bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of osteomalacia in British Asians: A comparison of clinical score with biochemical measurements
Authors: Nisbet J. A. , Eastwood J. B. , Colston K. W. , Ang L. , Flanagan A. M. , Chambers T. J. , Maxwell J. D.
Published: August 2015

1. In a prospective study of 160 Asian outpatients, plasma calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D and parathyroid hormone were compared with a clinical score to determine which measurements singly or in combination were most useful in the detection of osteomalacia.

2. Bone biopsies were performed in 45 of 48 patients considered to be at risk of osteomalacia. Of the 39 quantifiable bone biopsies, nine showed unequivocal osteomalacia, 13 were judged to be borderline and 17 biopsies were normal.

3. The clinical score was highly sensitive, identifying eight of nine patients with osteomalacia, but not specific, six of 17 normal patients having an abnormal score.

4. Plasma parathyroid hormone was the best single biochemical test for identifying osteomalacia. By using a discriminant function based on parathyroid hormone and alkaline phosphatase, it was possible to classify 96% cases correctly; a discriminant function utilizing calcium, phosphate and alkaline phosphatase was successful in 85% of cases. It was not possible to discriminate between histological groups on the basis of plasma 25-hydroxyvitamin D values.

5. We confirm that the clinical score is a useful and inexpensive screening test for osteomalacia in British Asians. In those patients with an abnormal score we suggest that parathyroid hormone and alkaline phosphatase are measured. Where both parathyroid hormone and alkaline phosphatase are high, in the absence of hypercalcaemia, histological osteomalacia is extremely likely.
Bradykinin has no acute effect on the response of forearm blood flow to sympathetic stimulation in man
Authors: Cullen M. J. , Cockcroft J. R. , Webb D. J.
Published: August 2015

1. Six healthy male subjects received 0.9% (w/v) NaCl (saline) followed by incremental doses of bradykinin (1, 3 and 10 pmol/min), via the left brachial artery. Blood flow and the response of blood flow to lower-body negative pressure were measured in both forearms during infusion of saline and each dose of bradykinin.

2. Bradykinin produced a moderate and dose-dependent increase in blood flow in the infused, but not the non-infused, forearm. Lower-body negative pressure produced an approximately 15–20% reduction in blood flow in both forearms, and this response was unaffected by local infusion of bradykinin.

3. Bradykinin, in contrast to angiotensin II, had no acute effect on peripheral sympathetic responses to lower-body negative pressure. We conclude that, in forearm resistance vessels in man, withdrawal of angiotensin II, rather than accumulation of bradykinin, is likely to account for the attenuation of peripheral sympathetic responses after acute administration of a converting-enzyme inhibitor.
Influences of propranolol and atenolol on the circadian rhythm of heart rate in elderly patients with essential hypertension
Authors: Shimamoto Hiroyuki , Shimamoto Yoriko , Sakata Shogo
Published: August 2015

1. The influence of long-acting propranolol and of atenolol on the circadian rhythm of heart rate was assessed using 24 h electrocardiographic recordings in elderly patients with essential hypertension. Eighteen elderly patients were investigated before treatment and after 12 weeks on 60 mg of long-acting propranolol once a day; 21 elderly patients were studied before treatment and after 12 weeks on 50 mg of atenolol once a day. The mean hourly heart rate in 24 h electrocardiographic recordings was used to fit cosine curves by the statistical technique of least squares, and the following parameters were estimated: mesor (rhythm-adjusted mean of the heart rate), amplitude (one-half of the total diurnal variation of the heart rate) and acrophase (the time when the heart rate was at its peak above the mean).

2. The cosine curves were fitted with a P value of 0.01 or less before and after treatment in all patients.

3. In the long-acting propranolol group, the mesor and amplitude were reduced significantly after treatment. The acrophase appeared significantly earlier after treatment than before treatment.

4. In the atenolol group, the mesor and amplitude decreased significantly after treatment. However, the acrophase did not change with treatment.

5. We conclude that both propranolol and atenolol decrease the mesor and amplitude through blocking cardiac β1-receptors, and that only propranolol may have some effects on the central nervous system, resulting in the circadian phase shift.
Airway β-adrenoceptor number in cystic fibrosis and asthma
Authors: Sharma Rajiev K. , Jeffery Peter K.
Published: August 2015

1. Maximal binding capacity (Bmax.) and the dissociation constant (KD) for the β-adrenoceptor antagonist 125I-cyanopindol were estimated in membrane preparations of hilar, lobar/main bronchi (level 1) and peripheral lung (level 11) of grossly normal lungs resected for bronchial carcinoma. The tissue distribution of 125I-cyanopindol-binding sites was assessed by autoradiography of complementary cryostat sections. The data obtained from the resections for carcinoma and bronchiectasis were used as disease controls for comparison with those obtained from patients with cystic fibrosis and asthma.

2. In carcinoma controls, mean Bmax. values (± sem) for airway levels 1 and 11 were 89 ± 4 and 133 ± 6 fmol/mg of protein, respectively (P <0.01). The corresponding KD values at each airway level were similar, i.e. 29 ± 2 and 33 ± 1 pmol/l, respectively. Autoradiography revealed that there was dense labelling of bronchial and bronchiolar epithelium and most strikingly of the alveolar wall.

3. Compared with carcinoma controls, mean Bmax. values in cystic fibrosis were significantly reduced in membrane preparations of both airway levels 1 and 11 (P <0.01). Autoradiography showed the reduction was most apparent in alveolar wall and bronchial epithelium.

4. There was a tendency to reduction of Bmax. in membrane preparations from patients with bronchiectasis at airway level I, but this failed to reach statistical significance. Autoradiography demonstrated that the density of labelling was significantly reduced in bronchial epithelium and bronchial smooth muscle as compared with carcinoma controls (P <0.01).

5. The Bmax. values were not significantly altered in membranes prepared from both airway levels in asthma, albeit there was a tendency towards reduction in Bmax. at level 1. At this level autoradiography demonstrated significantly reduced labelling of bronchial epithelium (P>0.01) and submucosal glands (P>0.05) but not of bronchial smooth muscle.

6. It is most likely that the reduction in β-adrenoceptor number that we have found in cystic fibrosis is secondary to pulmonary infection and airway inflammation. Its relationship to the primary defect remains unclear.
Increased spillover of dopa into arterial blood during dietary salt loading
Authors: Grossman Ehud , Hoffman Aaron , Chang Peter C. , Keiser Harry R. , Goldstein David S.
Published: August 2015

1. We measured urinary excretion rates of dopamine (3,4-dihydroxyphenethylamine) and dopa (3,4-dihydroxyphenylalanine) and the spillover rate of dopa into arterial blood during dietary salt loading in conscious Dahl salt-sensitive and salt-resistant rats with intact or denervated kidneys.

2. Dopa spillover was calculated from the steady-state clearance of intravenously infused l-[3H]dopa and arterial levels of endogenous dopa.

3. Daily excretion rates of dopa and dopamine increased by about sixfold during salt loading in both rat strains. Bilateral renal denervation delayed these increases and the natriuretic responses.

4. During dietary salt loading, dopa spillover increased to approximately the same extent as simultaneously measured dopamine excretion.

5. The results suggest that increases in urinary excretion of dopamine during dietary salt loading can be accounted for by increases in the release of dopa into the bloodstream and that the renal nerves contribute to the dopa and dopamine excretory responses.
Dissociation between uric acid and urea clearances in the syndrome of inappropriate secretion of antidiuretic hormone related to salt excretion
Authors: Decaux G. , Prospert F. , Cauchie P. , Soupart A.
Published: August 2015

1. Our purpose was to determine why hypouricaemia is more frequently observed than hypouraemia in the syndrome of inappropriate secretion of antidiuretic hormone. We have retrospectively analysed the scores of 35 patients with a chronic form of hyponatraemia related to the syndrome of inappropriate secretion of antidiuretic hormone and studied prospectively six patients.

2. The patients with high fractional excretion of filtered urea (>55%) presented lower blood urea and lower salt excretion than the patients with normal fractional excretion of filtered urea, despite similar levels of hyponatraemia and of osmotic and uric acid clearances. In six hyponatraemic patients, an increase in salt intake was accompanied by a decrease in fractional excretion of filtered urea. In the syndrome of inappropriate secretion of antidiuretic hormone, the fractional excretion of filtered urea was inversely correlated to the fractional excretion of filtered sodium (r = −0.66; P <0.001), whereas the fractional excretion of filtered uric acid was not dependent on sodium excretion.

3. Hypouraemia with high fractional excretion of filtered urea in patients with the syndrome of inappropriate secretion of antidiuretic hormone is related to low urinary sodium excretion and thus reflects low sodium intake.
Splenic responses to acute insulin-induced hypoglycaemia in humans
Authors: Fisher B. M. , Gillen G. , Hepburn D. A. , Dargie H. J. , Barnett E. , Frier B. M.
Published: August 2015

1. The effects of acute hypoglycaemia on the spleen were examined in normal humans using radioisotopic techniques, complemented by ultrasonic examination of the spleen. Hypoglycaemia had a modest effect on splenic area, measured by ultrasonography, which declined to 62 ± 6% (mean ± sem) of the basal value after the onset of the acute hypoglycaemic reaction.

2. Hypoglycaemia had a pronounced effect on the splenic radioactivity, which decreased significantly to a mean of 10 ± 7% of basal radioactivity at 15 min after the onset of hypoglycaemia. The splenic image completely disappeared at some time after hypoglycaemia in all subjects.

3. The reduction of splenic radioactivity was abolished during non-selective α-adrenergic blockade with phentolamine, but was unaffected by β-adrenergic blockade with propranolol, or cholinergic blockade with atropine, which suggests that the response of vessels perfusing the spleen is mediated by α-adrenoceptors.
Atrial natriuretic peptide and chronic renal effects of changes in dietary protein and sodium intake in man
Authors: Doorenbos C. J. , Iestra J. A. , Papapoulos S. E. , Odink J. , Van Brummelen P.
Published: August 2015

1. Plasma levels of atrial natriuretic peptide and several other hormones were measured and related to the renal responses to chronic changes in the dietary intake of protein and sodium, alone and in combination. Eight healthy subjects consumed four diets for 1 week: a basal diet containing 140 mmol of sodium/day and 1 g of protein day−1 kg−1, the same diet with isocaloric addition of 1 g of meat protein day−1 kg−1, the basal diet with addition of 170 mmol of sodium chloride/day and the basal diet with both additions.

2. Creatinine clearance was increased significantly both by protein and, to a smaller extent, by sodium. Plasma atrial natriuretic peptide and the urinary excretion of guanosine 3′:5′-cyclic monophosphate were increased significantly by sodium but were not affected by protein. Protein induced a significant rise in plasma glucagon levels, whereas the rise in somatomedin C (insulin-like growth factor I) just failed to reach statistical significance.

3. These findings demonstrate that atrial natriuretic peptide does not mediate chronic protein-induced hyper-filtration, although it may contribute to the renal effects of sodium. Glucagon and somatomedin C (insulin-like growth factor I) may have contributed to chronic protein-induced hyperfiltration.
Time-course and relationship of the early changes in renal sodium excretion and aldosterone secretion during dietary sodium restriction in normal man
Authors: Carmichael D. J. S. , Sutters M. S. , Unwin R. J. , Gordon D. , Few J. , James V. H. T. , Wadsworth J. , Peart W. S.
Published: August 2015

1. The fall in renal sodium excretion after dietary sodium restriction is prompt and reproducible. The importance of increased aldosterone secretion during the early phase (within 48 h) of this response is unclear. Using two indirect measures of aldosterone secretion (in urine and saliva), we have tried to relate changes in excretion and concentration of this hormone to renal sodium excretion during the abrupt transition from a normal (approximately 150 mmol/day) or high (260 mmol/day) to a low (5–25 mmol/day) sodium intake in 11 and seven male volunteers, respectively.

2. All subjects showed reduced renal sodium excretion within 36 h of dietary restriction, but the times at which increases in renal aldosterone excretion, saliva aldosterone concentration and plasma renin activity became statistically significant varied widely (8–72 h, 2.5–>62.5 h and 38 h for renal aldosterone secretion, saliva aldosterone concentration and plasma renin activity, respectively). Circadian fluctuations in saliva aldosterone concentration were apparent and increased in amplitude during sodium restriction.

3. Urine flow rate tended to increase on the first day of sodium restriction and this reached statistical significance in the group initially on a high sodium intake (64.0 ± 8.8 to 84.3 ± 11.2 ml/h, P <0.01); although the pattern of urine flow did correlate with plasma arginine vasopressin concentration (r = −0.49, P <0.01), there was no significant decrease in mean plasma arginine vasopressin concentration [1.15 (0.92–1.44) to 0.90 (0.72–1.12) pmol/l, P = 0.08; geometric mean and 95% confidence limits]. Renal arginine vasopressin excretion fell significantly after the change from a normal or high to a low sodium diet [2.70 (2.38–8.69) to 2.19 (1.72–4.00) and 3.80 (2.92–5.01) to 2.50 (1.26–2.35) pmol/h, respectively, P <0.05]; in four subjects assayed, plasma atrial natriuretic peptide concentration also fell significantly [20.1 (16.3–24.9)to 13.1 (10.6–16.2) pmol/l, P <0.05].

4. We conclude that after acute dietary sodium withdrawal: (1) unless enhanced renal sensitivity to aldosterone develops rapidly, increased secretion alone is unlikely to account for the initial decline in renal sodium excretion; (2) decreased atrial natriuretic peptide secretion may have a permissive role in ‘low-sodium’ adaptation; (3) the early ‘low-sodium’ diuresis is probably vasopressin-dependent and is an important mechanism in the preservation of normal plasma osmolality.
Capillary Hypertension and Abnormal Pressure Dynamics in Patients with Essential Hypertension
Authors: Williams S. A. , Boolell M. , MacGregor G. A. , Smaje L. H. , Wasserman S. M. , Tooke J. E.
Published: August 2015

1. Pressure was measured within 28 capillaries of the nailfolds of nine patients with essential hypertension and in 33 capillaries of nine age- and sex-matched normotensive control subjects, using direct micropuncture, a dynamic servo-nulling system and computerized analysis.

2. Average pressure at the apex of the capillary was found to be elevated in the patients with hypertension (21.1 ± 4.9 mmHg compared with 13.0 ± 2.0 mmHg in the control subjects; mean ± SD, P < 0.01). If the two groups were combined, there was an overall correlation between average capillary pressure and mean blood pressure (r = 0.68, P < 0.01, n = 18), but within each group separately there was no significant relation between these parameters.

3. There were also abnormalities in the waveforms of pulsations in capillary pressure in the group with hypertension, with an increased attenuation of high-frequency harmonics. Pulses appeared to be conducted more rapidly along the vascular tree in the patients with hypertension.

4. The elevation of capillary pressure in essential hypertension demonstrated in this study is in agreement with indirect evidence of capillary hyperfiltration provided by other studies which showed a reduced plasma volume and increased transcapillary escape rate of plasma proteins.

5. The finding of elevated capillary pressure demands the inclusion of the postcapillary segment (and possibly vascular density) in the resistance equation in essential hypertension.
Impaired Natriuretic Response to Atrial Natriuretic Peptide in the Isolated Kidney of Rats with Experimental Cirrhosis
Authors: Panos Marios Z. , Gove Christopher , Firth John D. , Raine Anthony E. G. , Ledingham John G. G. , Westaby David , Williams Roger
Published: August 2015

1. Sodium retention in cirrhosis may be partly attributable to resistance to a putative circulating natriuretic factor. In cirrhosis, plasma concentrations of atrial natriuretic peptide are often increased in the presence of sodium retention.

2. In order to determine whether the kidney of cirrhotic animals may be insensitive to atrial natriuretic peptide, isolated perfused kidneys from six cirrhotic and five control rats were exposed to increasing concentrations of atrial natriuretic peptide. Cirrhosis had been induced by carbon tetrachloride administration.

3. Excretion in vivo of a 2 mmol sodium load, administered by gavage, was impaired in cirrhotic animals for up to 4 h as compared with control animals (4.2 ± 1.9 vs34.9± 13.4% P < 0.05).

4. During perfusion at 110 mmHg in the absence of atrial natriuretic peptide, sodium excretion by isolated kidneys of cirrhotic animals tended to be lower than in control animals, but the difference was not significant (4.93 ± 1.01 vs 8.41 ± 1.48 μmol min−1 g−1 kidney weight, P = 0.09). There was a smaller increase in urinary sodium excretion by the kidneys of cirrhotic rats compared with control rats in the presence of atrial natriuretic peptide at 10, 50 and 200 pmol/l (respectively: 0.06 ± 0.08 vs 1.29 ± 0.35 μmol min−1 g−1 kidney weight, P < 0.02; 0.49 ± 0.08 vs 1.82 ± 0.42 μmol min−1 g−1 kidney weight, P < 0.03; 1.42 ± 0.16 vs 3.23 ± 0.73 μmol min−1 g−1 kidney weight, P < 0.05), but not at 1000 pmol/l.

5. In this animal model of cirrhosis, renal resistance to the natriuretic action of atrial natriuretic peptide at physiological and pathophysiological concentrations may contribute to sodium retention.
Comparison of Dye-Dilution and Plethysmographic Blood Flow Measurements: An Evaluation of the Influence of Invasive Techniques on Blood Flow and on Arterial and Femoral Venous Substrate Variables in Man
Authors: Jorfeldt Lennart , Rutberg Hans
Published: August 2015

1. In eight healthy volunteers we compared leg blood flow, as determined in a calf segment by strain-gauge plethysmography, with the flow measured by a constant-rate infusion of Indocyanine Green dye into the femoral artery. The representativeness of the calf segment was evaluated by complementary measurements with additional strain gauges attached around the proximal and distal crural and the distal thigh segments (n = 6). Furthermore, we investigated the influence of the catheterization procedure and a simulated vascular puncture, as well as repeated venous occlusions, on blood flow and on arterial and femoral venous substrate concentrations and blood gases (n = 8).

2. The leg blood flow measured by dye dilution was 0.31 ± 0.03 litre/min (mean ± sem). The blood flow in the calf segments was 14.8 ± 1.6 ml min−1 litre−1 and no difference between the legs was observed. Extended to the whole leg the plethysmographic blood flow was 0.17 ± 0.01 litre/min and thus lower (43 ± 7%, P < 0.001) than the flow determined by the indicator-dilution method. Blood flow in the legs was not influenced by catheterization or sham punctures of the vessels or by repeated venous occlusions.

3. The concentrations of glucose, lactate and glycerol, as well as blood gas variables, in arterial and femoral venous blood did not change during the study or decreased so slightly (pH and lactate) that the arteriovenous difference was not influenced.

4. We conclude that the blood flow of the total leg cannot be satisfactorily estimated from strain-gauge plethysmography of a single calf segment. Strain-gauge plethysmography can therefore not be recommended for quantitative studies of substrate turnover in the leg tissues applying the Fick principle. Catheterization of the femoral vessels, or manipulations close to them with a thin cannula or repeated venous occlusions, has no significant effect on leg blood flow and substrate exchange.
Simplifying the Lithium-Marker Technique Used to Assess the Dietary Intake of Discretionary Sodium in Population Studies
Authors: Leclercq C. , Avalle V. , Ranaldi L. , Toti E. , Ferro-Luzzi A.
Published: August 2015

1. Lithium has been used by Sanchez-Castillo et al. (Clin. Sci. 1987; 72, 81–6) for tracking sodium in order to monitor the domestic use of salt. The present study was designed to simplify the original protocol, which is too cumbersome for epidemiological studies.

2. A preliminary study conducted on nine volunteers showed that sharp modifications of lithium intake are detected within 24 h in urinary excretion. The average intake over a 5-day period could be predicted by the mean excretion of the last 3 days. Lithium recovery established from 1 baseline day and 3 plateau days was 95 ± 6% (mean ± sd), not significantly different from the recovery obtained by the integrated excretion curve over 12 days.

3. A simplified protocol was therefore developed, reducing to 4 the 12 days of urine collection originally required.

4. This simplified protocol was tested on five households (14 adults and five children). All domestic salt was substituted with lithium-tagged salt. Urine samples were collected on 1 baseline day and on 3 plateau days. The lithium/sodium ratio of all urine collections (both complete and incomplete) could be used to estimate the proportion of discretionary sodium. In our sample it was about 29% of total sodium intake.

5. The simplified protocol can thus be proposed for population studies.
Impaired Nutritive Skeletal Muscle Blood Flow in Patients with Chronic Renal Failure
Authors: Bradley John R. , Anderson Janice R. , Evans David B. , Cowley Alan J.
Published: August 2015

1. The possibility that abnormalities of skeletal muscle may limit the exercise tolerance of patients with chronic renal failure was investigated in patients undergoing regular haemodialysis.

2. Blood flow to the calf, a vascular bed consisting predominantly of skeletal muscle, was measured in six patients before and after exercise and compared with values obtained from 12 control subjects.

3. The patients were limited on exertion and had an abnormal response of calf blood flow to bicycle exercise. Resting calf blood flow was similar in patients and control subjects, but the mean increase in calf blood flow in response to submaximal exercise was 0.55 (sem 0.12) ml min−-1 100 ml−-1 in the patients and 1.43 (sem 0.17) ml min−-1 100 ml−-1 in the control subjects. The increase after symptom-limited maximal exercise was 1.50 (sem 0.80) ml min−-1 100 ml−-1 in the patients and 4.20 (sem 0.40) ml min−-1 100 ml−-1 in the control subjects.

4. Skeletal muscle biopsies from eight haemodialysis patients were studied by histochemistry and electron microscopy.

5. Oxidative enzyme activity was increased and there were large subsarcolemmal aggregates of structurally normal mitochondria. Necrotic capillaries were observed as empty basement membrane tubes containing fragments of degenerating endothelium.

6. The changes were compatible with a response to a chronic reduction in skeletal muscle blood flow.
Diurnal and Postural Variations in Plasma Atrial Natriuretic Factor, Plasma Guanosine 3′:5′-Cyclic Monophosphate and Sodium Excretion
Authors: Bell Gordon M. , Atlas Steven A. , Pecker Mark , Sealey Jean E. , James Gary , Laragh John H.
Published: August 2015

1. We studied diurnal patterns of plasma atrial natriuretic factor, plasma guanosine 3′:5′-cyclic monophosphate and urinary sodium excretion in normal subjects after 3 days on a 200 mmol of sodium/60 mmol of potassium diet. On the fourth day blood samples and urine were collected every 3 h.

2. Two studies were performed. In study 1, normal subjects (n = 8) were recumbent for 23 h from 09.00 hours to 08.00 hours the next day. In study 2, normal subjects (n = 10) were permitted to ambulate from 09.00 hours to 23.00 hours and then were recumbent until 08.00 hours the next day.

3. In study 1, assumption of the recumbent posture was associated with increases in plasma atrial natriuretic factor (P < 0.01), plasma guanosine 3′:5′-cyclic monophosphate (P < 0.05) and urinary sodium excretion (P < 0.05).

4. In contrast, in study 2 there were no significant changes in plasma atrial natriuretic factor during the day; instead, plasma atrial natriuretic factor increased overnight, reaching a peak at 24.00 hours after 1 h of recumbency (P < 0.01). A smaller rise in plasma guanosine 3′:5′-cyclic monophosphate (P < 0.05) occurred; urinary sodium excretion decreased markedly (P < 0.01) and there was no change in creatinine clearance.

5. In both studies, recumbency was associated with an initial drop, followed by a rise, in packed cell volume.

6. These data demonstrate that assumption of the supine position induces a rise in plasma atrial natriuretic factor and accounts for most of the observed variation. This is associated with natriuresis during the day, but it does not reverse the pattern of antinatriuresis that occurs at night. Instead, changes in plasma atrial natriuretic factor appear to reflect and, in turn, influence changes in intravascular volume.
Platelet-Activating Factor Mediates Glycerol-Induced Acute Renal Failure in Rats
Authors: López-Farré Antonio , Gómez-Garre Dulcenombre , Bernabeu Fernando , Cajal Santiago Ramón Y , Perez-Rodrigo Paloma , Braquet Pierre , López-Novoa José Miguel
Published: August 2015

1. We have studied the effect of inhibiting the interaction of platelet-activating factor with its receptor by using two structurally different antagonists BN-52021 (1 mg/kg, intraperitoneally) and alprazolam (1 and 5 mg/kg, intraperitoneally) on the evolution of glomerular filtration and renal blood flow, in the experimental model of acute renal failure induced by the intramuscular injection of glycerol in rats.

2. We have also measured arteriovenous differences in platelet-activating factor concentration, as well as platelet-activating factor content in glomeruli from rats with glycerol-induced acute renal failure.

3. After glycerol injection, untreated rats showed a marked reduction in inulin clearance which reached 77% in the first 30 min. The reduction was only 27% in the rats treated with BN-52021 and 38% in the rats treated with alprazolam (5 mg/kg), with statistically significant differences between treated and untreated groups.

4. Clearance of p-aminohippuric acid was also improved with BN-52021 or alprazolam treatment.

5. This protective effect of BN-52021 was observed in a more prolonged follow-up (3 days).

6. Glomeruli from rats with acute renal failure, treated or untreated with BN-52021, showed similar amounts of platelet-activating factor, whereas it was undetectable in glomeruli from normal rats. Furthermore, rats with glycerol-induced acute renal failure released greater amounts of platelet-activating factor.

7. These results provide evidence of a role for platelet-activating factor in the genesis of this model of experimental acute renal failure.
Skeletal Muscle Metabolism in Heart Failure: A 31P Nuclear Magnetic Resonance Spectroscopy Study of Leg Muscle
Authors: Arnolda Leonard , Conway Michael , Dolecki Michael , Sharif Hasanat , Rajagopalan Bheeshma , Ledingham John G. G. , Sleight Peter , Radda George K.
Published: August 2015

1. The gastrocnemius muscle of seven patients with mild to moderate chronic heart failure and of five healthy control subjects was studied using 31P nuclear magnetic resonance spectroscopy. Spectra were collected at rest and during an incremental, symptom-limited, exercise protocol. Blood flow was measured in the same study during brief interruptions to exercise.

2. The phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio was lower in patients with heart failure than in control subjects at an exercise rate of 1.5 W, although intracellular pH and blood flow were similar.

3. The cytosolic free adenosine 5′-diphosphate concentration was markedly increased in patients with heart failure exercising at 1.5 W compared with control subjects exercising at the same workload.

4. Although the maximum workload achieved by patients with heart failure was less than half of that reached by control subjects, the pH and the phospho-creatine/(phosphocreatine plus inorganic phosphate) ratio were lower in patients with heart failure at maximal load. Blood flow was less at maximal exercise in patients with heart failure than in control subjects in keeping with the reduced work load.

5. The phosphocreatine depletion induced in the gastrocnemius muscle by exercise was more severe than previously described in the forearm of patients with heart failure.

6. Metabolic abnormalities in skeletal muscle may contribute to exercise intolerance in heart failure, particularly during submaximal exercise.
Mucosal Peptide Hydrolase and Brush-Border Marker Enzyme Activities in Three Regions of the Small Intestine of Rats with Experimental Uraemia
Authors: Haines D. J. , Swan C. H. J. , Green J. R. B. , Woodley J. F.
Published: August 2015

1. The activities of nine peptide hydrolases and three non-peptidase brush-border marker enzymes have been quantified in crude homogenates prepared from the proximal, mid and distal regions of small-intestinal mucosa for sham-operated (n = 9) and uraemic (n = 14) rats. Abnormalities in enzyme activities were observed in all regions studied in the uraemic group, although no reduction in food intake occurred.

2. The proximal region of the small intestine from uraemic rats showed a general fall in enzyme activities associated with the brush-border. This fall was combined with a decline in mucosal protein content. In contrast, the mid and distal regions showed increased activity against the dipeptide tyrosyl-glycine.

3. It is proposed that the fall in brush-border enzyme activities in the proximal small intestine of uraemic rats is a response to the increased water intake associated with this, and presumably other, rat models of uraemia. The increased enzyme activity against tyrosyl-glycine found in the mid and distal regions of the small intestine of uraemic rats may be caused by an increased small-intestinal transit rate, but could be an attempt to maximize tyrosine absorption in response to decreased plasma tyrosine levels.

4. This study casts doubt on specific activities being the most useful units of enzyme activity, when measured in crude homogenates prepared from the proximal small intestine of uraemic rats. It also demonstrates that enzyme activities measured at a single site in the small intestine of uraemic rats may not be representative of the enzymatic changes occurring in the small-intestinal mucosa as a whole.
Alterations of Platelet Membrane Microviscosity in Essential Hypertension
Authors: Sang Kim-Hanh Le Quan , Montenay-Garestier Thérèse , Devynck Marie-Aude
Published: August 2015

1. The metabolism of blood platelets, taken as an accessible model of excitable cells, has been reported to be altered in hypertension. Most of the identified alterations concern the functions of various plasma membrane constituents.

2. A possible modification of membrane microviscosity was investigated by 1,6-diphenyl-1,3,5-hexatriene and 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene fluorescence depolarization. In order to determine whether or not the membrane structures probed by these indicators were related to platelet physiological functions, the cytosolic free Ca2+ concentration was determined in parallel.

3. At physiological temperature, the fluorescence anisotropy of 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene was decreased in untreated hypertensive patients (0.276 ± 0.002 versus 0.288 ± 0.002, n = 23 and 22, P < 0.001), indicating a lowered microviscosity at the lipid-water interface of cell membrane. It correlated inversely with blood pressure (P < 0.001) and cytosolic free Ca2+ concentration (P < 0.030). On the contrary, 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy was observed to vary with sex but not with blood pressure.

4. These results suggest that structural membrane modifications may participate in the various functional abnormalities observed in platelets from hypertensive patients.
Cardiac and Whole-Body [3H]Noradrenaline Kinetics during Adrenaline Infusion in Man
Authors: McCance Alastair J. , Forfar J. Colin
Published: August 2015

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min−1 kg−1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom β-adrenoceptor antagonists had been discontinued for 72 h.

2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 ± 129 pg/ml to 245 ± 29 pg/ml (P < 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 ± 40 ng min−1 m−2 to 358 ± 41 ng min−1 m−2, P < 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease.

3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions.

4. Infusion of adrenaline to produce ‘physiological’ increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma. This is consistent with the hypothesis that adrenaline may modulate noradrenaline release by acting upon pre-junctional β-adrenoceptors, but could also be explained by reflexogenic responses to the haemodynamic effects of adrenaline.
Plasma Exudation into Airways Induced by Inhaled Platelet-Activating Factor: Effect of Peptidase Inhibition
Authors: Lötvall Jan O. , Elwood Wayne , Tokuyama Kenichi , Barnes Peter J. , Chung K. Fan
Published: August 2015

1. To evaluate whether endogenous peptide release is involved in the airway responses to inhaled platelet-activating factor, we measured lung resistance and airway microvascular leakage in anaesthetized guinea pigs pre-treated with inhalation of either saline or a combination of the peptidase inhibitors phosphoramidon (0.1 mmol/l: 60 breaths; 7.5 nmol), to inhibit neutral endopeptidase, and captopril (4.6 mmol/l: 60 breaths; 350 nmol), to inhibit angiotensin-converting enzyme.

2. Airway microvascular leakage was determined by the albumin marker Evans Blue dye injected intravenously (20 mg/kg) before platelet-activating factor or sham challenge.

3. Inhaled platelet-activating factor induced a maximum increase in lung resistance (1.43 ± 0.33 cmH2O s−1 ml−1) which was not significantly different after pretreatment with phosphoramidon and captopril (1.44 ± 0.21 cmH2O s−1 ml−1).

4. Inhalation of platelet-activating factor caused a significant increase in extravasated Evans Blue dye at all airway levels, an effect which was not potentiated by peptidase inhibition. Similar results were obtained with dye extravasated into the airway lumen and absorbed by a filter paper placed on the tracheal mucosa. Approximately 11% of the total tracheal dye was found in the lumen. There was a high correlation between tracheal tissue and tracheal lumen Evans Blue dye (r = 0.91; P < 0.001).

5. We found a significantly lower dry to wet weight ratio in proximal intrapulmonary airways of animals exposed to platelet-activating factor, suggesting that platelet-activating factor caused airway oedema at this airway level.

6. Inhaled platelet-activating factor does not induce immediate release of peptides degraded by either neutral endopeptidase or angiotensin-converting enzyme in high enough quantities to cause bronchoconstriction. Inhaled platelet-activating factor may cause airway narrowing in guinea pigs largely due to plasma exudation into the airway wall and lumen.
Achlorhydria-induced hypergastrinaemia: the role of bacteria
Authors: Calam J. , Goodlad R. A. , Lee C. Y. , Ratcliffe B. , Coates M. E. , Stamp G. W. H. , Wright N. A.
Published: August 2015

1. Studies of Helicobacter pylori show that microbes can alter gastrin release. Lack of gastric acid (achlorhydria) causes hypergastrinaemia and allows bacteria to grow within the stomach. We speculated that the bacteria contribute to the rise in gastrin seen after acid inhibition, and tested the idea by comparing plasma gastrin levels during inhibition of acid secretion between germ-free and conventional rats.

2. Matched germ-free and conventional rats (n = 8 per group) received either vehicle (saline) or one of two doses of the histamine-H2-receptor antagonist loxtidine for 1 week. Gastrin was measured in cardiac blood by a specific r.i.a.

3. Plasma gastrin concentrations in germ-free and conventional rats were 59 ± 11 pmol/l (mean ± SEM) and 36 ± 8 pmol/l, respectively, after vehicle, and 153 ± 30 pmol/l and 181 ± 27 pmol/l, respectively, after loxtidine at a dose of 10 mg day−1 kg−1, which partially inhibits acid secretion. Administration of loxtidine at a dose of 70 mg day−1 kg−1, which completely inhibits acid secretion, did not produce a significant extra rise in plasma gastrin concentration in germ-free rats (178 ± 11 pmol/l), but further elevated plasma gastrin concentrations to 278 ± 26 pmol/l in conventional rats (P <0.005 compared with germ-free rats).

4. Loxtidine produced a dose-dependent rise in the number of eosinophils in the gastric mucosa of conventional rats.

5. We conclude that partial inhibition of gastric acid secretion increases gastrin release independently of bacteria, but that bacteria are involved in the further rise in gastrin which occurs on more profound inhibition of gastric acid secretion.
Adrenoceptors on blood cells from patients with primary Raynaud's phenomenon
Authors: Graafsma Sietze J. , Wollersheim Hub , Droste Herman T. , Dam Marc A. G. J. ten , van Tits Lambertus J. H. , Reyenga Joeke , de Miranda Jaap F. Rodrigues , Thien Theo
Published: August 2015

1. α2-Adrenoceptors on platelet membranes and β2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups, a standardized mental arithmetic test and a finger-cooling test were performed.

2. Baseline blood pressure, heart rate and forearm blood flow did not differ between the two groups.

3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 ± 15 arbitrary units) compared with control subjects (33 ± 14 arbitrary units) (P <0.01).

4. Baseline plasma noradrenaline concentration (2.0011.44 versus 1.16 ± 0.36 nmol/l) and α2-adrenoceptor density (301 ± 119 versus 210 ± 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The α2-adrenoceptor density/β2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was, with a value of 0.37 ± 0.04, higher than in the control subjects, where a value of 0.25 ± 0.02 was measured (P <0.001). Plasma adrenaline concentration, β2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions.

5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured, the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group. The increase of plasma noradrenaline concentration during the mental arithmetic test was only statistically significant in the control group.

6. The results are discussed in relation to the two common theories concerning the aetiology of primary Raynaud's phenomenon: a local vascular defect and a primary sympathetic hyperfunction.
Aldosterone, atrial natriuretic factor and sodium intake as determinants of the natriuretic response to head-out water immersion in healthy subjects
Authors: Warner Leonard C. , Morali Gilles A. , Miller Judith A. , Logan Alexander G. , Skorecki Karl L. , Blendis Laurence M.
Published: August 2015

1. The effect of sodium intake on the natriuresis and hormonal changes induced by head-out water immersion was studied in seven normal subjects during head-out water immersion and on a control day while successively on 20 mmol of sodium/day and 100 mmol of sodium/day diets. The effects of head-out water immersion were compared with those seen on the control day for both diets.

2. The natriuresis on the 100 mmol of sodium/day diet was significantly greater than on the 20 mmol of sodium/day diet (natriuretic peak: 10.3 ± 2.2 versus 3.9 ± 1 mmol of sodium/h; P < 0.01). The total sodium excretion during the 3 h of head-out water immersion was 26.2 ± 2.0 mmol on the 100 mmol of sodium/day diet and 9.9 ± 0.9 mmol on the 20 mmol of sodium/day diet (P < 0.01). In contrast, the increase in the plasma atrial natriuretic factor level was similar on both diets (peak plasma atrial natriuretic factor level 23.1 ± 1.9 versus 26.2 ± 1 pg/ml; not significant). As expected, the baseline serum aldosterone level was higher on the 20 mmol of sodium/day diet and, despite a significant suppression, remained significantly higher at the end of the third hour of head-out water immersion (peak serum aldosterone level: 495 ± 130 versus 197 ± 26 pmol/l, P < 0.06). Furthermore, there was an inverse relationship between the serum aldosterone level and the urinary sodium excretion at the time of peak natriuresis (r = −0.59, P < 0.01).

3. We conclude that the effect of sodium intake on the natriuresis induced by head-out water immersion is more dependent upon anti-natriuretic agents, such as aldosterone, than on natriuretic factors, such as atrial natriuretic factor.
Ranitidine suppresses aluminium absorption in man
Authors: Rodger R. S. C. , Muralikrishna G. S. , Halls D. J. , Henderson J. B. , Forrest J. A. H. , MacDougall A. I. , Fell G. S.
Published: August 2015

1. Intragastric pH monitoring was performed before and after the single-blind administration of ranitidine or placebo (saline) in eight healthy subjects and four patients with end-stage renal disease who were on regular haemodialysis.

2. The subjects were studied on two occasions and were given aluminium hydroxide (1185 mg) orally 90 min after the administration of ranitidine or saline.

3. Plasma aluminium concentrations and, in normal men, urinary excretion of aluminium were monitored before and after the oral aluminium load.

4. Intragastric pH increased significantly with ranitidine but not with placebo (P < 0.001). Urinary aluminium excretion increased significantly after the administration of aluminium hydroxide during the placebo phase (P < 0.001) but not during the ranitidine phase. Plasma aluminium concentrations were higher in the patients with renal failure than in the normal subjects (P < 0.05), but were unchanged in both groups after the oral aluminium load.

5. This study shows that gastric pH is an important factor in the modulation of aluminium absorption in man, and indicates that reducing gastric acid secretion with ranitidine may reduce the toxicity of orally administered aluminium compounds.
A cross-sectional study of platelet cyclic AMP in healthy and hypertensive pregnant women
Authors: Horn E. H. , Cooper J. , Hardy E. , Heptinstall S. , Rubin P. C.
Published: August 2015

1. Platelet activation in vivo occurs in healthy pregnant women and is more marked in women with preeclampsia. During pregnancy platelets have also been shown in vitro to be less susceptible to the inhibitory effects of prostacyclin. The cyclic nucleotide cyclic AMP has a key role as an inhibitory second messenger in platelets and mediates the inhibitory effects of prostacyclin.

2. We have studied cyclic AMP in relation to platelet behaviour in healthy pregnant women in the third trimester and in women with pregnancy-induced hypertension and pre-eclampsia. Non-pregnant young women were used as controls.

3. Pharmacological agents which increase levels of cyclic AMP were significantly less effective as inhibitors of platelet activation during pregnancy, but there was no difference between the healthy and hypertensive pregnant subjects.

4. Basal platelet cyclic AMP levels were the same in all three groups. However, the production of cyclic AMP in response to a range of adenylate cyclase stimulators was reduced during pregnancy, but again there was no difference between healthy and hypertensive pregnant subjects.

5. The reduction in platelet cyclic AMP levels in pregnancy occurred not only with those adenylate cyclase stimulators which operate via surface receptors, but also on direct stimulation of the enzyme with forskolin.

6. The most likely explanation of these observations is a reduction in the ability of the platelet adenylate cyclase enzyme to respond to stimulation in the third trimester of pregnancy. The consequent reduction in formation of the inhibitory second messenger cyclic AMP may in part be responsible for platelet activation in vivo during pregnancy. There does not appear to be a further difference in platelet cyclic AMP production in hypertensive pregnant women.
Glutathione depletion during experimental damage to rat skeletal muscle and its relevance to Duchenne muscular dystrophy
Authors: Jackson M. J. , Brooke M. H. , Kaiser K. , Edwards R. H. T.
Published: August 2015

1. The release of glutathione has been studied in comparison with the release of creatine kinase from isolated rat soleus muscles subjected to certain forms of experimental damage.

2. Excessive electrically stimulated contractile activity or treatment of muscles with the mitochondrial inhibitor, 2,4-dinitrophenol, induced a substantial release of both creatine kinase and glutathione and a reduction in the total glutathione content of the muscle. The time course of this release and depletion indicates that the efflux of the two molecules is not directly related and that a reduction in muscle glutathione content does not occur before cytosolic enzyme release.

3. 2,4-Dinitrophenol-stimulated release of creatine kinase was significantly reduced by the omission of external calcium from the incubation media, but glutathione release and depletion was relatively unaffected by this. Deliberate elevation of the muscle intracellular calcium content with the calcium ionophore, A23187, induced a substantial loss of creatine kinase, but had no significant effect on the release of glutathione.

4. Muscle biopsies from patients with Duchenne muscular dystrophy were found to have an elevated content of glutathione and an equivalent protein-thiol content compared with control subjects.

5. We conclude that, although release of glutathione from skeletal muscle occurs after excessive contractile activity or inhibition of mitochondrial metabolism, this is not a key step in the damaging processes leading to cytosolic enzyme release, neither is it relevant to the ongoing damage to skeletal muscle which occurs in patients with Duchenne muscular dystrophy.