in the presence of excess renin substrate, and total renin concentration was determined in the same way after trypsin activation. Inactive plasma renin concentration was calculated as the difference between total renin and active plasma renin concentrations.

3. Resting active plasma renin concentration was significantly greater in third-trimester primigravidae compared with normotensive non-pregnant women and active plasma renin and total renin concentrations rose significantly without a fall in inactive plasma renin concentration in both groups after 2 h ambulation, suggesting increased release of active plasma renin and not conversion of circulating inactive to active renin. These responses were blunted in women taking oral contraceptives.

4. Although the active plasma renin concentration was significantly reduced in third-trimester primigravidae with pregnancy-induced hypertension, total renin concentration was not significantly different compared with normotensive women of similar gestation and in both groups 30 min 60° head-up tilt increased active but not inactive plasma renin concentration.

5. These studies show that in normal pregnancy active plasma renin concentration can be stimulated to a similar extent as in non-pregnant women, despite a higher resting level. This appears to be due to increased secretion of active plasma renin rather than conversion of circulating inactive to active renin. Women with pregnancy-induced hypertension are also still able to stimulate secretion of active renin despite resting concentrations similar to those of non-pregnant women. These data suggest that in pregnancy-induced hypertension basal secretion of active renin is prematurely reset to that in the non-pregnant state but that secretion of active renin responds normally to posture.
Blood Pressure, Heart Rate and Neuroendocrine Responses to a High Carbohydrate and a High Fat Meal in Healthy Young Subjects
Authors: Heseltine D. , Potter J. F. , Hartley G. , MacDonald I. A. , James O. F. W.
Published: August 2015

1. The responses of blood pressure, heart rate, autonomic function and plasma insulin to a high carbohydrate and a high fat meal of equivalent energy value were studied in nine young volunteers.

2. Neither meal produced a significant change in supine or erect blood pressure. The high carbohydrate meal, however, resulted in an overall rise in both supine (6 beats/min) and erect (6 beats/min; P < 0.05) heart rate, no such changes being seen after the high fat meal.

3. Plasma noradrenaline levels increased by a maximum of 126% at 90 min (0.98 to 2.22 nmol/l) after the high carbohydrate meal but were virtually unchanged after the high fat meal (P < 0.01). Parasympathetic function showed no between-meal differences. Plasma insulin and glucose levels were significantly higher after the high carbohydrate meal than after the high fat meal. No postprandial difference in packed cell volume was found between meal types.

4. We conclude that, in young subjects, the postprandial blood pressure after a high carbohydrate meal is maintained by an increase in heart rate associated with increased sympathetic nervous system activity. These changes are at variance with the blood pressure and heart rate responses seen in the elderly after a high carbohydrate meal. A high fat meal has no significant cardiovascular or neuroendocrine effects in the young or old. The nutrient composition of meals has to be taken into account when studying the postprandial cardiovascular and neuroendocrine responses in the young.
Vascular Hypertrophy, Renin and Blood Pressure in the Young Spontaneously Hypertensive Rat
Authors: Morton James J. , Beattie Elisabeth C. , Griffin Sheila A. , MacPherson Fiona , Lyall Fiona , Russo Domenico
Published: August 2015

1. Cardiovascular reactivity, blood vessel morphology, blood pressure and the activity of the renin—angiotensin system were determined in the 3-week-old spontaneously hypertensive (SHR), Wistar—Kyoto (WKY) and outbred Wistar (WIS) rat.

2. In an isolated perfused mesenteric artery preparation the SHR had a significantly increased maximum response to KCl and noradrenaline (P < 0.02) compared with the WKY. Using a myograph, vascular structure was measured over a range of resistance arteries and showed a significant correlation between lumen diameter and both media cross-sectional area and thickness, with the regression line for the SHR shifted upwards indicating both increased media area and thickness. This was associated with a slight, but significant, narrowing of the lumen (P < 0.01) and an increased media/lumen ratio (0.049 ±0.01, 0.034 ±0.007, 0.036 ±0.008 for SHR, WKY and WIS, respectively, means ±sd P < 0.001). The SHR had a greater heart/body weight ratio than either the WKY or the WIS (P < 0.001).

3. Both mesenteric artery and membrane protein content were higher in the SHR, indicating an increase in cell size or number.

4. Plasma renin activity (means ±sd) was lower in the SHR (1.0 ± 0.7 pmol of angiotensin I h−1 ml−1) than in the WKY (2.2±1.2 pmol of angiotensin I h−1 ml−1, P < 0.001) but not different from that in the WIS (1.2±0.8 pmol of angiotensin I h−1 ml−1). Mesenteric artery vascular renin concentration was also lower in the SHR (P = 0.06). Plasma angiotensin II concentration (mean±sd) was similarly lower in the SHR (11.9 ±3.8 fmol/ml) than in the WKY (18.8 ± 6.2 fmol/ml, P < 0.001) but not different from that in the WIS (14.5 ±5.8 fmol/ml). There was no difference in angiotensin II receptor number or affinity between the three rat strains.

5. Quiescent intra-arterial blood pressure was significantly higher in the SHR both 1 and 2 days after cannula insertion. On day 2 the pressure (mean ± sd) in the SHR was 112.7 ± 19.9 mmHg, in the WKY 81.1 ± 14.4 mmHg and in the WIS 75.1 ± 7.8 mmHg (P < 0.001).

6. These data indicate the presence of marked vascular and cardiac hypertrophy in the SHR at a very early period in its development. Blood pressure is elevated and there is no overactivity of the renin system. We conclude that, at this time, there is no prehypertensive phase nor is there evidence of angiotensin II-mediated pressure-independent mechanism in the hypertrophic development.
Limits of brain tolerance to daily increments in serum sodium in chronically hyponatraemic rats treated with hypertonic saline or urea: advantages of urea
Authors: Soupart Alain , Stenuit Alain , Perier Olivier , Decaux Guy
Published: August 2015

1. At present there is no consensus about the optimal management of hyponatraemia to prevent demyelinating brain lesions. We have evaluated in a large series of rats (n = 136) the protective role of urea for the brain in the treatment of severe chronic hyponatraemia. Urea (group I, n = 51) was compared with hypertonic saline in boluses (group II, n = 46) and with hypertonic saline in divided doses (group III, n = 39). Treatment was administered intraperitoneally over 48 h. The severity of brain lesions was assessed by histological scoring.

2. For 95% of the injured animals treated with hypertonic saline, brain lesions appeared for an absolute increment in serum Na+ concentration (δSNa+) of 20 mmol day−1 l−1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (δSNa+ 20–23 mmol day−1 l−1) 89% (group III) to 100% (group II) of the animals were injured. This limit can be reached rapidly, as attested by the comparable severity of brain lesions observed in group II (mean δSNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean δSNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily δSNa+.

3. A correction above the threshold of 20 mmol day−1 l−1 is as toxic during the first 24 h as during the second day of the treatment. This can be deleterious even if a mildly hyponatraemic level (>120 <129 mmol/l) is achieved after 48 h. The maximum δSNa+ over 48 h tolerated by the brain can exceed 30 mmol/l (31−42 mmol/l), with a correction of serum Na+ concentration up to a normonatraemic level, provided that the successive daily δSNa+ was not greater than 20 mmol/l. The severity of the pre-existing hyponatraemia does not influence the outcome of the correction phase.

4. We have confirmed the protective effect of urea against the development of brain damage when used to correct hyponatraemia. The threshold of tolerance to daily δSNa+ after urea is identical to the limit defined for hypertonic saline, but a further rise in serum Na+ concentration (range of daily δSNa+ >23 >30 mmol/l) leads to a significantly lower incidence (47%, P <0.01 compared with group II and P <0.02 compared with group III) and severity (P <0.03 compared with group II and P <0.005 compared with group III) of neurological complications.