bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucose Polymer in the Fluid Therapy of Acute Diarrhoea: Studies in a Model of Rotavirus Infection in Neonatal Rats
Authors: Thillainayagam A. V. , Dias J. A. , Salim A. F. M. , Mourad F. H. , Clark M. L. , Farthing M. J. G.
Published: August 2015

1. Unlike standard glucose-electrolyte oral rehydration solutions, solutions containing polymeric glucose as substrate can significantly reduce stool output, duration of diarrhoea and total oral rehydration solution requirements. However, neither the underlying mechanisms nor the optimal size and concentration of glucose polymer has been defined.

2. We have used a model of rotavirus diarrhoea in neonatal rats to compare the effects on water and solute absorption of varying the concentration of a glucose polymer (mean chain length five glucose residues) in experimental oral rehydration solutions. Three polymer (P) solutions were compared with solutions of identical electrolyte content (mmol/l: sodium, 60; potassium, 20; chloride, 60; citrate, 10) containing equivalent amounts of free glucose (G) as substrate by perfusion of the entire small intestine in situ. The polymer (9, 18, 36 mmol/l; 159, 168, 186 mosmol/kg, respectively) and the monomer (45, 90, 180 mmol/l; 195, 240 320 mosmol/kg) solutions were perfused in normal and rotavirus-infected neonatal rats.

3. In normal intestine polymer solutions promoted greater water absorption [P9, mean 291.4 (SEM 16.4); P18, 331.9(13.1); P36, 284.3 (11.8) μl mi−1 g−1] than their equivalent monomer solutions [G45, 220.8 (8.4); G90, 240 (21); G180,79.4 (145) μl min− g−1; P < 0.02]. In rotavirus-infected intestine, water absorption from all solutions declined, but the fall was much less pronounced from the polymer solutions [P9, 232.8 (6); P18, 277.2 (20.5); P36, 166 (18.2) μl min−1 g−1] than from their monomeric counterparts [G45, 116.7 (25.5); G90, 68.7 (12.4); G180, 21 (11.6) μl min−1 g−1; P < 0.005].

4. In both the normal net absorptive state and the net secretory state induced by rotavirus infection, there was a striking inverse correlation between net water absorption and perfusate osmolality (r = −0.94 and r = −0.88, respectively; P < 0.05). In rotavirus-infected intestine, increasing the polymer concentration from 18 to 36 mmol/l resulted in a relative fall in water absorption (P < 0.01). The hypertonic solution G180 was associated with the lowest water absorption (P < 0.01). None of the solutions was able to reverse rotavirus-induced net secretion of sodium, which was similar from all solutions, whether polymer- or monomer-based.

5. These results (i) emphasize the pre-eminence of hypotonicity among the factors promoting water absorption from polymer-based oral rehydration solutions in acute diarrhoea, (ii) confirm the adverse consequence of raising substrate concentration (whether polymer or monomer) beyond certain limits and (iii) indicate that the concentration of this glucose polymer yielding the optimum compromise between substrate availability and low osmolality may be approximately 9–18 mmol/l.
No Mandatory Role for the Spleen in the Exercise-Induced Leucocytosis in Man
Authors: Iversen P. O. , Arvesen B. L. , Benestad H. B.
Published: August 2015

1. Short-lasting strenuous physical exercise leads to a marked increase in the blood concentration of leucocytes in healthy humans. The cell sources of this leucocytosis have not been definitely identified, neither has the contribution made by the various subtypes of leucocytes.

2. We have compared the exercise-induced leucocytosis in six splenectomized and six intact subjects. The blood concentrations of leucocytes as well as of most subtypes, except monocytes and eosinophilic granulocytes, increased substantially at the end of a 5 min exercise (200 W) bout.

3. The increases were similar in the splenectomized subjects and in the control subjects. Thirty minutes after completion of the exercise the various leucocyte blood concentrations had returned to pre-exercise levels.

4. The plasma concentrations of several cytokines (interleukins-1α and −6; tumour necrosis factor-α and granulocyte colony-stimulating factor) known to affect leucocyte kinetics did not change appreciably with exercise in either group.

5. We conclude that exercise-induced leucocytosis can take place in the absence of the spleen. There was no evidence that cytokines known to affect leucocyte formation, mobilization and activity are involved in this leucocytosis.
Recovery from Acute Ischaemic Renal Failure is Accelerated by Des-(1–3)-Insulin-Like Growth Factor-1
Authors: Clark Ross , Mortensen Deborah , Rabkin Ralph
Published: August 2015

1. Acute renal failure carries a high risk of morbidity and mortality, so there is a need for agents that minimize renal injury after an insult and that hasten repair. Insulin-like growth factor-1 is mitogenic for renal tubular cells; in normal kidneys it has haemodynamic effects and it is potently anabolic. We tested the theory that insulin-like growth factor-1 may be of use in the treatment of acute renal failure by administering recombinant des-(1–3)-insulin-like growth factor-1, a truncated form of insulin-like growth factor-1, which occurs naturally. Ischaemic renal failure was induced in normal rats by occluding both renal pedicles for 60 min. Then des-(1–3)-insulin-like growth factor-1 (0.8 mg day−1 kg−1) or vehicle was given by subcutaneous minipump for 7 days. The rats were weighed and bled daily and in one experiment were housed in metabolic cages and urine was collected.

2. Des-(1–3)-insulin-like growth factor-1 caused a lower and earlier peak in both serum creatinine and blood urea-nitrogen levels, and a more rapid and complete return toward basal values than in untreated animals. Also des-(1–3)-insulin-like growth factor-1 significantly increased creatinine clearance and reduced fractional excretion of filtered sodium. Besides these beneficial effects on kidney function, des-(1–3)-insulin-like growth factor-1 was anabolic as treated rats gained weight while control rats lost weight. The mortality in control rats was 28% compared with 6% in treated rats.

3. Thus des-(1–3)-insulin-like growth factor-1 accelerated recovery from acute ischaemic injury and may be useful for the treatment of acute renal failure.
Plasma Endothelin Levels and Vascular Effects of Intravenous l-Arginine Infusion in Subjects with Uncomplicated Insulin-Dependent Diabetes Mellitus
Authors: Smulders Ronald A. , Stehouwer Coen D. A. , Olthof Cornelis G. , Van Kamp Gerard J. , Teerlink Tom , De Vries Peter M. J. M. , Donker Ab J. M.
Published: August 2015

1. Uncomplicated insulin-dependent diabetes mellitus is associated with generalized vasodilatation. This vasodilatation is believed to contribute to the development of microvascular complications. The endothelium plays an important role in the regulation of vascular tone.

2. To investigate the role of endothelial mediators, we measured plasma endothelin levels and studied the vascular effects of intravenous l-arginine (the precursor of NO) in 10 male type 1 diabetic patients and 10 non-diabetic subjects.

3. The baseline plasma endothelin level was significantly lower in the diabetic patients [mean 1.7 (SD 0.5) versus 2.1 (0.4) pmol/l; P < 0.05] than in the control subjects.

4. During l-arginine infusion, plasma cyclic GMP (the second messenger for NO) increased in the control subjects [from 5.1 (2.9) to 6.9 (2.9) nmol/l; P < 0.05 versus saline] and in the diabetic patients [from 4.6 (1.8) to 5.7 (2.2) nmol/l; P = 0.09]. l-Citrulline (a by-product of NO synthesis from l-arginine) increased in both groups. The responses to l-arginine were not significantly different between the control subjects and the diabetic patients. The plasma atrial natriuretic peptide level did not change in either group during infusion of l-arginine or of an equal volume of isotonic saline.

5. Blood pressure decreased slightly during l-arginine administration in both groups. In control subjects, the extracellular fluid volume in the lower leg increased during l-arginine infusion as compared with saline; in the diabetic patients both l-arginine and saline increased the extracellular fluid volume.

6. In conclusion, the vascular effects of l-arginine are similar in men with uncomplicated insulin-dependent diabetes mellitus and in control subjects. Whether these effects are due to an increase in NO synthesis remains unclear. The increase in extracellular fluid volume during saline infusion in diabetic patients suggests an increase in microvascular permeability in
Blood Flow Responses to Intra-Arterial Acetylcholine in Man: Effects of Basal Flow and Conduit Vessel Length
Authors: Chowienczyk P. J. , Cockcroft J. R. , Ritter J. M.
Published: August 2015

1. Acetylcholine relaxes human resistance vessels and releases nitric oxide and other factors from the endothelium. Comparison of responses to acetylcholine with those to an endothelium-independent vasodilator (such as nitroprusside) forms the basis of the so-called acetylcholine test of endothelial function. However, when this test is applied in vivo by intraarterial infusion, the metabolic instability of acetylcholine may result in differential responses to these drugs arising from anatomical rather than functional differences.

2. Vasodilator responses to brachial Artery infusions of acetylcholine (41 and 83 nmol/min) and sodium nitroprusside (11 and 38 nmol/min) were measured in 30 healthy human subjects using venous occlusion plethysmography.

3. Responses to acetylcholine showed a greater dependence on resting blood flow (P < 0.05) and on forearm length (P < 0.05) than those to sodium nitroprusside (results predicted by a simple blood flow model).

4. Correction for forearm length abolished an apparent difference of 59% between responses to acetylcholine in men and women. Conduit vessel geometry and resting blood flow influence the acetylcholine test of endothelial function.
Increased Platelet Volume and Platelet Mass in Patients with Atherosclerotic Renal Artery Stenosis
Authors: Bath Philip M. W. , Missouris Constantinos G. , Buckenham Timothy , MacGregor Graham A.
Published: August 2015

1. Platelet volume was measured in citrated blood in two groups of patients at risk of having atherosclerotic renal artery stenosis, namely (i) 30 patients with severe hypertension, and (ii) 44 patients with peripheral vascular disease.

2. Platelet volume was increased in patients with hypertension who had atherosclerotic renal artery stenosis diagnosed by angiography: no renal artery stenosis, median 7.2 (interquartile range 0.5) × 10−15/l; renal artery stenosis 7.8 (0.8) × 10−15/l; platelet mass also increased with increasing severity of renal artery stenosis. Platelet volume correlated with severity of renal artery stenosis (rs = 0.391, 2p = 0.033, n = 30). Similarly, platelet volume correlated with severity of renal artery stenosis in patients with peripheral vascular disease (rs = 0.319, 2p = 0.035, n = 44). Serum immunoreactive platelet-derived growth factor (predominantly released from platelets) and plasma immunoreactive interleukin-6 (a cytokine which has been postulated to regulate platelet volume) concentrations were not different between hypertensive patients with and without renal artery stenosis.

3. Since large platelets are hyperactive, increased platelet volume may contribute to the development of atherosclerotic renal artery stenosis. However, the present data do not lend support to the hypothesis that platelet-derived growth factor is central to renal artery atherogenesis. Interleukin-6 does not appear to regulate platelet volume.
Changes in Pulse Transit Time and Pulse Rate as Markers of Arousal from Sleep in Normal Subjects
Authors: Pitson D. , Chhina N. , Knijn S. , van Herwaaden M. , Stradling J.
Published: August 2015

1. Obstructive sleep apnoea and its variants often provoke hundreds of short arousals that lead to the most important symptom, disabling hypersomnolence. The measurement of sleep in these conditions requires the documentation of these short arousals and this is conventionally done by manual inspection of the sleeping EEG, a laborious procedure.

2. Other markers of ‘arousal’, that are easier to measure and document, include several cardiovascular signals that change as part of the orienting reflex: pulse rate rise, blood pressure rise, skin vasoconstriction, for example.

3. Pulse transit time (measured as the interval from the ECG R-wave until the arrival of the pulse pressure wave at the periphery, about 250 ms) varies inversely with blood pressure and provides a beat-to-beat estimation of blood pressure changes.

4. In eight normal subjects we have assessed the relationship between transient EEG arousals of different length (provoked by external stimuli) and changes in both pulse transit time and heart rate.

5. Significant falls in pulse transit time occurred in response to external stimuli [15.1 (SEM 1.4) ms], indicating a rise in blood pressure, and were significant even when there was no discernible change in the EEG [9.9 (SEM 2.6) ms]. Significant changes in heart rate also occurred [10.3 (SEM 1.2) beats/min], but were slightly less sensitive than changes in pulse transit time.

6. Changes in pulse transit time (and to a lesser extent pulse rate) are sensitive markers of EEG arousal. As such they should be useful to include when monitoring sleep and its disorders, particularly since pulse transit time recorders can easily be made portable for home use.
Changes in Bone Mineral Density Associated with Dietary-Induced Loss of Body Mass in Young Women
Authors: Ramsdale S. J. , Bassey E. J.
Published: August 2015

1. Moderately overweight, premenopausal women were assessed for bone mineral density of the total body, lumbar spine and proximal femur before and after 6 months of modest dietary restriction (minimum 4800 kJ/day). The aim was to evaluate the effect of loss of body mass on bone mineral density.

2. Dietary assessment included two analyses of 3 day weighed food intakes, one before and the other after 4 months of dietary restriction. Energy and calcium intakes were significantly reduced by 27% and 5%, respectively. The change in calcium intake was negatively and significantly related to initial levels of calcium intake.

3. A significant mean loss of 3.4 ± 3.1 kg in body mass was achieved mainly in the first 3 months of the study; it was accompanied by significant losses at 6 months in bone mineral density in the total body of 0.7% and in the lumbar spine of 0.5%. There were no changes in the femur.

4. The change in bone mineral density in the total body was significantly related to the reduced absolute calcium intake, initial bone mineral density and loss of body mass. The change in bone mineral density in the spine was significantly related to the change in calcium intake.

5. These modest losses could be a threat in women with lower bone mineral density, and indicate the importance of maintaining a high intake of calcium during dietary restriction.
Total Forearm Blood Flow as an Indicator of Skeletal Muscle Blood Flow: Effect of Subcutaneous Adipose Tissue Blood Flow
Authors: Blaak E. E. , van Baak M. A. , Kemerink G. J. , Pakbiers M. T. W. , Heidendal G. A. K. , Saris W. H. M.
Published: August 2015

1. In studying forearm skeletal muscle substrate exchange, an often applied method for estimating skeletal muscle blood flow is strain gauge plethysmography. A disadvantage of this method is that it only measures total blood flow through a segment of forearm and not the flow through the individual parts such as skin, adipose tissue and muscle.

2. In the present study the contribution of forearm subcutaneous adipose tissue blood flow to total forearm blood flow was evaluated in lean (% body fat 17.0 ± 2.2) and obese males (% body fat 30.9 ± 1.6) during rest and during infusion of the non-selective β-agonist isoprenaline. Measurements were obtained of body composition (hydrostatic weighing), forearm composition (magnetic resonance imaging) and of total forearm (venous occlusion plethysmography), skin (skin blood flow, laser Doppler), and subcutaneous adipose tissue blood flow (133Xe washout technique).

3. The absolute forearm area and the relative amount of fat (% of forearm area) were significantly higher in obese as compared to lean subjects, whereas the relative amounts of muscle and skin were similar.

4. During rest, the percentage contribution of adipose tissue blood flow to total forearm blood flow was significantly higher in lean compared with obese subjects (19 vs 12%, P < 0.05), whereas there were no differences in percentage contribution between both groups during isoprenaline infusion (10 vs 13%). Furthermore, the contribution of adipose tissue blood flow to total forearm blood flow was significantly lower during isoprenaline infusion than during rest in lean subjects (P < 0.05), whereas in the obese this value was similar during rest and during isoprenaline infusion.

5. In conclusion, although the overall contribution of adipose tissue blood flow to total forearm blood flow seems to be relatively small, the significance of this contribution may vary with degree of adiposity. Calculations on the contribution of adipose tissue blood flow and SBF to total forearm blood flow indicate that the contribution of non-muscular flow to total forearm blood flow may be of considerable importance and may amount in lean subjects to 35–50% of total forearm blood flow in the resting state.
Assessment of the Salt-Arterial Pressure Relationship in Mild Hypertensive Subjects by 24-Hour Ambulatory Monitoring
Authors: Zoccali Carmine , Mallamaci Francesca , Leonardis Daniela
Published: August 2015

1. We have assessed the relationship between salt intake and 24 h ambulatory arterial pressure in middle aged men with essential hypertension.

2. During the run-in phase (1 month) we estimated the habitual sodium intake (the average Na excretion of two 24 h urine collections) of each participant (n = 14). In the randomized and crossover part of the study we contemplated a ‘habitual’ sodium intake phase, in which each individual received a fixed diet (about 30 mmol of Na+ and 65 mmol of K+) with additional salt so as to equalize the average intake of the run-in phase, as well as high sodium phases (habitual intake +50 and + 100 mmol/day) and low sodium phases (habitual intake −50 and −100 mmol/day). After the trial, 10 patients under-went an additional week of fixed salt intake to assess the reproducibility of 24 h ambulatory monitoring.

3. Average 24 h arterial pressure at habitual sodium intake was significantly lower than that at high intake and significantly higher than at low sodium intake. Clinic arterial pressure showed similar trends but only systolic pressure changes at low sodium intake achieved statistical significance.

4. Analysis of the data on an individual basis showed a linear increase in 24 h mean arterial pressure with increasing levels of sodium intake in all but two cases (flat response in one case and a non-linear rise in the other case). The response pattern of clinic measurements was much less homogeneous. In the aggregate, there was a highly significant linear trend for ambulatory arterial pressure to rise with increasing levels of salt intake. The association of clinic pressure with sodium excretion was weaker than that of ambulatory pressure. The reproducibility of 24 h arterial pressure at fixed salt intake was better than that of clinic diastolic pressure.

5. The data support the view that, in the usual range of salt intake, the relationship between arterial pressure and sodium is linear.
Interaction of Polyacrylates with Porcine Pepsin and the Gastric Mucus Barrier: A Mechanism for Mucosal Protection
Authors: Foster S. N. E. , Pearson J. P. , Hutton D. A. , Allen A. , Dettmar P. W.
Published: August 2015

1. The mechanism of interaction of the polyacrylates, carbopols with the mucus barrier in vivo has been investigated in vitro.

2. Carbopol caused a dramatic increase in the viscosity of porcine gastric mucin solutions that was up to 19-fold greater than that of the sum of the individual polymers.

3. The mucin-carbopol interaction was stable after an initial 30 min period for up to 36 h at 25°C or 37°C. It was reduced by increasing the temperature from 20°C to 45°C, was unaffected by pH and ionic strength, but was enhanced by Ca2+.

4. The magnitude of the interaction between mucin and carbopol depended on the polymeric structure of the mucin and the molecular size and level of cross-linking of the carbopol.

5. The interactions were reversible and increased with increasing carbopol and mucin concentration. The dramatic increase in viscosity can be explained in terms of space filling by the mucin molecules leading to predominantly carbopol-carbopol interactions.

6. Carbopol 934P inhibits pepsin hydrolysis and therefore has potential as a mucosal protective agent in vivo.
An Abnormal Methylation Ratio Induces Hypomethylation In Vitro in the Brain of Pig and Man, But Not in Rat
Authors: McKeever M. , Molloy A. , Weir D. G. , Young P. B. , Kennedy D. G. , Kennedy S. , Scott J. M.
Published: August 2015

1. The ratio of the methyl donor, S-adenosylmethionine, to the co-product, S-adenosylhomocysteine (the methylation ratio) is known to control the activity of methyltransferases in tissues. Inactivation of the vitamin B12-dependent enzyme, methionine synthase, reduces the methylation ratio in rats and pigs in vivo.

2. We have determined the effect that such alterations have on neural protein ‘O’ and ‘N’ methyltransferases using an in vitro assay in rats, pigs and humans in the presence of the normal methylation ratio and the abnormal methylation ratios found experimentally in vivo in rats and pigs.

3. The methylation ratio found in the neural tissues of vitamin B12-inactivated pigs significantly inhibits the protein methyltransferases of pigs and humans.

4. By contrast, the altered methylation ratio found in vitamin B12-inactivated rats only marginally inhibits the equivalent rat methyltransferases.

5. This is consistent with the induction of a myelopathy by such treatment in pigs and humans, but not in the rat.

6. Dietary supplements of methionine given to vitamin B12-inactivated pigs have been shown to prevent the myelopathy in vivo by both elevating the neural S-adenosylmethionine level and resetting the methylation ratio. We find in our in vitro assay that these events reinstate the methyltransferase activity to near normal levels, thus explaining its protective effect in vivo.
l-Arginine Increases Exhaled Nitric Oxide in Normal Human Subjects
Authors: Kharitonov Sergei A. , Lubec Gert , Lubec Barbara , Hjelm Magnus , Barnes Peter J.
Published: August 2015

1. Endogenous nitric oxide plays an important physiological role and is synthesized by several isoforms of nitric oxide synthase from the semiessential amino acid l-arginine. Nitric oxide is detectable in the exhaled air of normal individuals and may be used to monitor the formation of nitric oxide in the respiratory tract.

2. We have investigated the effect of orally administered l-arginine (0.05, 0.1, 0.2 g/kg) compared with matched placebo on the concentration of nitric oxide in the exhaled air in 23 normal individuals.

3. l-Arginine caused significant increases in the concentration of nitric oxide in exhaled air at doses of 0.1 and 0.2 mg/kg, which was maximal 2 h after administration. This was associated with an increase in the concentration of l-arginine and nitrate in plasma. There were no significant changes in heart rate, blood pressure or forced expiratory volume in 1 s.

4. These results suggest that an increase in the amount of substrate for nitric oxide synthase can increase the formation of endogenous nitric oxide. This may have therapeutic relevance in diseases in which there is defective production of nitric oxide.
Role of Protein Kinase C in the Anti-Aggregatory Effects of Endothelin-1 on Human Platelets
Authors: Touyz R. M. , Schiffrin E. L.
Published: August 2015

1. Endothelin-1 has anti-aggregatory properties, but the mechanism underlying this inhibitory action is unknown. This in vitro study investigates effects of endothelin-1 on thrombin-stimulated aggregation and intracellular free calcium concentration in human platelets and assesses the role of protein kinase C in the interactions between endothelin-1 and thrombin. Aggregation was measured turbidometrically and the intracellular free calcium concentration was determined with the fluorescent indicator fura 2-acetoxymethyl ester.

2. Endothelin-1 at concentrations from 10−11 to 10−6 mol/l had no effect on platelet aggregation or intracellular free calcium concentration but inhibited in a dose-dependent manner aggregation induced by 0.05 unit/ml thrombin (pD2 for inhibition by endothelin = 8.1 ± 0.12).

3. Endothelin-1 at 10−9 mol/l significantly decreased (P<0.01) thrombin-stimulated aggregation from 81.4 ± 1.5% (in the absence of endothelin-1) to 53.5 ± 1.1% (in the presence of endothelin) and thrombin-stimulated intracellular free calcium concentration from 179 ± 1.7 nmol/l to 140 ± 1.8 nmol/l.

4. Preincubation of platelets with 10−7 mol/l staurosporine (protein kinase C inhibitor), calphostin C (highly selective protein kinase C inhibitor) or 5-(N,N-hexamethylene) amiloride (highly selective Na+-H+ exchange blocker) significantly inhibited (P < 0.01) thrombin-stimulated platelet responses and suppressed the inhibitory effect of endothelin-1 on thrombin-induced aggregation and intracellular free calcium concentration.

5. In conclusion, endothelin-1 decreases the aggregatory response of human platelets to thrombin by mechanisms that probably involve protein kinase C and Na+-H+ linked pathways.
Endothelins as Regulators of Vascular Tone in Man
Authors: Haynes William G.
Published: August 2015

1. The vascular pharmacology, physiological relevance and pathophysiological roles of the endothelium-derived vasoconstrictor peptide endothelin-1 have been unclear. These issues were investigated, in vivo in man, using infusion of drugs into the brachial artery or dorsal hand vein, with responses measured by forearm plethysmography and the hand vein displacement technique respectively.

2. Endothelin-1 is a potent and sustained constrictor of resistance and capacitance vessels in vivo in man, acting through both subtypes (ETA and ETB) of endothelin receptors. Endothelin-1 stimulates generation of vasodilator prostaglandins, but not of nitric oxide, that act to oppose its direct constrictor actions. Venoconstriction to endothelin-1 is blocked more effectively by K+-channel openers than by Ca2+-channel antagonists, suggesting a novel cellular mechanism of action for this peptide.

3. The forearm vasculature is able to convert the precursor big endothelin-1 to the mature peptide, endothelin-1, thus demonstrating the local presence of ‘endothelin-converting enzyme’ in man. Local inhibition of this enzyme, or blockade of ETA receptors, causes slow-onset forearm vasodilatation, suggesting that endogenously generated endothelin-1 contributes to basal resistance vessel tone in man.

4. Venoconstriction to endothelin-1 is selectively enhanced in patients with untreated essential hypertension. Endothelin-1 also potentiates sympathetically mediated vasoconstriction, but only in hypertensive subjects.

5. Endogenous generation of endothelin-1 plays a fundamental physiological role in the maintenance of basal vascular tone. Endothlin-converting enzyme inhibitors and endothelin receptor antagonists possess novel vasodilator properties and should represent a major therapeutic advance in cardiovascular disease.
Selective Impairment of Acetylcholine-Mediated Endothelium-Dependent Relaxation in Isolated Resistance Arteries of the Streptozotocin-Induced Diabetic Rat
Authors: Taylor P. D. , Graves J. E. , Poston L.
Published: August 2015

1. There is growing evidence that an impairment in the function of nitric oxide synthase may play a role in the vascular complications of diabetes mellitus. The relaxation of resistance arteries from the mesenteric and hindlimb circulations of streptozotocin-induced diabetic rats and age-matched controls were investigated using two endothelium-dependent vasodilators, bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. The contractile responses to the α1-adrenergic agonist phenylephrine were also studied.

2. Endothelium-dependent relaxation to acetylcholine was impaired in the diabetic rats in arteries from both mesenteric and hindlimb circulations (hindlimb pEC50, 7.93 ± 0.08 in the control compared with 7.38 ± 0.10 in the diabetic rat; mesenteric pEC50, 7.47 ± 0.04 in the control compared with 6.65 ± 0.06 in the diabetic rat; unpaired t-test P < 0.0001). Bradykinin elicited relaxation in only the mesenteric arteries, and this was not attenuated in the diabetic rats compared with controls.

3. Endothelium-independent relaxation to sodium nitroprusside was similar in the two circulations and was not abnormal in the diabetic rats. There was no significant difference in constrictor responses to phenylephrine between diabetic rats and controls in either the hindlimb or mesenteric arteries, in contrast to an earlier study in which we showed increased sensitivity to noradrenaline.

4. The diabetic rats therefore demonstrated a specific impairment of receptor-mediated endothelium-dependent relaxation to acetylcholine. These results suggest that, in this diabetic model, the ability of the endothelium to relax arteries via nitric oxide may involve a defect of a specific signal transduction pathway, leading to reduced production of nitric oxide.
Increased Secretion of Atrial and Brain Natriuretic Peptides during Acute Myocardial Ischaemia Induced by Dynamic Exercise in Patients with Angina Pectoris
Authors: Marumoto Kazumasa , Hamada Mareomi , Hiwada Kunio
Published: August 2015

1. This study was conducted to assess the role of atrial and brain natriuretic peptides during acute myocardial ischaemia associated with dynamic exercise.

2. Study subjects consisted of 35 angiographically proven patients with angina pectoris and 35 angiographically normal control subjects. All subjects underwent 201Tl dynamic exercise testing. The presence and localization of the exercise-induced acute myocardial perfusion defect were assessed by 201Tl single-photon emission computed tomography. The severity score was calculated using the early image for quantitative assessment of the acute myocardial perfusion defect.

3. Plasma levels of atrial natriuretic peptide increased from 21.3 ± 3.8 to 72.2 ± 26.7 pg/ml (P < 0.01) in the angina pectoris group, and increased from 19.4 ± 2.4 to 36.4 ± 17.4 pg/ml (P < 0.01) in the control group during dynamic exercise. Plasma levels of brain natriuretic peptide increased from 2.8 ± 0.8 to 6.9 ± 2.6 pg/ml (P < 0.01) in the angina pectoris group, but did not change significantly in the control group (from 2.7 ± 0.7 to 2.9 ± 1.0 pg/ml) during dynamic exercise. At peak exercise, plasma levels of these natriuretic peptides in the angina pectoris group were significantly higher than those in the control group (P < 0.01).

4. At peak exercise, there were correlations between the plasma level of atrial natriuretic peptide and heart rate in both the angina pectoris and control groups (P < 0.01, r = 0.46; P < 0.01, r = 0.51, respectively), but no significant correlations between the plasma level of brain natriuretic peptide and heart rate in either group. The plasma levels of these peptides at peak exercise correlated well with the severity score in the angina pectoris group (atrial natriuretic peptide, r = 0.71, P < 0.01; brain natriuretic peptide, r = 0.69, P < 0.01).

5. The present study showed that plasma levels of atrial and brain natriuretic peptides significantly increased during acute myocardial ischaemia associated with dynamic exercise.
Stimulation of DNA and RNA Synthesis in Cultured Rabbit Cardiac Fibroblasts by Angiotensin IV
Authors: Wang L. , Eberhard M. , Erne P.
Published: August 2015

1. Although angiotensin II (ANG II) has been identified as a key factor in the development of cardiac hypertrophy and remodelling, the role of its degradation fragment ANG II (3–8), angiotensin IV (ANG IV), is unknown. The presence of ANG IV in the blood circulation as well as the identification of ANG IV receptors in the heart and other organs indicates that ANG IV may act as a peptide hormone.

2. ANG IV receptors were characterized by binding of 125I-ANG IV to membranes of cultured rabbit cardiac fibroblasts. Incorporation of [3H]thymidine, [3H]uridine and [3H]Ieucine into DNA, RNA and proteins, respectively, was determined to analyse the growth effects of ANG IV, ANG II and the combination of both peptides.

3. ANG IV displaces 125I-ANG IV bound to membranes of rabbit cardiac fibroblasts with high affinity, whereas ANG II receptor-specific ligands ([Sar1,Ile8]ANG II, losartan, CGP 42 112 A) do not. 125I-ANG IV binds to a single class of binding site with a dissociation constant (Kd) of 4.87 ± 0.11 nmol/l. The density of ANG IV receptors (Bmax.) is 371 ± 8.3 fmol/mg of protein. 125I-ANG IV binding is not markedly affected in the presence of the non-hydrolysable GTP analogue GTPγS, whereas binding of 125I-ANG II is reduced.

4. In quiescent cells, a 24 h exposure of ANG IV (100 nmol/l) increased rates of thymidine and uridine incorporation by 127% and 246%, respectively. A small but statistically insignificant increase in leucine incorporation was observed under these conditions. Similar effects have been observed after stimulation by ANG II (100 nmol/l, 24 h). The combination of ANG II and ANG IV has additive effects on uridine, but not on thymidine and leucine incorporation.

5. In conclusion, rabbit cardiac fibroblasts express a specific ANG IV receptor, distinct from the known ANG II receptors, which mediates the stimulation of cellular DNA and RNA synthesis.
Vasodilatory Responses of Isolated Arteries of Cirrhotic Rats
Authors: Lee Samuel S. , Pak Jung-Min , Medlicott Shaun M. , Bomzon Arieh
Published: August 2015

1. There is currently considerable interest in the role of locally produced vasodilators such as nitric oxide and adenosine in the pathogenesis of the peripheral vasodilatation of cirrhosis. However, the signal transduction pathways involving guanylate cyclase and adenylate cyclase have not been clearly delineated in the isolated blood vessel.

2. We therefore aimed to examine the in vitro vasorelaxant effects of the endothelium-dependent dilator bethanechol, the endothelium-independent dilator sodium nitroprusside and adenosine, as drugs that work via activation of guanylate and adenylate cyclases, in isolated aortic and superior mesenteric arterial rings from cirrhotic and control rats.

3. Cirrhosis was induced by chronic bile duct ligation and section of 24–28 days' duration, while controls underwent sham operation. The vessels were precontracted with the α1-adrenoceptor agonist phenylephrine, then relaxed by incremental doses of the three drugs.

4. Marked attenuation of vasoconstriction induced by phenylephrine in isolated aortic and mesenteric arterial rings from cirrhotic rats compared with the control vessels was observed.

5. There were no significant differences in relaxation between the cirrhotic and control vessels to the three drugs. We conclude that in vitro vasodilatory responses mediated through signal transduction pathways involving guanylate cyclase and adenylate cyclase remain unchanged in a rat model of biliary cirrhosis.
Cholecystokinin is a Satiety Hormone in Humans at Physiological Post-Prandial Plasma Concentrations
Authors: Ballinger Anne , McLoughlin Lorraine , Medbak Sami , Clark Michael
Published: August 2015

1. Intravenous infusions of the brain/gut hormone, cholecystokinin, have been shown to reduce food intake in a subsequent test meal. However, in previous studies the doses administered were large and likely to have produced plasma concentrations far in excess of the normal post-prandial range.

2. In this study cholecystokinin-8 was infused intravenously to six healthy subjects in doses that reproduced physiological post-prandial concentrations. Plasma concentrations of cholecystokinin were measured using a novel sensitive and specific radioimmunoassay. The effect of cholecystokinin-8 infusion on subsequent food intake in a standard test meal was compared with the effect of saline infusion in the same subjects.

3. Food intake (mean ± SEM) was significantly less during cholecystokinin (5092 ± 665 kJ) than during saline infusion (6418 ± 723 kJ, P = 0.03). During cholecystokinin infusion, plasma concentrations increased from 0.45 ± 0.06 pmol/l to 7.28 ± 2.43 pmol/l immediately before the meal. With saline infusion there was no premeal increase in plasma cholecystokinin concentration.

4. This paper describes a novel radioimmunoassay for measurement of plasma concentrations of cholecystokinin. Using this assay we have demonstrated that cholecystokinin is important in control of satiety in humans.
Effect of Acute and Chronic Caffeine Use on the Cerebrovascular, Cardiovascular and Hormonal Responses to Orthostasis in Healthy Volunteers
Authors: Debrah Kwasi , Haigh Rob , Sherwin Robert , Murphy June , Kerr David
Published: August 2015

1. The effects of acute and chronic caffeine ingestion on supine- and tilt- (60 min at 70°) induced changes in middle cerebral artery velocity (Vmca), heart rate, blood pressure and counter-regulatory hormone levels (catecholamines, growth hormone and cortisol) were studied in nine healthy volunteers. A double-blind, placebo-controlled design was used to study acute effects followed by an open study after 6 days of chronic caffeine use.

2. In the supine position, acute ingestion of caffeine (250 mg) was associated with a fall in Vmca [−11 cm/s, point estimate of difference versus placebo (95% confidence interval: −17, −6) cm/s, P < 0.001] and a rise in mean arterial pressure [+4 (1, 6) mmHg, P < 0.01] and plasma adrenaline levels [+138 (53, 223) pmol/l, P < 0.01]. After chronic caffeine use, the pressor and adrenaline responses, but not the drop in Vmca, were significantly attenuated.

3. On tilting to 70° the fall in Vmca was greater with placebo than after acute caffeine ingestion [−10 (−14, −15) cm/s, P < 0.01], whereas increments (above supine values) in heart rate, mean arterial pressure and hormone levels were unchanged by caffeine. In contrast, the adrenaline [+126 (29, 282) pmol/l, P < 0.01] and noradrenaline [+ 0.6 (0.1, 0.9) nmol/l, P < 0.05] responses to tilting were augmented after acute caffeine ingestion. Chronic caffeine supplementation did not alter the fall in Vmca associated with tilting, but significantly attenuated the adrenaline response (P < 0.01 compared with the acute study).

4. Acute caffeine ingestion and orthostasis are both associated with a reduction in Vmca and a rise in mean arterial pressure and adrenaline levels. The acute effects of caffeine on mean arterial pressure and adrenaline but not on Vmca are lost with sustained caffeine intake. These results suggest dissociation between the development of central and peripheral tolerance after chronic caffeine use.
Low Selenium Status in the Elderly Influences Thyroid Hormones
Authors: Olivieri Oliviero , Girelli Domenico , Azzini Margherita , Stanzial Anna Maria , Russo Carla , Ferroni Massimiliano , Corrocher Roberto
Published: August 2015

1. Iodothyronine 5′-deiodinase, which is mainly responsible for peripheral triiodothyronine (T3) production, has recently been demonstrated to be a selenium-containing enzyme. In the elderly, reduced peripheral conversion of thyroxine (T4) to T3 and overt hypothyroidism are frequently observed.

2. We measured serum selenium and erythrocyte glutathione peroxidase (as indices of selenium status), thyroid hormones and thyroid-stimulating hormone in 109 healthy euthyroid subjects (52 women, 57 men), carefully selected to exclude abnormally low thyroid hormone levels induced by acute or chronic diseases or calorie restriction. The subjects were subdivided into three age groups. To avoid conditions of undernutrition or malnutrition, dietary records were obtained for a sample of 24 subjects, randomly selected and representative of the whole population for age and sex.

3. In order to properly assess the influence of selenium status on iodothyronine 5′-deiodinase type I activity, a double-blind placebo-controlled trial was also carried out on 36 elderly subjects, resident at a privately owned nursing home.

4. In the free-living population, a progressive reduction of the T3/T4 ratio (due to increased T4 levels) and of selenium and erythrocyte glutathione peroxidase activity was observed with advancing age. A highly significant linear correlation between T4, T3/T4 and selenium was observed in the population as a whole (for T4, R = −0.312, P < 0.002; for T3/T4 ratio, R = 0.32, P < 0.01) and in older subjects (for T4, R = −0.40, P < 0.05; for T3/T4 ratio, R = 0.54, P < 0.002).

5. The main result of the double-blind placebo-controlled trial was a significant improvement of selenium indices and a decrease in the T4 level in selenium-treated subjects; serum selenium, erythrocyte glutathione peroxidase activity and thyroid hormones did not change in placebo-treated subjects.

6. We concluded that selenium status influences thyroid hormones in the elderly, mainly modulating T4 levels.
Effects of Depolarizing or Non-Depolarizing Preservation Solutions on Human Endothelial cells during Cold Hypoxia
Authors: Hidalgo M. A. , Mann D. J. , Fuller B. J. , Green C. J.
Published: August 2015

1. Hypothermic storage of whole organs flushed with a preservation solution is common practice in clinical transplantation. This procedure leaves vascular endothelial cells in direct contact with the preservation solution during the length of the cold ischaemic period.

2. Aiming to study the effects of organ preservation on vascular endothelium, we subjected cultures of human umbilical vein endothelial cells to hypoxic and hypothermic storage conditions in vitro for 3 or 16 h. Four preservation solutions with different levels of sodium and potassium were tested. Morphometric analysis and 51Cr leakage index were used to assess monolayer continuity, cell viability and membrane integrity.

3. Hypothermic storage resulted in severe changes in endothelial cell morphology with formation of intercellular gaps that destroyed monolayer continuity after only 3 h. Cellular blebbing was a common feature in seriously damaged cells.

4. Morphometric analysis and 51Cr leakage results correlated well. No significant differences between the solutions tested were found after 3 h of hypothermic hypoxic storage. After 16 h, viability and monolayer continuity were significantly better preserved (Mann—Whitney, P < 0.01) in cells stored in lactobionate-based solutions than in hypertonic citrate solutions. No significant differences were found between endothelial cells stored in extracellular versus intracellular types of solutions for the lactobionate-based solutions.

5. The results of the present experiment showed that after a period of hypothermic hypoxic storage, vascular endothelial cells appeared morphologically deformed and poorly attached in vitro. Lactobionate-based preservation solutions were more effective in preserving viability and continuity. Protection of vascular endothelium under cold hypoxic conditions could be a critical factor in successfully preserving organs for transplantation.
Alteration of Atrial Natriuretic Peptide and Brain Natriuretic Peptide Gene Expression Associated with Progression and Regression of Cardiac Hypertrophy in Renovascular Hypertensive Rats
Authors: Kawakami Hideo , Okayama Hideki , Hamada Mareomi , Hiwada Kunio
Published: August 2015

1. We assessed the changes of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats (RHR).

2. Two-kidney, one-clip hypertensive rats (6-week-old male Wistar) were made and studied 6 (RHR-1) and 10 weeks (RHR-2) after the procedure. Regression of cardiac hypertrophy was induced by nephrectomy at 6 weeks after constriction, and the nephrectomized rats were maintained further for 4 weeks (nephrectomized rat: NEP). Sham operation was performed, and the rats were studied after 6 (Sham-1) and 10 weeks (Sham-2). Atrial natriuretic peptide and brain natriuretic peptide gene expression in the left ventricle was analysed by Northern blotting.

3. Plasma atrial natriuretic peptide and brain natriuretic peptide were significantly higher in RHR-1 and RHR-2 than in Sham-1, Sham-2 and NEP. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels in RHR-1 were approximately 7.2-fold and 1.8-fold higher than those in Sham-1, respectively, and the corresponding levels in RHR-2 were 13.0-fold and 2.4-fold higher than those in Sham-2, respectively. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels of NEP were normalized. Levels of atrial natriuretic peptide and brain natriuretic peptide mRNA were well correlated positively with left ventricular weight/body weight ratios. There was a significant positive correlation between the levels of atrial natriuretic peptide and brain natriuretic peptide mRNA (r = 0.86, P<0.01).

4. We conclude that the expression of atrial natriuretic peptide and brain natriuretic peptide genes is regulated in accordance with the degree of myocardial hypertrophy and that the augmented expression of these two natriuretic peptides may play an important role in the maintenance of cardiovascular haemodynamics in renovascular hypertension.