bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Output, Oxygen Consumption and Renal Blood Flow in Essential Hypertension
Authors: London G. M. , Safar M. E. , Bouthier J. L. , Gitelman R. M.
Published: August 2015

1. Cardiac output, oxygen consumption, total blood volume and mean circulatory transit time were investigated at rest in men with sustained essential hypertension in comparison with normal subjects of the same age and sex.

2. In normal subjects and in patients with hypertension, oxygen consumption was positively correlated to cardiac output. In hypertensives, the slope of the curve was significantly shallower with an increase in arteriovenous oxygen difference.

3. Oxygen consumption in both populations was negatively correlated with mean circulatory transit time but not with total blood volume.

4. In normal subjects, mean circulatory transit time and arteriovenous oxygen difference were positively correlated. The correlation was not significant in hypertensive patients.

5. The study suggests important abnormalities in the transport and cost of energy in erythrocytes of patients with sustained essential hypertension.
Isolation of Micro- and Macro-Droplet Fractions from Needle Biopsy Specimens of Human Liver and Determination of the Subcellular Distribution of the Accumulating Liver Lipids in Alcoholic Fatty Liver
Authors: Cairns S. R. , Peters T. J.
Published: August 2015

1. Needle biopsy specimens of liver were obtained from six control subjects with histologically normal liver and 11 chronic alcoholics with fatty liver.

2. Micro- and macro-lipid droplet fractions were isolated by differential flotation. These fractions, together with the sedimenting membranes, were assayed for cholesterol, cholesteryl ester, phospholipid, free fatty acids and triglyceride.

3. Electron microscopy demonstrated marked differences in the range of lipid droplet sizes in the two fractions and biochemical analysis suggested that the microdroplet lipid corresponded to pre-very low density lipoprotein (VLDL) particles.

4. Studies on biopsies from patients with alcoholic fatty liver showed a 2–3-fold increase in triglyceride in both lipid droplet fractions but most of the accumulating triglyceride was sedimentable and membrane-bound.

5. Needle biopsy specimens from two patients with alcoholic fatty liver were fractionated with a vertical pocket re-orientating rotor. The principal organelles were separated and the subcellular distribution of triglyceride, phospholipid and free cholesterol determined. Triglyceride showed a bimodal distribution to a particulate fraction tentatively located to Golgi particles and to droplet-lipid remaining in the sample layer.
Dependence of Urinary Prostaglandin E2 Excretion on Urinary Volume Rather than Solute Handling or Segmental Nephron Function in Man
Authors: Kaojarern Sming , Chennavasin Polavat , Burdette Ann , Campbell William B. , Brater D. Craig
Published: August 2015

1. Eight normal subjects underwent water loading alone and water loading plus 40 mg of frusemide IV, fluid intake ad libitum alone and fluid intake ad libitum plus frusemide, plus each of the preceding after pretreatment with indomethacin.

2. After frusemide administration, increases in urinary sodium excretion paralleled increases in urinary volume, and urinary prostaglandin E2 (PGE2) excretion correlated closely with sodium excretion (y = 1.03x −0.28; r = 0.940; P<.0001).

3. In the absence of the diuretic, urinary volume varied over a wide range with little change in sodium excretion. Again, urinary PGE2 excretion correlated with urinary sodium excretion (y = 0.12x + 0.05; r = 0.789; P<.002). However, the correlation differed markedly from that observed in the studies with frusemide.

4. Expressing urinary PGE2 excretion as a function of urinary volume for all of the studies resulted in a highly significant correlation (y = 10.7x −0.70; r = 0.975; P<.0001).

5. Multiple and stepwise regression analyses assessing the correlation of urinary PGE2 excretion with urinary flow rate and with indices of function of various nephron segments indicate that the correlation with urinary PGE2 could be predominantly accounted for by urinary volume.

6. We conclude that in the condition of this study in man, urinary PGE2 excretion is a correlate of urinary volume.
Two Different Types of Inactive Renin in Human Plasma: Molecular and Kinetic Properties
Authors: Imamura Yoichi , Hiwada Kunio , Kokubu Tatsuo
Published: August 2015

1. We separated inactive renin in human plasma into two types, adsorbed and non-adsorbed, by chromatography on a concanavalin A-Sepharose column. About 75% of fresh plasma inactive renin was adsorbed to the column, and the rest passed through it. Non-adsorbed and adsorbed inactive renins were partially purified.

2. Non-adsorbed inactive renin had a molecular weight of 48000 and an isoelectric point of 5.44. Adsorbed inactive renin had a molecular weight of 46000 and isoelectric points of 5.56 and 5.80.

3. After activation with trypsin, both activated inactive renins were similar with respect to molecular weight (45000), thermostability, Km value (0.56 μmol/l) and pH profile. But pI values of both activated inactive renins differed.

4. These results indicate that there exist in human plasma two different types of inactive renin which differ in carbohydrate composition.
Biliary Inter-Relationship between Phospholipid, Bilirubin and Taurocholate in the Anaesthetized Rat
Authors: García-Marín J. J. , Esteller A.
Published: August 2015

1. The interference between biliary phospholipid and bilirubin secretion was investigated in rats with bile fistulae, under conditions of normal and maximal bilirubin secretion. The enterohepatic circulation of bile salts was interrupted and the animals received infusions of sodium taurocholate, a micelle-forming physiological bile salt.

2. Sodium taurocholate infusion (0.19 μmol min−1 100 g−1 body weight) induced an increase in bile flow and phospholipid secretion, while basal bilirubin secretion was not increased.

3. Bilirubin infusion (0.26 μmol min−1 100 g−1 body weight) induced a decrease in basal and taurocholate-stimulated phospholipid secretion. Biliary mixed micelle formation was presumably altered during bilirubin infusion, although bile taurocholate concentration, taurocholate secretion rate and bile flow were not modified.

4. When sodium taurocholate was infused during bilirubin-decreased phospholipid secretion, this secretion was restored but maximal biliary bilirubin secretion was not increased.

5. These results provide circumstantial evidence for the hypothesis that mixed micelle formation is not an important determinant of maximal bilirubin transport into bile.
Hypophosphataemic Osteomalacia and Myopathy: Studies with Nuclear Magnetic Resonance Spectroscopy
Authors: Smith R. , Newman R. J. , Radda G. K. , Stokes M. , Young A.
Published: August 2015

1. A patient with familial adult-onset hypophosphataemia, whose myopathy was closely related to the plasma phosphate concentration, was investigated by phosphorus nuclear magnetic resonance spectroscopy (31P n.m.r.) in vivo of the right flexor digitorum superficialis muscle.

2. During hypophosphataemia induced by stopping oral phosphate a significant reduction in measured muscle strength occurred, but the ratios of the intramyocellular levels of phosphocreatine (PCr), adenosine triphosphate (ATP) and inorganic phosphate (Pi) remained unchanged at rest. During exercise these levels changed, as did the intramyocellular pH, but they did not differ from the pattern previously recorded in normal subjects.

3. In four adults with inherited infantile-onset hypophosphataemia (vitamin D-resistant rickets, VDRR) without myopathy, the n.m.r. measurements were normal at rest and during exercise.

4. In one patient with inherited hyperphosphataemia (tumoral calcinosis) the resting PCr: Pi ratio was significantly reduced.
Calmodulin Reduces Ouabain-Sensitive Atpase of Cardiac Sarcolemmal Membranes: High Reduction in Spontaneously Hypertensive Rats
Authors: Cirillo M. , David-Dufilho M. , Devynck M. A.
Published: August 2015

1. Calmodulin and calcium effects on cardiac ouabain-sensitive adenosine triphosphatase (ATPase) activity were studied in young spontaneously hypertensive rats (SHR) and in their normotensive control Wistar—Kyoto rats (WKY).

2. Cardiac sarcolemmal membranes from SHR showed significantly higher ouabain-sensitive ATPase activity than membranes from WKY rats. This activity was unaffected by calmodulin or calcium alone.

3. However, when both calmodulin and calcium were added, ouabain-sensitive activity was significantly reduced without changes in the total ATPase activity.

4. The calcium-dependent calmodulin effect was dose-dependent and greater in SHR than in WKY membranes.

5. An altered interaction between the calcium-calmodulin system and sodium handling by the plasma membrane in SHR may play a role in the pathogenesis of hypertension.
Intestinal Absorption of Calcium in Greyhounds: The Response to Intermittent and Continuous Administration of Human Synthetic Parathyroid Hormone Fragment 1–34 (Hpth 1–34)
Authors: Podbesek R. D. , Mawer E. B. , Zanelli G. D. , Parsons J. A. , Reeve J.
Published: August 2015

1. Long-term studies of gastrointestinal radio-calcium absorption were undertaken in adult greyhounds before and during two treatment regimes with human parathyroid hormone fragment 1–34 (hPTH 1–34). The results were correlated with plasma vitamin D metabolite levels and kinetic indices related to the balance of fluxes of calcium between plasma and the rapidly exchangeable calcium pools of bone.

2. Compared with adult man, results obtained before treatment started showed lower indices of gastrointestinal calcium absorption and considerably higher concentrations of 24-hydroxycalcidiol in the dogs.

3. Daily injections of hPTH 1–34 at 1.7 μg day−1 kg−1 significantly increased indices of radiocalcium absorption and plasma calcitriol concentrations, while only causing transient calcaemic responses. The individual magnitudes of the calcaemic response correlated positively with indices of radiocalcium retention in the exchangeable pools of bone which in turn correlated positively with ‘late-phase’ absorption of radiocalcium from the gut.

4. Subcutaneous infusions of hPTH 1–34 at 0.5 μg day−1 kg−1 to the same dogs were just insufficient to cause hypercalcaemia, but increased plasma calcitriol concentrations. Indices of radiocalcium absorption were not increased.

5. Continuous parathyroid hormone (PTH) infusion is now known to substantially down-regulate renal PTH receptor density, whereas recovery after a brief exposure to PTH occurs within 24 h. It is possible that the differences in response of the gut to the two regimes may in part be related to their differing effects on some PTH receptors.
Some problems associated with adenylate cyclase bioassays for parathyroid hormone
Authors: Seshadri M. S. , Chan Y. L. , Wilkinson M. R. , Mason R. S. , Posen S.
Published: August 2015

1. A renal adenylate cyclase system was assessed for its suitability in the performance of parathyroid hormone (PTH) bioassays. Membrane preparations from 1 week old chicks were found to be more sensitive to PTH than material from humans, dogs or rats.

2. Because of the presence of non-specific inhibitors and stimulators of adenylate cyclase in human serum, each serum sample was assayed in the presence and in the absence of a specific PTH inhibitor and the difference was used to calculate PTH activity.

3. Calcium, an inhibitor of adenylate cyclase, was either removed from serum samples by pretreatment with Chelex resin or chelated during assay by means of EGTA.

4. Human and bovine PTH (1-34) stimulated adenylate cyclase in this system to the same extent. The lower limit of detectability was 19.5 pg/ml (final concentration). The intra-assay coefficient of variation at a final concentration of 45 pg/ml was 18%. The index of precision was 0.08 ± 0.04 (n = 7).

5. When synthetic human PTH (1-34) was infused into three normal volunteers, the mean biological half-life of this material was found to be 3.2 min.

6. PTH-like bioactivity could be routinely detected in sera from normal rats, while such activity was significantly decreased in rats subjected to thyroparathyroidectomy.
A comparison of body protein determination in rats by in vivo neutron activation and carcass analysis
Authors: Preston T. , Reeds P. J. , East B. W. , Holmes P. H.
Published: August 2015

1. Total body nitrogen (TBN) was determined in 16 rat carcasses ranging in weight from 55 to 550 g, by non-destructive 14 MeV neutron activation analysis (NAA).

2. The rat carcasses were subsequently analysed for TBN by Kjeldahl digestion, for total body water (TBW) by loss of weight after freeze-drying and for body fat by adiabatic bomb calorimetry after subtraction of protein energy.

3. TBN results by the two methods were in good agreement, the precision by NAA (coefficient of variation = 1.5%) being superior to that by chemical analysis (coefficient of variation = 2.8%).

4. Body fat calculated by difference from a combination of measured TBW and NAA data agreed closely with bomb calorimetry measurements. The use of indirect estimates of TBW to determine fat gave poor results.

5. A group of four growing rats was analysed sequentially by NAA four times in 2 weeks. The maximum total radiation dose received by each animal was < 50 rem (< 500 mSv) and no significant differences in growth rate were observed compared with non-irradiated control groups.

6. 14 MeV NAA in vivo can be conducted with sufficient precision to measure 0.14 g TBN changes in growing rats at 2 weeks post-weaning.
A comparison of cobalamin binding by liver and kidney in rat and man
Authors: Scott J. S. D. , Bowman E. P. W. , Cooksley W. G. E.
Published: August 2015

1. Binding of cobalamin (Cbl) was compared in liver and kidney plasma membranes prepared from rat and human tissues.

2. Single, high-affinity, saturable (200 pmol/l), binding sites for TC II-Cbl were found in all tissues; by contrast no receptors were present for free cobalamin, for which only non-specific adsorption occurred.

3. Binding constants for TC II-CNCbl determined for liver and kidney plasma membranes were of a similar magnitude. Mean values for Ka (litre/nmol) were 16.7 (rat liver), 18.8 (rat kidney), 8.0 (human liver) and 7.5 (human kidney).

4. Results for binding TC II-OHCbl instead of TC II-CNCbl showed no difference in Ka and Bmax. values, although the non-specific adsorption was decreased to a third.

5. Competitive inhibition results showed that the receptors are specific for the TC II molecule and that binding is unaffected either by the cobalamin moiety or by the presence of free cobalamin. Degradation of the receptor protein molecules by trypsin (10 μg/ml) resulted in 90% inhibition of binding.

6. It is concluded that differences between liver and kidney in cobalamin uptake and accumulation cannot be attributed to differences in their TC II receptors.
Some observations on the role of the abdomen in breathing in patients on peritoneal dialysis
Authors: Bush Andrew , Miller Juliet , Peacock Andrew J. , Sopwith Tom , Gabriel Roger , Denison David
Published: August 2015

1. We studied a total of 29 patients on continuous ambulatory peritoneal dialysis (CAPD), who had no present or past respiratory impairment, before and after drainage of dialysate (2.324 ± se 0.033 litres).

2. We measured spirometry, lung volumes and carbon monoxide transfer sitting and supine in 20 patients. The only statistically significant changes on drainage were a small increase in supine functional residual capacity (+ 214 ± se 61 ml, P<0.01) and a small fall in supine peak expiratory flow rate (−26.6 ± se 12.1 litres/min, P<0.05).

3. Measurement of maximal mouth and transdiaphragmatic pressures in ten patients made under the same circumstances showed no statistically significant changes on drainage.

4. A model of the abdomen demonstrates that fluid distension is likely to be better tolerated than gaseous distension, and review of previous studies suggests that a wide range of changes in intraabdominal fluid volume can be tolerated without respiratory embarrassment.

5. These results suggest that fluid volumes used for CAPD do not interfere with breathing in patients with previously normal lungs. The nature of the mechanisms compensating for the fluid suggests that patients with chest disease should be able to tolerate this form of dialysis.
Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis
Authors: Gutteridge J. M. C. , Rowley D. A. , Griffiths E. , Halliwell B.
Published: August 2015

1. The sera of patients with idiopathic haemochromatosis and iron-overload have been found to contain low-molecular-weight iron complexes detectable in the ‘bleomycin assay'.

2. These complexes stimulate both the peroxidation of membrane lipids and the formation of the highly reactive and damaging hydroxyl radical.

3. The iron chelator desferrioxamine interferes with these reactions.

4. We suggest that oxygen radical reactions stimulated by iron salts are important in the pathology of idiopathic haemochromatosis.
Assessment in vitro and in vivo of muscle degradation in chronic skeletal muscle myopathy of alcoholism
Authors: Martin Finbarr C. , Peters Timothy J.
Published: August 2015

1. Muscle protein breakdown in vivo has been studied by measurements of urinary 3-methylhistidine/creatinine ratios. No differences were found between control subjects and chronic alcoholics either with or without proximal muscle wasting or cirrhosis.

2. Calculation of muscle turnover rates, with the correction of Afting et al. (1981, Biochemical Journal, 200, 449-452) for non-skeletal muscle contributions of 3-methylhistidine and creatinine, showed lower values for alcoholics compared with controls.

3. Tissue activities of a neutral protease, assayed by a novel, rapid and sensitive fluorimetric method, were similar in patients and controls. The activity did not vary with severity of atrophy or the presence of cirrhosis.

4. No evidence was therefore obtained to suggest that alcoholic myopathy is due to increased muscle breakdown.
Commentary on Workshop on α-Adrenoceptors
Authors: McGrath J. C. , Reid J. L.
Published: August 2015

1. A Workshop on α-Adrenoceptors was held at Loch Lomond, Scotland in July 1984. Forty participants from different disciplines in the pharmacological, biochemical, physiological and clinical fields considered the questions:

(i) How many subtypes of α-receptor do we need at present?

(ii) What are the activation steps set in motion by α-adrenoceptors?

(iii) What are the physiological roles of α-adrenoceptors in circulatory control?

(iv) What are the pathophysiological roles and how can α-receptors be manipulated in disease?

2. This paper reviews the major points which arose and is intended as a guide to the papers in this Supplement.
Factors determining α-adrenoceptor-mediated responses of human digital arteries and metacarpal veins
Authors: Stevens M. J. , Moulds R. F. W.
Published: August 2015

We have previously suggested that differences in α-adrenoceptor-mediated responses of human digital arteries and metacarpal veins cannot be completely reconciled with mixed populations of postsynaptic α1- and α2-adrenoceptors in these tissues [1, 2].

These suggestions were based on the following observations: (a) the Arunlakshana and Schild plots constructed on the basis of antagonism of either phenylephrine or noradrenaline by yohimbine had slopes which were less than unity, thus confirming that the receptors could not be a homogeneous population; (b) prazosin reduced the maximal responses to noradrenaline in both veins and arteries, but to a greater extent in the former than in the latter; (c) pD2 values for the α1-adrenoceptor agonists methoxamine and phenylephrine, and for the α2-adrenoceptor agonists clonidine and oxymetazoline, were the same in arteries and veins, whereas pD2 values for noradrenaline and adrenaline were significantly higher in veins than in arteries; (d) the difference between the arteries and veins in their pD2 values for noradrenaline was maintained in the presence of neuronal and extraneuronal uptake blockade and α-adrenoceptor blockade, thus suggesting it was due to differences in the α-adrenoceptors themselves rather than reflecting differences in populations of other receptors or of neurotransmitter uptake mechanisms [3].

The second of these observations would suggest that if there was a mixed population of typical α1- and α2-adrenoceptors in the arteries and veins the proportion of prazosin-resistant (α2-) receptors was greater in arteries than in veins. This conclusion, however, was not compatible with the observation of the greater sensitivity of veins than arteries to noradrenaline, but not phenylephrine or methoxamine, which would indicate a greater proportion of α2-adrenoceptors in veins than in arteries.
Electrical membrane events in response to α-adrenoceptor stimulation
Authors: Haeusler G. , Peyer J. E. De
Published: August 2015

1. Strips of rabbit main pulmonary artery (RMPA) were used to study the effects of several agonists on tension development and membrane potential of the vascular smooth muscle cells.

2. The following α-adrenoceptor agonists were employed: methoxamine and St 587 (α1-selective), B-HT 920 (α2-selective) and clonidine, which stimulates preferentially α2-adrenoceptors. By the use of the selective antagonists prazosin and yohimbine it was not possible to differentiate convincingly between α1- and α2-adrenoceptors in the RMPA. Methoxamine and B-HT 920 produced depolarization of similar magnitude of the membrane of the vascular smooth muscle cells. In spite of these results, which point to a uniform α-adrenoceptor in the RMPA, contractions to α1-and α2-agonists differed in some important aspects.

3. Contractions in response to α2-agonists were highly susceptible to the inhibitory effects of calcium withdrawal and calcium antagonists whereas contractions to α1-agonists were much less so. Reduction of the membrane potential of the vascular cells by K+ at 12 mmol/l had no effect on the concentration-contraction curve of methoxamine but shifted that of B-HT 920 to the left. Conversely hyperpolarization of the membrane of the vascular smooth muscle cells by strychnine totally suppressed contraction to B-HT 920 and caused only a rightward shift of the concentration-contraction curve of methoxamine and St 587.

4. Interaction of α1- and α2-agonists with an apparently uniform α-adrenoceptor induces in the RMPA contraction which seems to be triggered by different membrane processes.
Role of endothelium in the contractile response of rat aorta to α-adrenoceptor agonists
Authors: Godfraind ThéOphile , Egleme Cécile , Osachie Iyad Al
Published: August 2015

1. The influence of endothelium on the response of rat isolated aorta to α-adrenergic agonists has been studied by comparing the response of intact and denuded preparations before and after treatment with calcium entry blockers flunarizine and nifedipine.

2. Endothelium removal enhanced the response of the preparations, especially to α2-agonists that had a weak effect in intact preparations. In the absence of endothelium, about 80% of the maximum response to clonidine was blocked by calcium entry blockers, whereas only 25% of the maximum response to noradrenaline was sensitive to them. In contrast about 40% of maximum noradrenaline-evoked contractions was sensitive to calcium entry blockers in the presence of endothelium. This may be attributed to an increase in the intracellular exchangeable calcium fraction, likely to be due to a slight depolarization of smooth muscle membrane of denuded preparations, which are highly sensitive to the calcium agonist BAY K 8644.

3. The results indicate that a factor liberated by endothelial cells controls both calcium entry and calcium release evoked by α-adrenoceptor agonists in vascular smooth muscle.
Lack of differential inhibition by nifedipine of pressor responses induced by α1- and α2-adrenoceptor agonists and by angiotensin II in anaesthetized cats
Authors: Alabaster V. A. , Solca A. M.
Published: August 2015

1. The effect of nifedipine on pressor dose-response curves to phenylephrine, α-methylnoradrenaline and angiotensin II was determined in anaesthetized cats pretreated with propranolol and atropine.

2. The selectivity of phenylephrine and α-methylnoradrenaline for postjunctional α1- and α2-adrenoceptors respectively was demonstrated by using the selective α1-adrenoceptor antagonist doxazosin and the relatively selective α2-adrenoceptor antagonist rauwolscine.

3. Nifedipine infused intravenously produced a degree of inhibition of rises in diastolic blood pressure similar to that induced by all three agonists.

4. It is concluded that α1- and α2-adrenoceptor activation induced by phenylethanolamine derivatives is equally dependent on extracellular calcium for vascular smooth muscle contraction. Antagonism of sympathetically mediated or angiotensin-induced vasoconstriction could contribute to the vasodilator effects of nifedipine.
Influence of blood gases, Ca2+-entry blockade and angiotensin converting enzyme inhibition on pressor responses to α-adrenoceptor agonists: evidence in vivo for subtypes of response independent of receptor subtype?
Authors: O'Brien J. W. , Flavahan N. A. , Grant T. L. , McGrath J. C. , Marshall R. J.
Published: August 2015

1. The pressor responses in the pithed rat to α-adrenoceptor agonists can be modified by alterations in arterial blood gas levels or by drugs which interfere with excitation-contraction coupling processes in the vascular smooth muscle, e.g. Ca2+-entry blockers or angiotensin converting enzyme (ACE) inhibitors. However, the extent of these influences depends on which agonist is used.

2. The pressor response to intravenous injection of α-adrenoceptor agonists consists of two phases: an initial rapid but transient response (phase I) is followed by a response of slower onset but longer duration (phase II). We have examined the effects of manipulation of arterial blood gases, a Ca2+-entry blocker, nifedipine, and an ACE inhibitor, teprotide, on the pressor responses to a series of α-adrenoceptor agonists. In each case, the effects showed selectivity for one or other of the two phases and the differences in susceptibility between agonists could be explained by the relative sizes of the two phases in their responses. In general, phase II was more susceptible to alkalosis, nifedipine and teprotide, so that drugs in which this component predominated were more susceptible to these factors. In contrast there was no direct correlation with the receptor subtypes activated by the agonists.

3. The results are discussed in relation to the modulation of adrenergic responses by physiological factors and drugs which disturb them.
Acute and chronic regulation of α2-adrenoceptor number and function in man
Authors: Jones C. R. , Hamilton C. A. , Whyte K. F. , Elliott H. L. , Reid J. L.
Published: August 2015

1. Agonist regulation of platelet α2-adrenoceptors was examined in human volunteers after acute elevations of adrenoceptor agonist and during chronic elevation of plasma catecholamines in two patients with phaeochromocytoma.

2. Platelet α2-adrenoceptor number was measured by radioligand binding ([3H]yohimbine) and α2-adrenoceptor function measured by turbidimetric platelet aggregation.

3. Short term infusion of adrenoceptor agonists with α2 activity caused reductions in the platelet response to adrenaline in vitro; conversely an increase in activity was observed postoperatively in two patients after removal of phaeochromocytoma.

4. The changes in platelet response were not accompanied by changes in α2-adrenoceptor number.

5. It is proposed that a process of receptor inactivation occurs during desensitization and this is responsible for the dynamic regulation of platelet responses.
Effect of Bromocriptine Treatment on Prolactin, Noradrenaline and Blood Pressure in Hypertensive Haemodialysis Patients
Authors: Esposti Ezio Degli , Sturani Alessandra , Santoro Antonio , Zuccalà Alessandro , Chiarini Carla , Zucchelli Pietro
Published: August 2015

1. Bromocriptine (2.5 mg/day orally) produced a significant fall in supine mean arterial pressure in nine hypertensive haemodialysis patients with high serum prolactin levels, without causing significant changes in heart rate.

2. On bromocriptine, there was a significant decrease in the mean value of both serum prolactin and plasma noradrenaline, without significant changes in the mean value of plasma renin activity.

3. A significant relationship was found between the changes in supine plasma noradrenaline and the changes in supine mean arterial pressure induced by bromocriptine.

4. The increase in mean arterial pressure in response to the tilt test was greater on bromocriptine than on placebo although the changes in plasma noradrenaline were reduced by bromocriptine. Similar results were observed during the cold pressor test.

5. These findings suggest that the arterial pressure-lowering effect of bromocriptine is related to the reduction in sympathetic out-flow. The parallel decrease in serum prolactin raises the question of the possible involvement of dopaminergic mechanisms in the development of hypertension in our patients.

6. Moreover, bromocriptine seems to enhance the vascular response to endogenous noradrenaline.
Antigenic Reactivity of Peptides Derived from Wheat Gluten with Sera from Patients with Coeliac Disease
Authors: Rawcliffe P. M. , Priddle J. D. , Jewell D. P.
Published: August 2015

1. Fraction B from a peptic-tryptic digest of gluten from Scout 66 wheat has already been shown to cause histological damage to the jejunal mucosa of coeliac patients. Peptide fractions, designated P1-P4, have been prepared from it by a combination of gel filtration (producing an intermediate fraction pseudo-B2: ψ B2) and reverse-phase high pressure liquid chromatography.

2. An enzyme-linked immunosorbent assay (ELISA) has been used to measure IgG antibodies to fraction B in sera from untreated coeliac patients, patients with inflammatory bowel disease (IBD) and healthy individuals. The coeliac group had significantly higher (P < 0.05) antibody levels to fraction B than either of the control groups [medians: coeliac disease (n = 21), 0.247; IBD (n = 17) 0.019; healthy controls (n = 13) 0.020]. Five coeliac sera which gave high absorbance values in the ELISA were chosen and pre-incubated with fraction B in a range of concentrations, before assay by ELISA: a dose-dependent inhibition of binding was found.

3. Two sera which gave high ELISA values were preincubated with fractions B2 and P1-P4. B2, P1, P2 and P4 gave a dose-dependent inhibition, with P1 being the most potent. Absolute values were different for the two sera but the same relative pattern of reactivity was observed for each. With the serum giving the higher ELISA value the concentration of fraction (μg/ml) giving a 50% inhibition of binding when 0.5 ml was added to 0.5 ml of a 1/500 dilution of the serum (IC50) was 2.6 for fraction B, 61 for P1, 155 for B2 and 285 and 295 for P4 and P2 respectively. Fraction P3 had negligible inhibitory effect at the doses tested. With the second serum, P1 was again the most active inhibitor.

4. It is concluded that different peptide fractions of wheat gluten have differing reactivity with antibodies to gluten fraction B present in the sera of two patients with untreated coeliac disease.
A study of Erythrocyte Membrane Proteins and Urinary Polypeptides in Conga Drumming Haemoglobinuria
Authors: Levy Richard D. , Khaleeli Ali A. , Griffiths Beatrice L. , Edwards Yvonne H.
Published: August 2015

1. The erythrocyte membrane proteins and glycoproteins and urinary polypeptides have been examined in a patient exhibiting intermittent pigmenturia associated with conga drumming.

2. Significant excretion of haemoglobin, albumin and probably erythrocyte carbonic anhydrase but not myoglobin occurred during the acute phase of the conga drumming-induced pigmenturia. This usually ceased within 24-48 h.

3. We found no evidence of aberrant erythrocyte membrane components on electrophoresis with either protein staining or a range of 125I-labelled lectins used for detection.
Blood Pressure and Dietary Polyunsaturated and Saturated Fats: A Controlled Trial
Authors: Margetts Barrie M. , Beilin Lawrence J. , Armstrong Bruce K. , Rouse Ian L. , Vandongen Robert , Croft Kevin D. , Mcmurchie Edward J.
Published: August 2015

1. Fifty-four healthy, omnivore normotensive volunteers aged 20-59 years were randomly allocated either to a control group eating a low polyunsaturated to saturated fat ratio (P/S ratio) diet (0.3) throughout, or to one of two experimental groups eating a high P/S ratio diet (1.0) for one of two 6-week experimental periods. Changes in other components were avoided.

2. Twenty-four hour diet records showed substantial changes in the P/S ratio for experimental groups when on the high P/S ratio diet (0.3 to 1.0).

3. There were significant increases in relative concentrations of linoleic acid in plasma phospholipids when on the high P/S ratio diet.

4. There was no consistent effect of dietary P/S ratio elevation from 0.3 to 1.0 on group mean systolic and diastolic blood pressures. Adjustment of blood pressure changes for changes in electrolytes, other dietary components, plasma lipids, weight and other lifestyle variables did not alter this result.

5. It was concluded that the blood pressure lowering effect of a vegetarian diet reported previously was unlikely to have been due to changes in dietary P/S ratio.
Demonstration of methionine synthetase in intestinal mucosal cells of the rat
Authors: Keating J. N. , Weir D. G. , Scott J. M.
Published: August 2015

1. Methionine synthetase was measured in the mucosal cells of the rat duodenum, jejunum and ileum by a previously employed method for mucosal cell isolation. No activity was found in these cells.

2. When a dual buffer system for the isolation of villous and crypt cell population was substituted, however, methionine synthetase was found to be active in the duodenum, jejunum and ileum, both in the villous and crypt cell populations. The activity was significantly higher in the crypt cells than in the villous cells throughout the intestine, and higher levels were found in the ileum than in the duodenum or jejunum.

3. As had been previously reported for the rat liver, nitrous oxide in vivo reduced the enzyme activity in both the villous and crypt cell populations, suggesting a role in vivo for the enzyme. We conclude that methionine synthetase is both present and active in the small intestinal mucosal cells of the rat.
Differential effects of sulindac and indomethacin on blood pressure in treated essential hypertensive subjects
Authors: Puddey I. B. , Beilin L. J. , Vandongen R. , Banks R. , Rouse I.
Published: August 2015

1. Attenuation of the effectiveness of antihypertensive therapy by non-steroidal antiinflammatory (NSAI) drugs has been attributed to inhibition of systemic or renal vasodilator prostaglandin synthesis, or a combination of both.

2. Indomethacin is a NSAI drug with both renal and extrarenal cyclo-oxygenase inhibition properties. Sulindac is a relatively selective cyclooxygenase inhibitor said not to affect urinary prostaglandin excretion.

3. This study examines the relative effect on blood pressure of 4 weeks' treatment, with indomethacin 25 mg three times daily and sulindac 200 mg twice daily, in a randomized placebo controlled trial in 26 hypertensive subjects.

4. In nine patients treated with indomethacin, supine blood pressure rose 11 mmHg systolic and 4 mmHg diastolic by the end of the first week, whereas nine subjects treated with sulindac showed a fall in blood pressure similar to the trend seen in placebo-treated subjects.

5. Indomethacin treatment inhibited renal cyclo-oxygenase with a 78% reduction in urinary prostaglandin E2 excretion and 89% suppression of plasma renin activity. Neither measurement was affected by sulindac. Extrarenal cyclo-oxygenase activity was inhibited by both indomethacin and sulindac with serum thromboxane B2 decreasing by 96% and 69% respectively.

6. The results suggest that the pressor effect of NSAI drugs is predominantly related to renal cyclo-oxygenase inhibition. The lack of effect of sulindac on blood pressure may make it a safer therapeutic option if NSAI drug therapy is necessary in the hypertensive patient.
Phosphate metabolism in erythrocytes of critically ill patients
Authors: Bevington A. , Asbury A. J. , Preston C. J. , Russell R. G. G.
Published: August 2015

1. Orthophosphate (Pi), adenosine 5′-diphosphate (ADP), adenosine 5′-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) were measured in the erythrocytes of patients in an intensive care unit.

2. The patients’ plasma concentration of Pi varied from 0.1 to 4.2 mmol/l, and the corresponding concentration in erythrocytes varied from 0.1 to 2.0 mmol/litre of cells.

3. Marked ATP depletion (less than 1 mmol/litre of cells) was only observed when erythrocyte Pi was less than 0.3 mmol/litre of cells and plasma Pi was less than 0.35 mmol/l. No dependence of 2,3-DPG concentration on the cellular concentration of Pi was detected.

4. The phosphorylation potential [ATP]/([ADP] × [Pi]) varied inversely with the erythrocyte concentration of Pi. Hence the calculated free energy of hydrolysis of ATP in the cell increased from −58 kJ/mol in the most hypophosphataemic samples to −51 kJ/mol in the most hyperphosphataemic. Such changes may adversely affect cell function by altering the steady state mass-action ratios of ATPase reactions.

5. When erythrocytes from normal donors were incubated in solutions containing 1 or 5 mmol/l Pi, the cellular concentrations of Pi stabilized at 1.09 and 2.85 mmol/litre of cells respectively. The corresponding rates of lactate production were 2.09 and 3.11 mmol h−1 litre−1 of cells.

6. In spite of this stimulation of glycolysis (and hence of the flux through ATP synthesizing steps of the Embden-Meyerhof pathway), no significant change in ATP concentration was observed. As in the patients' cells, this indicates that, when extracellular Pi concentrations are perturbed, the concentrations, in erythrocytes, of organic phosphates are more closely regulated than the concentration of Pi.
(Na+, K+)-ATPase regulation and NaCl intake: effects on circulating inhibitor and sensitivity to noradrenaline
Authors: Swann Alan C.
Published: August 2015

1. These experiments examined the effects of a high NaCl diet on (Na+, K+)-ATPase in kidney, heart and cerebral cortex, on the level of circulating inhibitor of (Na+, K+)-ATPase in plasma, and on stimulation of (Na+, K+)-ATPase by treatment with dextro (d)-amphetamine.

2. High salt diet increased indices of (Na+, K+)-ATPase activity (K+-activated p-nitrophenylphosphatase activity and ouabain binding) in kidney medulla, prevented stimulation by amphetamine in cerebral cortex and reduced amphetamine stimulation in heart.

3. High NaCl feeding increased the plasma level of circulating inhibitor of (Na+, K+)-ATPase.

4. Amphetamine alone had no effect on inhibitor level but amphetamine administration reduced the increase in inhibitor with high NaCl feeding.
Effects of physiological concentrations of vasopressin on haemostatic function in man
Authors: Grant P. J. , Davies J. A. , Tate G. M. , Boothby M. , Prentice C. R. M.
Published: August 2015

1. Plasma concentrations of vasopressin (aVP) attained under conditions of stress were simulated by infusing four volunteers with 0.25, 0.5, 1.0 and 2.0 pressor units of aVP over 1 h (units/h). Three subjects had all four infusions and one received only 1.0 unit/h.

2. Blood samples were taken for assay of factor VIII coagulant activity (FVIIIC), factor VIII related antigen (FVIIIRAg), the ristocetin cofactor (FVIIIRiCof), euglobulin lysis time (ELT) and aVP concentrations before infusion (time 0) and every 20 min for 80 min. Fibrinopeptide A (FPA) generation time was measured at time 0, 60 and 80 min.

3. At infusion rates of 0.25 unit/h median aVP levels peaked at 6.5 pg/ml and there was no change in haemostatic function. At 0.5 unit/h aVP levels peaked at 16.0 pg/ml, there was no change in FVIII or FPA generation time, and plasminogen activator activity (106/ELT2) rose from 100 to 400 units. At 1.0 unit/h, aVP levels rose to 25.4 pg/ml, FVIIIC rose by 160% and activator activity from 87 to 360 units. At 2.0 units/h, aVP concentrations reached 83 pg/ml, there was an increase in all modalities of FVIII and activator activity rose from 251 to 452 units. FPA generation time shortened and circulating plasma levels of FPA were increased.

4. There was a highly significant correlation between the percentage increases in all three components of FVIII and plasma aVP levels (FVIIIC: r = 0.87, P < 0.0001; FVIIIRAg: r = 0.61, P < 0.0001; FVIIIRiCof: r = 0.80, P < 0.0001) and between the increase in plasminogen activator activity and aVP levels (r = 0.56, P < 0.0001).

5. The results indicate that plasma concentrations of aVP comparable with those attained during stress cause a rise in FVIII, an increase in plasma activator activity and effects on FPA generation consistent with low-level activation of the coagulation mechanism. Endogenous vasopressin could mediate alterations in haemostatic function known to accompany events such as surgical operations.
Activities and subcellular distributions of hepatic lipases in control subjects and in patients with alcoholic fatty liver
Authors: Leung Nancy N. Y. , Cairns Stuart R. , Peters Timothy J.
Published: August 2015

1. Human hepatic lipase activities were studied in needle biopsy specimens by fluorogenic and radioisotopic assay methods. Using analytical subcellular fractionation by sucrose density gradient centrifugation a lysosomal acid lipase, with pH optimum of 4.0, and an endoplasmic reticulum alkaline lipase, with pH optimum of 8.5, were demonstrated with the fluorogenic assay.

2. The apparent Km of the acid lipase was 17 μmol/l by the fluorogenic method and 23 mmol/l by the radioisotopic method. The values for alkaline lipase were 94 μmol/l and 1.4 mmol/l respectively.

3. Assay of these activities in biopsies from 16 control subjects and 42 chronic alcoholics showed increasing activity with increasing hepatic fatty infiltration when the fluorogenic assay was used: no differences were demonstrated with radioisotopic assay. These results suggest that depressed lipolysis due to a relative deficiency of triglyceride lipase is not a causal factor in triglyceride accumulation in chronic alcoholic fatty liver.
Vitamin D-dependent rickets type I in pigs
Authors: Fox John , Maunder Eleni M. W. , Randall Valerie A. , Care Anthony D.
Published: August 2015

1. We have bred a strain of pigs with an inherited condition of hypocalcaemic rickets, transmitted by an autosomal-recessive mechanism.

2. Homozygous (affected) piglets grew at half the rate of their heterozygous (clinically normal) littermates, and developed profound hypocalcaemia with severe secondary hyperparathyroidism and hypophosphataemia by 8 weeks of age.

3. In the hypocalcaemic piglets, plasma 1,25-dihydroxyvitamin D levels were low or undetectable, and 24,25-dihydroxyvitamin D3 levels were also reduced despite 25-hydroxyvitamin D3 levels being 2-fold higher.

4. There was no detectable 25-hydroxyvitamin D3-1- or -24-hydroxylase enzyme activity in renal homogenates prepared from affected animals.

5. Plasma and intestinal calcium-binding protein levels were reduced in the hypocalcaemic piglets.

6. Sucrose density gradient analysis of intestinal cytosol, prepared in high-salt buffer, revealed the presence of a similar amount of a specific <4.2S 1,25-dihydroxyvitamin D3 binder in both groups of piglets.

7. Administration of pharmacological doses of vitamin D3 to affected animals reversed the hypocalcaemia.

8. We conclude that this strain of pigs has vitamin D-dependent rickets type I.
Metabolism of vitamin D in patients with primary biliary cirrhosis and alcoholic liver disease
Authors: Mawer E. Barbara , Klass H. J. , Warnes T. W. , Berry Jacqueline L.
Published: August 2015

1. The metabolism of isotopically labelled vitamin D2 and D3 has been investigated in eight patients with primary biliary cirrhosis and in five controls. The concentration of labelled vitamin D2 was lower than that of vitamin D3 in serum of patients with primary biliary cirrhosis on days 1 and 2 after intravenous injection (P < 0.005 and P < 0.05, respectively) but no difference was seen in controls.

2. Similar amounts of labelled 25-hydroxyvitamin D2 and D3 were seen in serum of the control group; the same pattern was observed in the primary biliary cirrhosis group, and no significant differences were observed between the two groups.

3. In both control and primary biliary cirrhosis groups, the serum concentration of labelled 24,25-dihydroxyvitamin D2 exceeded that of 24,25-dihydroxyvitamin D3 (significant for controls on day 2, P < 0.02) but concentrations in the two groups were not different.

4. Concentrations of labelled 25,26-dihydroxyvitamin D3 were significantly higher than those of 25,26-dihydroxyvitamin D2 in the primary biliary cirrhosis group at all times and in the control group on days 2 and 3. Both 25,26-dihydroxyvitamin D2 and D3 were higher in the serum of patients with primary biliary cirrhosis than in controls (significant on day 1, P < 0.05).

5. Urinary excretion over days 0–3 of radioactivity from both vitamins D2 and D3 was significantly higher in the primary biliary cirrhosis group than in controls: 12.03 vs 1.80% for vitamin D2 and 8.98 vs 1.76% for vitamin D3(P < 0.005). Vitamin D2-derived urinary radioactivity in primary biliary cirrhosis correlated strongly with serum bilirubin (P = 0.005).

6. The metabolism of labelled vitamin D3 was studied in seven patients with alcoholic liver disease, three of whom showed low serum concentrations of labelled 25-hydroxyvitamin D3 suggesting impaired hepatic synthesis. The 25-hydroxylation response was quantified as the relative index of 25-hydroxylation and was significantly related to two other indices of liver function. It is concluded that impaired 25-hydroxylation of vitamin D may occur in alcoholic liver disease and results from hepatocellular dysfunction.

7. Less than the predicted amounts of 1,25-dihydroxyvitamin D3 were produced in four of the seven patients with alcoholic liver disease; this defect may be attributable in part to decreased precursor 25-hydroxyvitamin D and to poor renal function.
Sex differences in the hepatic uptake of sulphobromophthalein in the rat
Authors: Orzes N. , Bellentani S. , Aldini R. , Simoni P. , Ferretti I. , Lunazzi G. C. , Sottocasa G. L. , Tiribelli C.
Published: August 2015

1. Sex difference in the hepatic uptake of sulphobromophthalein (BSP) was investigated in male and female rats in three different experimental models.

2. In the intact animal the BSP plasma disappearance rate was significantly higher (P < 0.01) in females than in males when 0.15 or 1.5 μmol/kg body wt. was injected. Comparable values were found at the highest BSP dose (15 μmol/kg body wt.) used.

3. In the perfused liver, the first-pass hepatic extraction and the uptake velocity were significantly higher (P < 0.001) in female rats at low BSP doses (0.3–750 μmol/g of liver) whereas identical values were found at higher concentrations.

4. In hepatocytes isolated by collagenase perfusion, the BSP uptake occurs via two different uptake sites in both sexes. The Km of the high affinity sites was lower in females than in males (3.67 ± 0.58 vs 7.24±0.68 Mmol/l, P < 0.001) whereas Vmax. showed comparable values (2.70 ± 0.36 vs 2.47 ± 0.45 nmol of BSP/mg of protein, NS). In contrast, no difference was found in the kinetic parameters of the low affinity sites (Km 50.6±31.1 vs 61.0±17.5 μmol/l; Vmax. 21.9 ± 13.2 vs 25.0±3.6 nmol of BSP/mg of protein, mean ± sd, NS, females and males respectively).

5. Taken together these data show that low doses of BSP are taken up by the liver more efficiently in female than in male rats and are consistent with a sex-related difference in the affinity but not in the number of the BSP high affinity uptake sites.