bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Assessment of Intestinal Permeability and Lactose Tolerance with Orally Administered Raffinose, Lactose and 1-Arabinose
Authors: Lobley R. W. , Burrows P. C. , Warwick R. , Dawson D. J. , Holmes R.
Published: August 2015

1. In order to develop an improved differential sugar absorption test for simultaneously assessing intestinal permeability and lactose intolerance, methods were established for determining raffinose, lactose and l-arabinose in human urine. Using NAD(P)H-coupled enzymatic assays and fluorimetry, each sugar was measurable over a concentration range of approximately 3–300 μmol/l in diluted urine specimens.

2. After an overnight fast, 40 normal volunteers drank an iso-osmotic solution containing raffinose, lactose and l-arabinose. The median 5 h urinary sugar excretion was 0.26% of the ingested raffinose, 0.05% of lactose and 17.5% of l-arabinose.

3. In 143 patients with gastrointestinal disease, excretion of both ingested raffinose and lactose was significantly increased in coeliac disease in relapse or in partial remission and in Crohn's disease, but not in the irritable bowel syndrome, coeliac disease in remission or ulcerative colitis. Excretion of lactose, but not raffinose, was increased in patients with mucosal lactase deficiency, whereas excretion of l-arabinose was reduced in all disease groups except ulcerative colitis.

4. Discrimination between diseases was poor when based on individual sugar recoveries, but improved dramatically when excretion was expressed relative to that of l-arabinose. The raffinose/l-arabinose excretion ratio, an index of intestinal permeability, was > 0.08 in 15/15 untreated coeliac patients but < 0.06 in all normal subjects and in 9/9 lactase-deficient patients, 15/16 recovered coeliac patients, 5/6 patients with ulcerative colitis, 13/16 patients with Crohn's disease and 61/62 patients with irritable bowel syndrome.

5. The lactose/l-arabinose excretion ratio, an index of lactose maldigestion, was >0.01 in 9/9 lactase-deficient patients and 14/15 untreated coeliac patients, but < 0.008 in all normal subjects, recovered coeliac patients and ulcerative colitis patients, and in 11/16 patients with Crohn's disease and 58/62 patients with irritable bowel syndrome.

6. The test reliably detected the altered intestinal permeability of coeliac disease and small-bowel Crohn's disease, and differentiated between lactosuria due to lactase deficiency and that secondary to villous atrophy. With automation of the analysis, it would be suitable for widespread use in screening for intestinal disease.
Kinetics of Influx of Peptides and Amino Acids into Hamster Jejunum in Vitro: Physiological and Theoretical Implications
Authors: Burston D. , Matthews D. M.
Published: August 2015

1. This paper reports a comparison of the kinetics of influx into hamster jejunum of a series of dipeptides of neutral, basic and acidic amino acids, and a tripeptide of neutral amino acids, with those of corresponding free amino acids.

2. Kt, the substrate concentration at which the transport rate is half the maximal transport rate, and Vmax, the maximal transport rate, were more similar from one peptide to another than among amino acids, with the result that, over a wide range of concentrations, rates of influx of individual peptides varied much less than those of amino acids.

3. It is suggested that this may account for the rates of absorption of amino acids being closely related to the amino acid composition of the protein fed, instead of being widely dissimilar as with corresponding mixtures of free amino acids.

4. With neutral amino acids, both Kt and Vmax. fell with increasing length of the side-chain, as observed on many previous occasions. This did not occur with the corresponding homologous dipeptides, which shows that the hypothesis that the apparent affinity for transport is related to the lipophilic properties of the side-chain cannot be applied to peptides.
Renal Function in Rats with Essential Fatty Acid Deficiency
Authors: Hjelte L. , Larsson M. , Alvestrand A. , Malmborg A.-S. , Strandvik B.
Published: August 2015

1. Renal function was studied in 50-, 70-, 90- and 200-day-old rats with essential fatty acid deficiency. The pharmacokinetics of tobramycin was investigated in 90-day-old essential fatty acid-deficient rats.

2. A higher glomerular filtration rate and a higher serum concentration of urea were seen in 50-day-old essential fatty acid-deficient rats compared with age-matched controls. Later, the glomerular filtration rate progressively deteriorated in parallel with a decline in effective renal plasma flow and with a concomittant rise in serum levels of urea and creatinine. The serum concentration of protein was lower in the rats with essential fatty acid deficiency and that of sodium was higher than in the control rats. The non-renal clearance of tobramycin was increased in the rats with essential fatty acid deficiency.

3. The early hyperfiltration in essential fatty acid-deficient rats with the subsequent fall in glomerular filtration rate, which was paralleled by a rise in serum levels of urea and creatinine, as well as the increased non-renal clearance of tobramycin, are in accordance with the clinical manifestations of cystic fibrosis. Rats with essential fatty acid deficiency might be a useful model with which to study the pathophysiological renal changes in cystic fibrosis related to the progressive essential fatty acid deficiency in this disease.
Effect of Facial Cooling on Mucosal Blood Flow in the Mouth in Humans
Authors: Fouke Janie M. , Wolin Alexis D. , Bowman H. Frederick , McFadden E. Regis
Published: August 2015

1. To determine the effects of facial cooling on intraoral thermal events, we placed a thermal conductivity sensor on the buccal surface of the left cheek in six normal and six asthmatic subjects. Room temperature and cold stimuli were then applied to the integument surface of both sides of the face while mucosal surface temperature and thermal conductivity, as an index of blood flow, were recorded.

2. The room temperature challenge had no effect. Application of the cold stimulus to the exterior of the left cheek caused a monotonic decrease in temperature in the mouth in all subjects and was associated with a change in thermal conductivity in which blood flow increased and then fell to baseline despite a continued drop in temperature. These responses were purely local in that cooling of the right side of the face did not change the temperature or blood flow on the left side. No differences were noted between the asthmatic and normal subjects.

3. The data indicate that lowering the temperature of the skin of the face produces significant alterations in the thermal environment within the mouth. With facial cooling, buccal temperature falls and mucosal blood supply transiently rises. This effect appears to be a purely local thermally mediated event. Facial pressure and cutaneous reflexes do not play a role. The above changes may contribute to the conditioning of inspired air during oral breathing.
Effect of Sodium-Transport Inhibitors on Bronchial Reactivity in Vivo
Authors: Knox Alan J. , Britton John R. , Tattersfield Anne E.
Published: August 2015

1. We have recently shown that ouabain, an inhibitor of Na+/K+-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis.

2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K+-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies.

3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values.

4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 μmol after amiloride and 0.54 μmol after placebo (95% confidence intervals for the difference: 0.9 to −0.2 doubling doses of histamine; P = 0.2).

5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10−2 mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 μmol and 4.3 μmol, respectively, in the normal subjects (95% confidence intervals for the difference: −0.53 to 1.52 doubling doses, P = 0.2), and 0.33 μmol and 0.29 μmol in the asthmatic subjects (95% confidence intervals for the difference: −0.95 to 0.57 doubling doses; P = 0.6).

6. In study 3, 24 atopic asthmatic men were treated for 7 days with placebo or oral digoxin (1.5 mg loading dose plus 0.25 mg twice daily for 6 days). The PD20FEV1 for histamine was measured before, 12 h after the loading dose and on day 7 of treatment. The change in PD20FEV1 did not differ significantly after digoxin and placebo, after either 1 day's treatment [mean (95% confidence intervals) difference: 0.56 doubling dose (−0.37 to 1.5 doubling dose)] or 7 day's treatment [mean (95% confidence intervals) difference: 0.3 doubling dose (−1.23 to 1.8 doubling doses)].

7. Although our work in vitro has suggested that membrane sodium transport may play an important role in determining airway smooth muscle contractility, we have been unable to demonstrate any effect of the sodium-transport inhibitors amiloride and digoxin on histamine reactivity in these studies.
Effect of Autologous Serum on Human Leucocyte Na+/H+ Exchange and Intracellular pH
Authors: Goldsmith D. J. A. , Poston L. , Watson M. , Morris J. , Hilton P. J. , Cragoe E. J.
Published: August 2015

1. Leucocyte Na+/H+ exchange and intracellular pH were investigated in physiological buffer containing bicarbonate.

2. The amiloride analogue 5-(N,N-hexamethylene) amiloride (1 × 10−5 mol/l), an inhibitor of Na+/H+ exchange, had no significant effect on resting leucocyte pH, Na+ influx or Na+ content.

3. Ammonium chloride washout induced a profound intracellular acidosis, stimulating Na+/H+ exchange. This led to a 236% increase in Na+ influx. Eighty-eight per cent of this increase was inhibited by 5-(N,N-hexamethylene) amiloride. This demonstrates that 5-(N,N-hexamethylene) amiloride is an effective inhibitor of Na+/H+ exchange in human leucocytes.

4. The recovery from intracellular acidosis was shown to be dependent entirely on the presence of extracellular Na+. The Ki for inhibition by 5-(N,N-hexamethylene) amiloride of the recovery was 0.5 μmol/l.

5. Incubation with serum increased Na+ influx and Na+ content: the maximal effect was reached at 20% dilution. Serum (10%, v/v) increased influx by 40%, and 20% (v/v) serum by 102%, over resting levels. Only 43% of the serum-induced increase in Na+ influx was inhibited by 5-(N,N-hexamethylene) amiloride. This represented one-fifth of total Na+ influx.

6. Leucocyte intracellular pH increased on incubation with serum. This alkalinization was inhibited using 5-(N,N-hexamethylene) amiloride.

7. Studies of Na+/H+ exchange in leucocytes in physiological and pathological states are more likely to reflect the state in vivo if carried out in the presence of autologous serum.
Increased Erythrocyte Sodium-Lithium Countertransport Activity in essential Hypertension is Due to an Increased Affinity for Extracellular Sodium
Authors: Rutherford P. A. , Thomas T. H. , Wilkinson R.
Published: August 2015

1. Sodium-lithium countertransport activity in a standard assay, its sodium affinity constant and maximum velocity were measured in erythrocytes from normal subjects and from essential hypertensive patients with and without a family history of hypertension.

2. In normal subjects the sodium concentration used in the standard assay was similar to the sodium affinity constant so that the activity measured in this assay was less than the maximum velocity.

3. In patients with essential hypertension and a positive family history, 33% had a sodium-lithium countertransport activity greater than the upper limit of the normal control range (0.4 mmol of Li+ h−1 l−1 of cells).

4. The reason for the raised sodium-lithium countertransport activity was an increased sodium affinity (lower sodium affinity constant) at the outside ion-binding site.

5. Of the patients with essential hypertension and a positive family history but sodium-lithium countertransport activity within the normal range in the standard assay, 30% also had a low sodium affinity constant.

6. A low sodium affinity constant at the outside site of the sodium-lithium countertransporter may be a more specific indicator for a group of patients with inherited hypertension than the standard sodium-lithium countertransport activity assay.
Elevated Plasma Noradrenaline Concentrations in Patients with Low-Output Cardiac Failure: Dependence on Increased Noradrenaline Secretion Rates
Authors: Abraham William T. , Hensen Johannes , Schrier Robert W.
Published: August 2015

1. Plasma noradrenaline concentrations are elevated in patients with congestive heart failure; however, the pathogenesis of these elevated noradrenaline levels is controversial.

2. Possible mechanisms for elevated noradrenaline concentrations in patients with congestive heart failure include increased noradrenaline secretion, decreased clearance of noradrenaline, and a combination of increased secretion and decreased clearance.

3. In the present study, plasma noradrenaline clearance and apparent secretion rates were determined using a whole-body steady-state radionuclide tracer method in six otherwise healthy patients with moderate degrees of low-output cardiac failure and in six normal control subjects.

4. The venous plasma noradrenaline level was elevated in the patients with congestive heart failure as compared with the control subjects (4.18±1.34 versus 1.54 ± 0.16 nmol/l, P < 0.05). There was no stimulation of the adrenal medulla as evident by normal plasma adrenaline levels in both groups (0.19 ±0.04 versus 0.1810.02 nmol/l, not significant). The apparent secretion rate of noradrenaline was elevated in the patients with congestive heart failure (4.75 ±1.95 versus 1.78±0.18 nmol min−1 m−2, P < 0.05), whereas the clearance rate of noradrenaline was similar in the two groups (1.26±0.27 versus 1.16±0.02 1 min−1 m−2, not significant).

5. We conclude that the high peripheral venous plasma noradrenaline concentrations in patients with mildly decompensated low-output cardiac failure are initially due to increased secretion, rather than to decreased metabolic clearance, perhaps in response to diminished effective arterial blood volume.
Effect of Infused Branched-Chain Amino Acids on Muscle and Whole-Body Amino Acid Metabolism in Man
Authors: Louard Rita J. , Barrett Eugene J. , Gelfand Robert A.
Published: August 2015

1. Using the forearm balance method, together with systemic infusions of l-[ring-2,6-3H]phenylalanine and l-[1-14C]leucine, we examined the effects of infused branched-chain amino acids on whole-body and skeletal muscle amino acid kinetics in 10 postabsorptive normal subjects; 10 control subjects received only saline.

2. Infusion of branched-chain amino acids caused a four-fold rise in arterial branched-chain amino acid levels and a two-fold rise in branched-chain keto acids; significant declines were observed in circulating levels of most other amino acids, including phenylalanine, which fell by 34%. Plasma insulin levels were unchanged from basal levels (8 ± 1 μ-units/ml).

3. Whole-body phenylalanine flux, an index of proteolysis, was significantly suppressed by branched-chain amino acid infusion (P < 0.002), and forearm phenylalanine production was also inhibited (P < 0.03). With branched-chain amino acid infusion total leucine flux rose, with marked increments in both oxidative and non-oxidative leucine disposal (P < 0.001). Proteolysis, as measured by endogenous leucine production, showed a modest 12% decrease, although this was not significant when compared with saline controls. The net forearm balance of leucine and other branched-chain amino acids changed from a basal net output to a marked net uptake (P < 0.001) during branched-chain amino acid infusion, with significant stimulation of local leucine disposal. Despite the rise in whole-body non-oxidative leucine disposal, and in forearm leucine uptake and disposal, forearm phenylalanine disposal, an index of muscle protein synthesis, was not stimulated by infusion of branched-chain amino acids.

4. The results suggest that in normal man branched-chain amino acid infusion suppresses skeletal muscle proteolysis independently of any rise of plasma insulin. Muscle branched-chain amino acid uptake rose dramatically in the absence of any apparent increase in muscle protein synthesis, as measured by phenylalanine disposal, or in branched-chain keto acid release. Thus, an increase in muscle branched-chain amino acid concentrations and/ or local branched-chain amino acid oxidation must account for the increased disposal of branched-chain amino acids.
Decreased Cyclic Nucleotide Phosphodiesterase Activity in Human Peripheral Blood Mononuclear Cells from Elderly Women
Authors: Meskini N. , MacOvschi O. , Prigent A. F. , Nemoz G. , Chapuy P. , Lagarde M.
Published: August 2015

1. Both adenosine 3′:5′-cyclic monophosphate and guanosine 3′:5′-cyclic monophosphate phosphodiesterase activities of peripheral blood mononuclear cells were markedly decreased in elderly women as compared with young control women.

2. In contrast, the ability of these cells to bind guanosine 5′-[β, γ-imido]triphosphate, a non-hydrolysable analogue of guanosine 5′-triphosphate, was the same in both groups.

3. These findings are discussed in the context of the decline in immune function which occurs with increasing age.
Systolic Wall Stress and Ventricular Arrhythmia: The Role of Acute Change in Blood Pressure in the Isolated Working Rat Heart
Authors: James M. A. , Jones J. V.
Published: August 2015

1. The effect of a sudden acute change in blood pressure upon arrhythmia provocation has been studied in an isolated working heart model from the Wistar—Kyoto strain of rat. Twenty-four hearts were studied.

2. They were perfused with two different, modified, Krebs—Henseleit solutions at a fixed left atrial pressure.

3. Acute changes in pressure, both increases and decreases, were arrhythmogenic. Whilst ectopic activity was more predictably produced by pressure reductions, this consisted of simple ventricular ectopics only. Pressure increases, in contrast, were capable of provoking more complex and sustained arrhythmias.

4. The effect of pressure changes were highly dependent upon electrolyte concentrations in the perfusate. Low potassium and magnesium concentrations increased the amount of arrhythmia provoked by pressure increases but tended to reduce that provoked by pressure reductions.

5. We conclude that the direct effect of an acute change in pressure upon the myocardium is arrhythmogenic. However, the myocardial response to a pressure change is interdependent upon prevailing electrolyte concentrations.
Short-Term Infusions of Insulin, Triacylglycerol and Glucose do not Cause Acute Increases in Plasminogen Activator Inhibitor-1 Concentrations in Man
Authors: Grant P. J. , Kruithof E. K. O. , Felley C. P. , Felber J. P. , Bachmann F.
Published: August 2015

1. To investigate the acute effects of insulin and triacylglycerol (‘triglyceride’) on circulating plasminogen activator inhibitor-1 concentrations, seven healthy volunteers were studied during hyperinsulinaemic clamps in the presence of euglycaemia (mean glucose concentration 5 mmol/l) and hyperglycaemia (mean glucose concentration 9 mmol/l) with and without triacylglycerol infusions.

2. During euglycaemia, plasma insulin levels rose from baseline values [median (range)] of 13 (6.6–20.6) m-units/l to 89 (74–105) m-units/l and 99 (74–109) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 fell from 27.5 (10–47) ng/ml to 25.0 (14.5–55) ng/ml and 15.5 (11.5–28.5) ng/ml (P < 0.02) over the same time.

3. During hyperglycaemia, plasma insulin concentrations were 12.1 (9.3–17.1) m-units/l at the run-in period and rose to 87 (73–112) m-units/l and 91 (84–97) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 again showed a gradual fall from 24.7 (22–50) ng/ml to 14 (8.3–25.5) ng/ml and 13 (6.0–35.0) ng/ml (P < 0.02) over the same period.

4. Infusion of Intralipid in the presence of hyperinsulinaemia with either euglycaemia or hyperglycaemia was associated with a similar fall in concentrations of plasminogen activator inhibitor-1 over the study period.

5. The results from this study indicate that short-term increases in insulin, glucose or triacylglycerol do not cause acute increases in plasma concentrations of plasminogen activator inhibitor-1.
Cyclosporin A and the humoral response to blood transfusion in the rat: definition of antigens which suppress alloantibody formation
Authors: Propper D. J. , Jones M. C. , Stewart K. N. , Catto G. R. D. , Power D. A.
Published: August 2015

1. Blood transfusions improve renal allograft survival rates, but may induce antibodies which are directed to class I major histocompatibility complex antigens and mediate hyperacute transplant rejection. A model to study the development of such antibodies was developed in inbred strains of rats.

2. The influence of transplantation antigens shared between an initial course of blood transfusions, given with cyclosporin A, and a subsequent antigenic challenge (blood transfusion), given without cyclosporin A, on alloantibody responses to class I major histocompatibility complex antigens was then investigated.

3. Cyclosporin A administration prevented the development of alloantibodies to class I major histocompatibility complex antigens during the initial transfusion period.

4. After the challenge transfusions, alloantibody responses to class 1 major histocompatibility complex antigens were suppressed when class I major histocompatibility complex or minor histocompatibility antigens were shared between the initial and final transfusions.

5. This suppression only extended to third party class I antigens when minor histocompatibility complex antigens were shared between the initial and final transfusions. Sharing of class I or class II antigens had no effect on alloantibody responses to third party class I antigens co-expressed on the same cell.

6. These studies suggest that cyclosporin A given with blood transfusions may prevent clinical sensitization while permitting the development of suppressor activity, mediated by shared minor histocompatibility complex determinants, to a broad range of potential donor antigens.
Changes in electrocardiographic patterns at different stages of Chagas' heart disease in rats
Authors: Bestetti Reinaldo B. , Pinto Lucimara Z. , Soares Edson G. , Muccillo Gerson , Oliveira J. Samuel M.
Published: August 2015

1. The resting electrocardiogram was obtained from 25 Trypanosoma cruzi-infected rats 30 days after infection (phase I). The resting electrocardiogram was abnormal in 12 (group I) and normal in 13 (group II) animals. Nineteen similar but non-infected animals served as controls. Both the resting electrocardiogram and the ajmaline test were performed 120 and 350 days after infection (phases II and III, respectively).

2. With regard to the resting electrocardiogram of group I animals, left axis deviation was found in 10 of 12 (83%) in phase I, one of 12 (8%) in phase II (P <0.05) and in none in phase III (P <0.05). An intraventricular conduction delay was found in four of 12 (33%) rats in phase I, two of 12 rats (16%) in phase II (P >0.05) and six of 12 rats (50%) in phase III (P >0.05). The ajmaline test was abnormal in nine of 10 (90%) rats of group I with normal resting electrocardiogram in phase II, and in three of six (50%) animals in phase III (P >0.05).

3. An intraventricular conduction delay was found in the resting electrocardiogram of one of 13 (7%) rats of group II in phase III. The ajmaline test was abnormal in one of 13 (7%) rats in phase II and in one of 12 (8%) rats in phase III.

4. No control rat showed pathological changes. Eight of 12 (66%) rats of group I and two of 13 (15%) rats of group II showed histopathological alterations consisting of mononuclear cell infiltrate, cellular vacuolation and myocardial necrosis.

5. We conclude that different abnormal patterns may be seen in the resting electrocardiogram in the same T. cruzi-infected rat over time. The QRS axis changes predominate during acute and intraventricular conduction disturbances in the chronic stage of Chagas' heart disease in rats.
Mechanism of reserpine-induced acute gastric mucosal injury in the rat: role of endogenous 5-hydroxytryptamine
Authors: Saum Aws S.
Published: August 2015

1. Reserpine (5 mg/kg intraperitoneally) produced gastric mucosal vasoconstriction and injury in all rats within 6 h (injury score 38.8 ± 2.1 mm2, mean ± SEM). Coeliac ganglionectomy or the β-adrenoceptor-blocking drug propranolol (5–15 mg/kg) did not influence these effects of reserpine, but vagotomy protected the rats against them. The α-adrenoceptor-blocking drugs phenoxybenzamine and phentolamine at 5 mg/kg were protective against injury. However, a 10 mg/kg dose of either blocker was more effective (2.2 ± 0.5 mm2 and 3 ± 0.8 mm2, respectively, versus 38.8 ± 2.1 mm2, mean ± SEM, P <0.01) and a dose of 15 mg/kg afforded complete protection.

2. Methysergide, a 5-hydroxytryptamine receptor antagonist, produced a dose-dependent increase in the reserpine-induced injury; a significant (P <0.05) increase was noted with 15 and 20 mg/kg (47.5 ± 2.9 mm2 and 49.4 ± 2.2 mm2, respectively, versus 38.8 ± 2.1 mm2, mean ± SEM).

3. The results suggest that, in the rat, reserpine causes vagal α-adrenoceptor stimulation producing gastric mucosal vasoconstriction and injury. 5-Hydroxytryptamine is not implicated in the mechanism of this injury and affords protection against it.
Platelet thromboxane A2 receptors in type I diabetes
Authors: Modesti Pietro Amedeo , Abbate Rosanna , Gensini Gian Franco , Colella Andrea , Serneri Gian Gastone Neri
Published: August 2015

1. Human platelet thromboxane A2 receptor expression on the membrane surface is possibly dynamically regulated by changes either in the ligand concentration or in membrane fluidity. An increased thromboxane A2 production and a decreased membrane fluidity has been reported in diabetic patients.

2. In the present study the binding characteristics of platelet thromboxane A2 receptors have been investigated in nine diabetic patients (type I) and in 15 healthy control subjects by a radioligand-binding method using 9,11-dimethylmethane-11,12- methane -16-[3-125I-4- hydroxyphenyl]-13,14-dihydro-13-aza-15-tetranor-thromboxane A2 as the radiolabelled ligand.

3. The maximum concentration of binding sites was 163 (sd 35) fmol/108 platelets (n = 15) with 987 (sd 209) receptors/platelet in controls, whereas in diabetic patients the maximum concentration of binding sites was 74.2 (sd 28) fmol/108 (n = 9) with 447 (sd 172) receptors/platelet (P < 0.001). The dissociation constants were 18 (sd 4) nmol/l and 21 (sd 6) nmol/l (not significant) in control subjects and in diabetic patients, respectively. Glycated haemoglobin, which is reported to reduce membrane fluidity, was found to be negatively correlated (r = 0.60, P < 0.05) with thromboxane A2 receptor number in the diabetic patient group. On the contrary, a positive linear correlation between the equilibrium dissociation constant and glycated haemoglobin was found in diabetic patients (r = 0.75, P < 0.01).
Functional properties in vitro of systemic small arteries from rabbits fed a cholesterol-rich diet for 12 weeks
Authors: Simonsen Ulf , Ehrnrooth Eva , Gerdes Lars Ulrik , Færgemann Ole , Buch Jan , Andreasen Frederik , Mulvany Michael J.
Published: August 2015

1. Recent evidence has suggested that the impairment of endothelium-dependent cholinergic relaxation in vitro, which is seen in atherosclerotic large arteries of animals and man, could be part of a general deleterious effect to the endothelium of hypercholesterolaemia.

2. This possibility has been investigated in vitro by measuring the response to acetylcholine, sodium nitroprusside, 5-hydroxytryptamine and noradrenaline in segments of aorta and of femoral, mesenteric and cerebral small arteries (internal diameter approximately 200 μm) from control rabbits (n = 12) and from rabbits fed a 1% (w/w) cholesterol and 3% (w/w) coconut oil diet (n = 12) for 12 weeks.

3. Thoracic aorta segments from the control rabbits exhibited a maximal relaxation in response to acetylcholine of 64 ± 11% compared with 10 ± 5% (P < 0.01) for thoracic segments from cholesterol-fed animals. Cerebral, femoral and mesenteric small arteries exposed to acetylcholine (10−9-10−4 mol/l) relaxed to the same degree as arteries from control rabbits. The responses to sodium nitroprusside and bradykinin of the small arteries from the cholesterol-fed rabbits remained unaffected. 5-Hydroxytryptamine evoked comparable contractions in the small arteries, while the sensitivity to noradrenaline of the femoral small arteries was significantly decreased and the response of cerebral small arteries to noradrenaline in cholesterol-fed rabbits slightly increased compared with control rabbits.

4. Aorta from the cholesterol-fed rabbits had extensive atheromatous lesions. Morphological measurements and histological examination showed unchanged thickness and light microscopic appearance of intima and media of small arteries from cholesterol-fed animals compared with control animals.

5. The present study indicates that hypercholesterolaemia in this rabbit model is followed by atherosclerotic lesions and changed function of large arteries, but that both function and structure of systemic small arteries are largely unaffected.
Glomerular binding and contractile response to angiotensin II in rats with chronic experimental cirrhosis of the liver
Authors: Villamediana Luis M. , Velo Mercedes , Olivera Ana , Hernando Luis , Caramelo Carlos , López-Novoa Jose M.
Published: August 2015

1. The effects of angiotensin II on glomerular filtration rate and renal plasma flow were studied in surgically instrumented conscious control and cirrhotic rats. In addition, angiotensin II binding and the contractile response to angiotensin II were studied in glomeruli isolated from cirrhotic and control rats.

2. Cirrhotic rats had a higher glomerular filtration rate and a higher renal plasma flow than control animals. A non-pressor dose of angiotensin II induced small but significant decreases in glomerular filtration rate and renal plasma flow in both control and cirrhotic rats, the effect on renal plasma flow being the most pronounced.

3. Plasma renin and aldosterone concentrations were similar in control and cirrhotic rats.

4. The cross-sectional area of glomeruli from cirrhotic rats was 42% greater than that of glomeruli from control animals. Angiotensin II (10−9 mol/l) decreased the cross-sectional area of glomeruli from control animals by 6.4 ± 0.9% and of glomeruli from cirrhotic rats by 6.6 ± 0.8% (P = not significant for comparison between control and cirrhotic animals).

5. There were no differences between control and cirrhotic rats in the affinity of angiotensin II for its glomerular receptors. However, the angiotensin II receptor density was higher in cirrhotic than in control rats, thereby producing an increased total angiotensin II binding in cirrhotic rats.

6. Since no functional differences between control and cirrhotic animals were present in the response to angiotensin II, even though angiotensin II binding was increased, a post-receptor blockade of the angiotensin II signal could be present in cirrhotic rats.
Tubular reabsorption of pepsinogen isozymogens in man studied by the inhibition of tubular protein reabsorption with dibasic amino acids
Authors: ten Dam M. A. G. J. , Zwiers A. , Crusius J. B. A. , Pals G. , van Kamp G. J. , Meuwissen S. G. M. , Donker A. J. M. , ten Kate R. W.
Published: August 2015

1. The fractional clearances of pepsinogen A (PGA), pepsinogen C (PGC) and the main PGA isozymogens, i.e. PGA-3, PGA-4 and PGA-5, were measured in 13 healthy male volunteers before and during blockade of tubular protein reabsorption by intravenous infusion of either l-arginine hydrochloride (n = 8; 0.5 g h−1 kg−1 body weight) or an equimolar amount of l-lysine hydrochloride (n = 5; 0.44 g h−1 kg−1 body weight). Glomerular filtration rate was measured by a radioisotope method.

2. The fractional baseline clearance of PGC (1 ± 1%) was lower than that of PGA (20 ± 10%). In addition, the fractional clearance of the PGA isozymogens appeared to be different: the fractional clearance of PGA-5 (7 ± 3%) was lower than that of PGA-4 (18 ± 9%), and the fractional clearance of PGA-4 was lower than that of PGA-3 (30 ± 10%). These differences in fractional clearance between PGA isozymogens decreased during infusion of both arginine and lysine.

3. Pepsinogens are freely filtered proteins. It can therefore be concluded that the differences in fractional clearance between PGA isozymogens imply differences in tubular reabsorption. This is remarkable as PGA isozymogens are proteins with an almost identical amino acid sequence and electric charge. The disappearance of the differences in tubular reabsorption during arginine and lysine infusion suggests that PGA isozymogens differ in affinity for negatively charged binding sites in the tubular cell membrane. In order to explain the low fractional clearance of PGC compared with that of PGA and the less marked effect of arginine or lysine infusion on the fractional clearance of PGC, an additional PGC-specific binding site has to be postulated.
Reassessment of the single intravenous injection method with inulin for measurement of the glomerular filtration rate in man
Authors: Prescott L. F. , Freestone S. , McAuslane J. A. N.
Published: August 2015

1. Factors influencing the total body and renal clearances of inulin were investigated in a total of 37 healthy adult volunteers and 10 patients with stable chronic renal failure after the single intravenous injection of a dose of 70 mg/kg given over 5 min.

2. The elimination of inulin was highly concentration-dependent, and in healthy volunteers the renal clearance fell from 103.7 ± 14.4 ml min−1 1.73 m−2 during the first hour after administration to 49.1 ± 20.9 ml min−1 1.73 m−2 over the period 6-8 h. In the patients with renal failure the renal clearance fell correspondingly from 39.7 ± 16.5 to 26.6 ± 8.6 ml min−1 1.73 m−2. There were no changes in the simultaneously measured clearances of creatinine.

3. The values obtained for the total body clearance of inulin after a single injection depend critically on dose, the number and timing of blood samples, the choice of pharmacokinetic model, the number of data points chosen for estimation of the slope of the terminal elimination phase for analysis by the methods of residuals, and the weighting used for curve fitting by non-linear regression analysis.

4. With standardized conditions of sampling from 0 to 2 h and weighted non-linear regression analysis of the plasma concentration-time data, the total body and renal clearances of inulin were almost identical in subjects with normal renal function at 105.2 ± 10.2 and 102.9 ± 13.0 ml min−1 1.73 m−2. In the patients with chronic renal failure sampling was continued for 3 h and the corresponding clearances were 40.4 ± 15.3 and 38.9 ± 15.7 ml min−1 1.73 m−2.

5. The 0-2 h total body and renal clearances of inulin were measured by the single injection method and the renal clearance was measured by the standard constant infusion method on different occasions in 10 healthy volunteers. The respective clearances were similar at 101.4 ± 6.6, 94.9 ± 11.9 and 88.4 ± 12.1 ml min−1 1.73 m−2.

6. The reproducibility of the single injection and constant infusion methods was compared by measuring the inulin clearance with both techniques on three occasions in separate groups of eight and nine healthy volunteers. The mean coefficient of variation for the total body clearance with the single injection method was only 3.9% compared with 9.5% for the renal clearance determined the same way and 12.0% for the renal clearance during constant infusion.

7. Urine collection and fluid loading are not required for the single injection technique, and it is more reproducible and less demanding than the constant infusion method. With simple precautions, the single injection method with inulin is suitable for routine estimation of the glomerular filtration rate.
Orotidine Accumulation in Human Erythrocytes during Allopurinol Therapy: Association with High Urinary Oxypurinol-7-Riboside Concentrations in Renal Failure and in the Lesch-Nyhan Syndrome
Authors: Simmonds H. A. , Reiter S. , Davies P. M. , Cameron J. S.
Published: August 2015

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol.

2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome.

3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol.

4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations.

5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels.

6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5′-mono-phosphate decarboxylase by oxypurinol-7-ribotide.
Renal and Cardiovascular Effects of Exogenous Insulin in Healthy Volunteers
Authors: Gans R. O. B. , v.d. Toorn L. , Bilo H. J. G. , Nauta J. J. P. , Heine R. J. , Donker A. J. M.
Published: August 2015

1. Renal and cardiovascular effects of three dosages of insulin [50 (Ins I), 300 (Ins II) and 500 (Ins III) m-units h−1 kg−1] were investigated in healthy males by using a euglycaemic clamp technique. On separate days, control experiments were carried out to correct for any circadian variation in the variables studied.

2. All three insulin dosages resulted in a marked decline in fractional sodium excretion (actual experiments: basal, 0.95 ± 0.15%, Ins I, 0.79 ± 0.10%, Ins II, 0.80 ± 0.12%, Ins III, 0.84 ± 0.08%; control experiments: basal, 0.96 ± 0.10%, Ins I, 1.20 ± 0.12%, Ins II, 1.53 ± 0.15%, Ins III, 1.43 ± 0.10%; means ± sem, P < 0.005, analysis of variance). With the highest insulin dosage, the reduction in fractional sodium excretion tended to be less striking. This coincided with a rise in heart rate, pulse pressure and pulse rate-systolic blood pressure product (double product). Although blood pressure itself did not change, systolic blood pressure also tended to increase (actual experiments: basal, 133 ± 5 mmHg, Ins I, 132 ± 5 mmHg, Ins II, 139 ± 5 mmHg, Ins III, 143 ± 4 mmHg; control experiments: basal, 128 ± 3 mmHg, Ins I, 129 ± 3 mmHg, Ins II, 130 ± 3 mmHg, Ins III, 133 ± 3 mmHg; means ± sem, P = 0.09, analysis of variance). There was a positive correlation between the change in fractional sodium excretion and the change in systolic blood pressure over control values (r = 0.696, P < 0.028). At a rise in systolic blood pressure of 18 mmHg, the sodium-retaining effect of insulin appeared to be offset. A shift of the pressure-natriuresis relation to the right is suggested.

3. Plasma catecholamines did not change. Plasma renin activity increased from 1.11 ± 0.17 (basal) to 2.13 ± 0.31 (Ins III) pmol of angiotensin I h−1 ml−1; on the control day, a decline from 1.28 ± 0.24 (basal) to 0.81 ± 0.13 (Ins III) pmol of angiotensin I h−1 ml−1 was noted (P < 0.001). Despite this rise no concomitant rise in plasma aldosterone occurred.

4. Chronic hyperinsulinaemia may lead to blood pressure elevation in the long-term if it is postulated that resistance to the glucose-lowering effect of insulin is absent for the effects of insulin on the kidney and the cardiovascular system.
Diurnal Blood Pressure Variation in Quadriplegic Chronic Spinal Cord Injury Patients
Authors: Krum Henry , Louis William J. , Brown Douglas J. , Jackman Graham P. , Howes Laurence G.
Published: August 2015

1. Measurement of blood pressure and heart rate over a 24 h period was peformed in 10 quadriplegic spinal cord injury patients and 10 immobilized, neurologically intact orthopaedic subjects by using the Spacelabs 90207 automated ambulatory monitoring system.

2. Systolic and diastolic blood pressure fell significantly at night in orthopaedic subjects but not in quadriplegic patients, and night-time blood pressures were similar in both groups.

3. Cumulative summation of differences from a reference value (cusum analysis) confirmed a markedly diminished diurnal blood pressure variation in the quadriplegic patients.

4. These findings could not be accounted for on the basis of blood pressure variations during chronic postural change.

5. Heart rate fell significantly at night in both groups.

6. The findings suggest that the increase in blood pressure during waking hours in neurologically intact subjects is a consequence of a diurnal variation in sympathetic activity (absent in quadriplegic patients with sympathetic decentralization) which is independent of changes in physical activity.
Extent of pulmonary emphysema in man and its relation to the loss of elastic recoil
Authors: Gugger M. , Gould G. , Sudlow M. F. , Wraith P. K. , MaCnee W.
Published: August 2015

1. We assessed lung density, determined by computerized tomography, as a measure of emphysema and related this to lung function and measurement of the elastic recoil of the lung in normal subjects and patients with chronic obstructive lung disease.

2. We found a significant correlation between measurements of elastic recoil pressure at 90% of total lung capacity and both the forced expiratory volume in 1 s (r = 0.80, P <0.001) and the transfer factor for carbon monoxide (r = 0.70, P <0.001). Measurements of elastic recoil of the lung also correlated with lung density as measured by computerized tomography scanning (P <0.001).

3. Multiple regression analysis demonstrated a correlation between the density of the lowest fifth percentile of the computerized tomography lung-density histogram, and both the natural logarithm of the shape parameter of the pressure-volume curve (P <0.01), and the transfer factor for carbon monoxide (P <0.01). However, the mean computerized tomography lung density correlated, in addition, with the elastic recoil pressure of the lungs at 90% of total lung capacity (P <0.001).

4. Since the elastic recoil pressure correlates with computerized tomography lung density, and hence with emphysema, and since elastic recoil pressure also correlates with the forced expiratory volume in 1 s, these results suggest that loss of elastic recoil is one determinant of airflow limitation in patients with chronic obstructive lung disease.
Hypothalamic regulatory peptides in obese and lean Zucker rats
Authors: Williams Gareth , Cardoso Helena M. , Lee Ying C. , Ball Joanna M. , Ghatei Mohammad A. , Stock Michael J. , Bloom Stephen R.
Published: August 2015

1. Hypothalamic concentrations of nine peptides with experimental effects on energy balance were compared in obese (fa/fa) and lean (Fa/?) male Zucker rats. To determine whether any peptide differences between obese and lean rats might be due to the overweight condition per se, separate groups of obese rats were food-restricted to reduce their body weight to lean values.

2. Concentrations of neuromedin B, a bombesin-like peptide, in the central hypothalamus were significantly higher in obese than in lean rats. This difference was not affected in food-restricted obese rats.

3. Hypothalamic levels of neuropeptide Y, an extremely potent central appetite stimulant, were similar in lean and freely fed obese rats but central hypothalamic levels of neuropeptide Y rose significantly in food-restricted obese rats.

4. These findings suggest that disturbances in hypothalamic neuromedin B concentrations may be involved in the obesity syndrome of the fa/fa Zucker rat. Increased central hypothalamic levels of neuropeptide Y in food-restricted rats suggest that this peptide may help to defend body weight by stimulating eating after weight loss.
Role of prostaglandins in the natriuresis of head-out water immersion in humans
Authors: Rabelink Ton J. , Koomans Hein A. , Mees Evert J. Dorhout
Published: August 2015

1. Prostaglandins may play a role in the natriuresis seen after acute circulatory challenges. To assess this role in head-out water immersion, we compared, in clearance studies, the effects of acute (24 h) and chronic (7 days) administration of indomethacin, an inhibitor of prostaglandin synthesis, on the renal response to head-out water immersion in six healthy subjects on a 200 mmol of sodium/day diet and on a 40 mmol of sodium/day diet.

2. Indomethacin caused a similar degree of sodium retention on each of these two diets.

3. During the 40 mmol of sodium/day diet, acute administration of indomethacin decreased sodium excretion before, as well as during, head-out water immersion; however, the relative increase caused by head-out water immersion was normal. After chronic administration of indomethacin, both baseline sodium excretion and the natriuresis induced by head-out water immersion were similar to those in control studies.

4. During the 200 mmol of sodium/day diet, indomethacin had no effect on baseline sodium excretion, nor on the natriuretic effect of head-out water immersion.

5. Head-out water immersion decreased tubular lithium reabsorption and increased diluting segment delivery. Despite opposite effects of indomethacin on these parameters, indomethacin did not prevent the tubular effects of head-out water immersion on either diet. However, indomethacin did prevent the marked increase in estimated renal plasma flow and the fall in filtration fraction that were observed during head-out water immersion in the absence of indomethacin (control).

6. Head-out water immersion was not associated with an increase in urinary excretion of prostaglandins. Indomethacin lowered baseline urinary excretion of prostaglandins, which did not change further during head-out water immersion.

7. We therefore conclude that renal prostaglandins are not essential for a normal natriuretic response to head-out water immersion, although they may mediate the vasodilatation induced by head-out water immersion.