bluuebunny/crossref_metadata_2025 huggingface dataset:
Conjugated linoleic acid induces lipid peroxidation in men with abdominal obesity
Authors: BASU S. , RISÉRUS U. , TURPEINEN A. , VESSBY B.
Published: August 2015

Conjugated linoleic acid (CLA) has been shown in experimental studies to have chemoprotective properties, and may decrease the deposition of body fat. CLA is prone to oxidation, and it has been suggested that increased lipid oxidation may contribute to the anti-tumorigenic effects of this agent. The present study investigates the urinary levels of 8-iso-prostaglandin F2α (8-iso-PGF2α), a major isoprostane, and of 15-oxo-dihydro-PGF2α, a major metabolite of PGF2α, as indicators of non-enzymic and enzymic arachidonic acid oxidation respectively after dietary supplementation with CLA in middle-aged men (mean age 53 years) with abdominal obesity for 1 month in a randomized controlled trial. Significant increases in the levels of both 8-iso-PGF2α and 15-oxo-dihydro-PGF2α in urine (P < 0.0001 and P = 0.0013 respectively) were observed after 1 month of daily CLA intake (4.2 g/day) as compared with the control group. The lipid peroxidation parameters had returned to their basal levels at 2 weeks after the cessation of CLA intake, and remained at the same levels for a further 2 weeks until the end of the study. CLA had no effect on serum α-tocopherol and γ-tocopherol levels, or on the urinary levels of 2,3-dinor-thromboxane B2. Thus CLA may induce both non-enzymic and enzymic lipid peroxidation in vivo in middle-aged men with abdominal obesity, without any side effects. The consequences of the increased lipid peroxidation after CLA supplementation are unknown.
The mechanism of resveratrol-induced vasorelaxation differs in the mesenteric resistance arteries of lean and obese rats
Authors: NADERALI Ebrahim K. , SMITH Sharon L. , DOYLE Patrick J. , WILLIAMS Gareth
Published: August 2015

Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P < 0.001) endothelial dysfunction, as indicated by a decrease (> 20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5–35 µmol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 µmol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of > 95% at a concentration of 35 µmol/l. In noradrenaline-preconstricted arteries from lean rats, NG-nitro-L-arginine methyl ester (L-NAME; 100 and 300 µmol/l) caused a significant (P < 0.01) concentration-dependent rightward shift in reseveratrol activity, with no effect on maximal responses. However, L-NAME (100 and 300 µmol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration–responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO.
Deterioration in peak systolic velocity is closely related to ischaemia during angioplasty: a vectorcardiographic and tissue Doppler imaging study
Authors: JENSEN Jens , BRODIN Lars-Åke , LIND Britta , ERIKSSON Sven V. , JENSEN-URSTAD Mats , SYLVÉN Christer
Published: August 2015

We tested the hypothesis that the extent of signs of ischaemia detected by vectorcardiography (VCG) during elective coronary angioplasty (percutaneous transluminal coronary angioplasty; PTCA) is related to systolic and diastolic myocardial velocities, as determined by tissue Doppler echocardiography. A total of 15 patients undergoing PTCA (12 men/three women; age 61±9 years), without prior myocardial infarction and with an ejection fraction of > 50%, were included. The balloon inflation was repeated three times, with minimum intervals of 2 min between inflations. Tissue Doppler echocardiography was performed, in an apical two- or four-chamber view, before and at the end of each inflation. Peak systolic velocity, time-to-peak systolic velocity (TTP), peak early (Em) and late (Am) diastolic velocities, the Em/Am ratio and isovolumic relaxation time were measured in the basal segments of the left ventricle. VCG recordings were carried out during the whole procedure. ST vector magnitude (ST-VM) and ST change vector magnitude (STC-VM) were monitored. The total duration and area of each VCG change during inflation were calculated for each patient. Isovolumic relaxation time, peak Em and Am values and the Em/Am ratio did not change significantly during inflation. Peak systolic velocity decreased (6.7±2.0 to 5.3±1.9 cm/s; P < 0.001) and TTP increased (157±60 to 192±60 ms; P < 0.01) during inflation. Both STC-VM time (r = -0.68, P < 0.01) and STC-VM area (r = -0.68, P < 0.01) were related to peak systolic velocity during inflation. STC-VM time was also related (r = 0.55, P < 0.05) to the difference in peak systolic velocity during compared with before inflation. ST-VM was less closely related to peak systolic velocity. Thus the duration and degree of ischaemia, as measured by VCG, are related to peak systolic velocity in the basal segments of the left ventricle.
Selective enhancement of sensitivity to endothelin-1 despite normal endothelium-dependent relaxation in subcutaneous resistance arteries isolated from patients with Type I diabetes
Authors: MCINTYRE Carol-Ann , HADOKE Patrick W. F. , WILLIAMS Brent C. , LINDSAY R. Mark , ELLIOTT Andrew I. , MCKNIGHT John A.
Published: August 2015

Type I diabetes mellitus is associated with abnormal vascular function, but few studies have documented its effects on human resistance arteries. This study aimed to determine whether endothelial cell and smooth muscle cell function was impaired in resistance arteries isolated from patients with this condition. Biopsies of subcutaneous gluteal fat were taken from 12 patients with Type I diabetes (age 32.3±1.9 years; duration of diabetes 13.9±2.5 years) and 12 matched controls (age 31.5±2.2 years). Levels of glycosylated haemoglobin were higher (P < 0.0001) in patients (9.38±0.35%) than in controls (5.48±0.11%), but most (11 out of 12) patients showed no evidence of microvascular disease. Small resistance arteries were isolated from the biopsies, and isometric responses to vasoconstrictors and vasodilators were measured in a small-vessel myograph. The magnitude and sensitivity of responses to noradrenaline and potassium were not different in diabetic patients compared with controls. In contrast, the sensitivity (pD2; negative logarithm of the concentration of the vasoconstrictor required to produce 50% of the maximum effect), but not the magnitude, of contraction in response to endothelin-1 in vessels from patients (8.87±0.12) was significantly (P = 0.02) greater than in those from controls (8.40±0.13). Endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (3´-morpholinosydnonimine) relaxation responses were unaltered in patients with Type I diabetes. These results suggest a selective alteration in receptor activity in the endothelium, and contrast strikingly with the considerable evidence of impaired endothelium-dependent relaxation in Type I diabetes. The present study indicates, therefore, that endothelial cell function is largely maintained in resistance arteries from patients with well controlled Type I diabetes. The increased response to endothelin-1 supports the possibility that more significant abnormalities would be evident in patients with severe microvascular complications.
Water ingestion increases sympathetic vasoconstrictor discharge in normal human subjects
Authors: SCOTT Eleanor M. , GREENWOOD John P. , GILBEY Stephen G. , STOKER John B. , MARY David A. S. G.
Published: August 2015

A marked pressor response to water drinking has been observed in patients with autonomic failure and in the elderly, and has been attributed to sympathetic vasoconstrictor activation, despite the absence of such a pressor response in healthy subjects with intact sympathetic mechanisms. We investigated whether water drinking in normal subjects affected peripheral sympathetic neural discharge and its effect on vascular resistance. In nine normal human subjects, we examined the effect of water ingestion on muscle sympathetic neural activity from the peroneal nerve, as multi-unit bursts (muscle sympathetic nerve activity; MSNA) and as single-unit impulses (s-MSNA) with vasoconstrictor function, and on calf vascular resistance for 120 min. In each subject, water ingestion caused increases in s-MSNA and MSNA which peaked at 30 min after ingestion; they increased respectively (mean±S.E.M.) from 42±4 to 58±5 impulses/100 beats (P < 0.01) and from 36±4 to 51±5 bursts/100 beats (P < 0.001). There were corresponding increases in calf vascular resistance and in plasma noradrenaline levels. A significant correlation occurred between all of these data. In conclusion, measurement of MSNA has provided direct evidence that water drinking in normal human subjects increases sympathetic nerve traffic, leading to peripheral vasoconstriction. This sympathetic activation was not accompanied by significant changes in arterial blood pressure.
Increased levels of high-density lipoprotein cholesterol are ineffective in inhibiting the development of immune responses to oxidized low-density lipoprotein and atherosclerosis in transgenic rabbits expressing human apolipoprotein (apo) A-I with severe hypercholesterolaemia
Authors: BOULLIER Agnès , HENNUYER Nathalie , TAILLEUX Anne , FURMAN Christophe , DUVERGER Nicolas , CAILLAUD Jean-Michel , CASTRO Graciella , FIEVET Catherine , FRUCHART Jean-Charles , DURIEZ Patrick
Published: August 2015

High levels of high-density lipoprotein (HDL) cholesterol have been reported to protect against the development of atherosclerosis in humans by increasing reverse cholesterol transport and inhibiting the oxidation of low-density lipoprotein (LDL) due to the paraoxonase content of HDL. The purpose of the present study was to assess if there are any relationships between in vivo increases in serum levels of immunological LDL oxidation markers [autoantibodies against oxidized LDL, autoantibodies against malondialdehyde-modified LDL, LDL immune complexes and anti-cardiolipin autoantibodies], paraoxonase activity and the development of atherosclerosis in control rabbits and in transgenic rabbits expressing human apolipoprotein (apo) A-I. A total of 13 apo A-I transgenic rabbits and 18 non-transgenic littermates were fed on a cholesterol-rich diet (0.4%, w/w) for 14 weeks, and were monitored at weeks 0, 2, 6, 10 and 14. Aortic atherosclerotic lesions were measured at the end of this period. Human apo A-I transgenic rabbits with high HDL cholesterol levels were not protected against the development of atherosclerosis when they were fed on a cholesterol-rich diet which induced dramatic hypercholesterolaemia. Immunological markers of LDL oxidation increased and serum paraoxonase activity decreased similarly in control and transgenic rabbits. In conclusion, the present study demonstrates that high HDL cholesterol levels are ineffective in inhibiting increases in immunological markers of LDL oxidation and the development of atherosclerosis in a mammal with severe hypercholesterolaemia.
GLAXO/MRS PAPERRoles of chemokines in the regulation of leucocyte recruitment
Authors: SABROE Ian , WILLIAMS Timothy J. , PEASE James E.
Published: August 2015

In the search for new treatments for human inflammatory disease, antagonism of chemokine receptors by small molecules is an attractive goal. Although there are overlapping patterns of expression of chemokine receptors between leucocyte types, an investigation of the chemokine responsiveness of cells important in allergic inflammation, such as the eosinophil and the basophil, is beginning to uncover how selective recruitment may be regulated. The story of the eotaxin receptor, CCR3, and its central role in allergic inflammation illustrates that therapeutic antagonism of these pathways is imminently achievable.
Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease
Authors: CUMMINS Adrian G. , THOMPSON Fiona M. , BUTLER Ross N. , CASSIDY John C. , GILLIS David , LORENZETTI Mark , SOUTHCOTT Emma K. , WILSON Peter C.
Published: August 2015

It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3–6 months, and even then remains incomplete.
Neurohormonal activation, the renal dopaminergic system and sodium handling in patients with severe heart failure under vasodilator therapy
Authors: FERREIRA António , BETTENCOURT Paulo , DIAS Paula , PESTANA Manuel , SERRÃO Paula , SOARES-DA-SILVA Patrício , CERQUEIRA-GOMES Mário
Published: August 2015

The benefits of tailoring therapy with vasodilators in patients with severe heart failure are well documented, but this may lead to neurohormonal activation and sodium retention. Renal dopamine has local natriuretic actions and interacts with other hormones involved in renal sodium handling. The aim of the present work was to determine the effects of arterial underfilling induced by vasodilator therapy on renal sodium handling, neurohormonal activation and the activity of the renal dopaminergic system in patients with severe heart failure. For this purpose we monitored haemodynamic parameters, plasma levels of type B natriuretic peptide (BNP), catecholamines, aldosterone, renin activity (PRA), sodium and creatinine, and urinary excretion of sodium, creatinine, l-DOPA, dopamine and its metabolites, before initiation of sodium nitroprusside therapy and every 6 h thereafter (for 42 h), and again after 5 days of angiotensin-converting enzyme (ACE) inhibition, in 10 male patients with severe heart failure. The results of nitroprusside therapy were a marked increase in cardiac index and a substantial decrease in systemic vascular resistance index. Plasma levels of BNP decreased significantly, while PRA, noradrenaline and aldosterone showed marked increases, resulting in a substantial reduction in urinary sodium excretion. Creatinine clearance was not affected. Urinary dopamine and dopamine metabolites increased in response to nitroprusside therapy. After 5 days of ACE inhibition, urinary sodium returned to baseline values, while urinary dopamine was markedly reduced. These results suggest that the renal dopaminergic system is activated in patients with severe heart failure by stimuli leading to sodium renal reabsorption.
Physiological relationships between central vascular haemodynamics and left ventricular structure
Authors: DEAGUE Jenny A. , WILSON Catherine M. , GRIGG Leeanne E. , HARRAP Stephen B.
Published: August 2015

Left ventricular hypertrophy is an independent cardiovascular risk factor. In hypertensives, the pattern of hypertrophy is influenced by central haemodynamic characteristics. Central haemodynamics may also determine physiological differences in left ventricular structure and predispose to particular responses of the left ventricle to pathological increases in load. M-mode echocardiography was used to measure left ventricular diastolic dimension and to estimate left ventricular mass index, relative wall thickness and stroke volume in 159 healthy volunteers aged between 19 and 74 years. Tonometric sphygmography was used to estimate augmentation index, central end-systolic and mean arterial blood pressure. Effective arterial elastance was calculated as the ratio of end-systolic pressure to stroke volume. Left ventricular mass index and relative wall thickness were adjusted for variation in age, sex and blood pressure before analyses. Left ventricular diastolic dimension exhibited significant inverse correlations with both effective arterial elastance (r =-0.72, P < 0.0001) and augmentation index (r =-0.23, P = 0.004). Adjusted left ventricular mass index was inversely correlated with effective arterial elastance (r =-0.35, P < 0.0001), but no correlation was observed between left ventricular mass index and augmentation index (r = 0.04). Adjusted relative wall thickness correlated with increasing effective arterial elastance (r = 0.32, P < 0.0001) and augmentation index (r = 0.18, P = 0.02). Relative wall thickness (r = 0.34, P < 0.0001), but not left ventricular mass index, correlated with age. Higher elastance and augmentation correlates with relatively smaller left ventricular cavity size but larger relative wall thickness. Age-related changes in left ventricular afterload may affect relative wall thickness more significantly than left ventricular mass index and may contribute to a particular change in left ventricular geometry with age.
Differing thresholds for modulatory effects of adrenomedullin infusion on haemodynamic and hormone responses to angiotensin II and adrenocorticotrophic hormone in healthy volunteers
Authors: TROUGHTON Richard W. , FRAMPTON Christopher M. , LEWIS Lynley K. , YANDLE Timothy G. , RICHARDS A. Mark , NICHOLLS M. Gary
Published: August 2015

Experimental data indicate that adrenomedullin (AM) interacts at various levels with the renin–angiotensin–aldosterone system and the hypothalamic–pituitary–adrenal axis, but data from humans are scant. We examined the effects of intermediate-dose, short-term AM infusion on angiotensin II- and adrenocorticotrophic hormone (ACTH)-mediated hormone and haemodynamic responses in healthy subjects. Seven normal volunteers (age 18–25 years) completed a placebo-controlled crossover study. Each subject was studied on day 4 of two periods of a low-salt diet (40 mmol of sodium and 80 mmol of potassium daily), receiving incremental infusions of angiotensin II in the morning and ACTH in the afternoon of each study day, on a background infusion of AM (4 pmol·min-1ƃkg-1) or vehicle (hemaccel). Achieved plasma AM levels (23±6 pmol/l) and peak angiotensin II levels (160 pmol/l) were similar on the two experimental days. While the pressor action of angiotensin II was attenuated by AM (P < 0.01) and noradrenaline levels rose (P < 0.05), the aldosterone response was unaltered. During ACTH infusion, AM increased heart rate (P < 0.01), plasma adrenaline (P < 0.01) and plasma noradrenaline (P < 0.05), and augmented the cortisol response (P < 0.01), but was without effect on aldosterone levels and blood pressure. We conclude that the threshold for the effects of AM on aldosterone secretion in humans is set higher than for other biological responses to this hormone, namely blood pressure, heart rate, sympathetic activity and cortisol secretion, under these experimental conditions.
Importance of glycolytically derived ATP for Na+ loading via Na+/H+ exchange during metabolic inhibition in guinea pig ventricular myocytes
Authors: SATOH Hiroshi , SUGIYAMA Shiho , NOMURA Noriyuki , TERADA Hajime , HAYASHI Hideharu
Published: August 2015

The increase in the intracellular Na+ concentration ([Na+]i) during myocardial ischaemia is crucial for ischaemia/reperfusion cell injury, and the cardiac subtype of the Na+/H+ exchanger (NHE-1) has been shown to be a major pathway for Na+ loading. While the importance of glycolytically derived ATP for the optimal functioning of membrane transporters and channels has been suggested, whether NHE-1 is actually activated during myocardial ischaemia remains controversial. Here we examined whether the activity of NHE-1 is predominantly dependent on intracellular ATP generated by glycolysis, and whether the additional inhibition of glycolysis can affect the increase in [Na+]i during the inhibition of oxidative phosphorylation in intact guinea pig ventricular myocytes. The selective inhibition of glycolysis by 2-deoxyglucose prevented the recovery of intracellular pH and the transient increase in [Na+]i following intracellular acidosis induced by a NH4Cl pre-pulse. During severe metabolic inhibition (SMI; induced by amobarbital and carbonyl cyanide m-chlorophenylhydrazone in a glucose-free perfusate), most myocytes changed from rod-shaped to contracted forms by ~ 15 min. [Na+]i increased linearly until rigor contracture occurred, but after rigor contracture the rate of increase was blunted. The increase in [Na+]i during SMI was suppressed significantly by an inhibitor of NHE-1, hexamethylene amiloride. The increase in the intracellular Mg2+ concentration, which can reciprocally indicate depletion of intracellular ATP, was small during the initial 10 min of SMI, but became larger from just a few minutes before rigor contracture. In the presence of 2-deoxyglucose, the time to rigor during SMI was shortened, but the increase in [Na+]i before rigor contracture was not significant, and was much less than that in the absence of 2-deoxyglucose. It is concluded that ATP generated by glycolysis is essential to activate NHE-1, and that the dependence of NHE-1 on glycolysis might affect the increase in [Na+]i observed during myocardial ischaemia.
Cytokine up-regulation in ischaemic/reperfused lungs perfused with University of Wisconsin solution and normal saline
Authors: CHIANG Chi-Huei , YU Cheng-Ping , WU Chin-Pyng , YAN Horng-Chin , PERNG Wann-Cherng
Published: August 2015

Ischaemia/reperfusion (I/R) lung injury using University of Wisconsin solution (UW) as perfusate has not been well studied. Isolated rat lungs were challenged with various periods of ischaemia and/or reperfusion. Haemodynamics, lung weight gain (LWG), capillary filtration coefficient (Kfc), tissue pathology, the concentrations of cytokines in the perfusate, and mRNAs for the various cytokines in the lung tissues were measured. I/R induced a permeability type of pulmonary oedema, as reflected by increases in LWG and Kfc. LWG and Kfc in the I45R60(UW) group (45 min of ischaemia followed by 60 min of reperfusion with UW) were only 2% and 5% respectively of those in the I45R60(NS) group (where NS is normal saline). LWG and Kfc in the UW group had both increased by 180 min, to values similar to those in the I45R60(NS) group. However, these findings show that UW was remarkably effective at preventing LWG after 60 min of reperfusion, and was more than 3-fold more effective than NS in delaying LWG. For longer ischaemic times only, or the same period of ischaemia followed by longer reperfusion periods, greater lung injury occurred. I/R lung injury also induced increased concentrations of tumour necrosis factor-α (TNF-α), interleukin 1 and interleukin 6 in the perfusate, and increased the mRNAs for these cytokines in lung tissue. A significant correlation was obtained between TNF-α concentration and LWG. TNF-α production in the I45R60(UW) group was only 7% of that in the I45R60(NS) group. However, TNF-α mRNA expression in the I45R60(UW) group was 80% of that in the I45R60(NS) group. This indicates that transcription/translation do not correlate well with cytokine production, and also suggests that one reason for the effectiveness of UW in delaying LWG may be because it delays TNF-α production. In summary, ischaemia or I/R caused a permeability-type pulmonary oedema that was associated with leucocyte infiltration and the up-regulation of various cytokines, regardless of the perfusion fluid. Except for pulmonary hypertension, less severe I/R lung injury and delayed cytokine production in lungs perfused with UW, the pattern of injury associated with I/R challenge was similar to that in lungs perfused with NS. We propose that more or long-acting protective agents are required as additives in order to modify UW to produce an optimal preservation solution.
Aging alters neuronal nitric oxide release from rat mesenteric arteries: role of presynaptic β-adrenoceptors
Authors: FERRER Mercedes , BALFAGÓN Gloria
Published: August 2015

This study examines the influence of aging on the neuronal nitric oxide (NO) and noradrenaline (NA) release elicited by electrical field stimulation (EFS; 200 mA, 0.3 ms, 1-16 Hz, 30 s) in endothelium-denuded mesenteric arteries from young and old rats, as well as the influence of the presynaptic β-adrenoceptors in that release. EFS induced frequency-dependent contractions. NG-nitro-l-arginine methyl ester (l-NAME) only enhanced EFS-elicited contractions in arteries from young rats. Capsaicin did not alter the EFS-induced contractions in either age group. Clenbuterol did not modify the contraction elicited by EFS in arteries from young or old rats either. A subsequent addition of l-NAME also induced an increase in the EFS-induced response in arteries from both age groups. In old rats, the presence of propranolol did not alter the response induced by EFS, and the subsequent addition of clenbuterol or clenbuterol plus l-NAME did not affect this response. In precontracted segments, sodium nitroprusside or clenbuterol induced similar relaxation in both age groups. None of the drugs used altered the response to exogenous NA or basal tone. In arteries preincubated with [3H]NA, EFS induced 3H release, which remained unmodified in the presence of clenbuterol or propranolol in young rats, whereas clenbuterol increased the 3H overflow in old rats, and this effect was abolished by propranolol. These drugs did not alter the basal 3H efflux and indicate that in rat mesenteric arteries EFS induces NA release in both age groups, and only NO release in young animals. Activation of presynaptic β-adrenoceptors increased NA and probably NO release in aged rats.
Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men
Authors: IVARSEN Per , GREISEN Jacob , VILSTRUP Hendrik
Published: August 2015

Intracellular hydration may play a role in the regulation of protein and nitrogen metabolism. The hepatic removal of nitrogen by urea synthesis has a key regulatory role in nitrogen balance. The purpose of the present study was to establish the acute effects of dehydration on the hepatic kinetics of urea synthesis, quantified by functional hepatic nitrogen clearance (FHNC), in healthy volunteers. Seven healthy men were studied twice in random order. On both study days, a primed continuous infusion of alanine was given. On the day of dehydration an intravenous bolus injection of a loop diuretic (furosemide, 1 mg/kg) was superimposed. FHNC was calculated as the ratio between measured synthesis rates of urea nitrogen and blood alanine concentrations. Furosemide induced a weight loss of 1 kg. During dehydration, FHNC decreased by approx. 25% (41±11 to 54±10 litres/h; P < 0.02). On both occasions individual FHNC and glucagon values were positively correlated (r2 >0.6). In addition, dehydration more than halved the linear slope of the relationship (P < 0.05). The FHNC values were correlated with the urinary excretion of both potassium and sodium (r2 = 0.68, P < 0.01 and r2 = 0.62, P < 0.02 respectively). Changes in the reactivity of urea synthesis to glucagon (i.e. the ratio between FHNC and glucagon concentration) was negatively correlated with an indirectly estimated change in intracellular water (r2 = 0.79, P < 0.05). We conclude that acute moderate dehydration down-regulates both total urea synthesis and its sensitivity to glucagon. The latter was related to estimated intracellular water loss. Dehydration may thus have nitrogen-saving consequences with regard to the hepatic contribution to whole-body nitrogen homoeostasis. The mechanism of this effect and the relationship with sodium and potassium fluxes is not known.
Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis
Authors: LEIPER Keith , CAMPBELL Barry J. , JENKINSON Michael D. , MILTON Jeremy , YU Lu-Gang , DEMOCRATIS Jane , RHODES Jonathan M.
Published: August 2015

Goblet cell depletion occurs in various forms of colitis, but its mechanism is unknown. We have investigated two linked hypotheses: (i) that bacterial peptides, such as formyl-methionyl-leucyl-phenylalanine (fMLP), interact with epithelial cells inducing the release of chemokines, including interleukin-8 (IL-8), which in turn leads to the recruitment of neutrophils which release mucin secretagogues; (ii) that fMLP acts directly on epithelial cells to cause mucus secretion. Studies were performed to measure the effects of fMLP on the synthesis and secretion of IL-8 and mucus by the goblet cell differentiated colon cancer cell lines HT29-MTX (methotrexate-conditioned HT29 colonic adenocarcinoma cell line) and LS174T, and to assess the effects of neutrophil-derived secretagogues on goblet cell secretion in these cell lines. fMLP (0.1μM) increased the secretion of IL-8 by 105% (P < 0.0001) in HT29-MTX cells and by 401% (P < 0.0001) in LS174T cells. fMLP also increased the synthesis and secretion of mucins by these cell lines, with maximal effects of 65% above control values for synthesis (P < 0.01) and 73% for secretion (P < 0.01). A dose-related increase (up to 67%; P < 0.01) in mucin secretion was demonstrated in HT29-MTX cells in response to incubation with supernatant from activated neutrophils. This effect was largely (83%; P < 0.02) inhibited by ICI 200,355, a specific inhibitor of neutrophil elastase. In conclusion, the bacterial peptide fMLP and neutrophil elastase are both potent mucus secretagogues for colon epithelial cells. fMLP also elicits release of the potent neutrophil chemoattractant IL-8 from colon epithelial cells. These findings support the hypothesis that the mucosal inflammation and mucus depletion seen in ulcerative colitis could result from interaction between bacterial peptides and the mucosa.
Effect of intrathecal fentanyl on oxytocin secretion in pregnant women not in labour
Authors: SHIBLI K.U. , DHILLON A.R. , GOODE J.A. , GILBERT C.L. , THOMPSON J.W. , RUSSELL I.F. , LINDOW S.W.
Published: August 2015

We studied the effects of spinal intrathecal fentanyl on oxytocin secretion in 20healthy women prior to an elective caesarean delivery at term under spinal anaesthesia. The women were randomly allocated into two groups with respect to spinal anaesthesia. Group I (n = 10) received intrathecal bupivacaine (15mg) plus fentanyl (25μg), and Group II (n = 10) received intrathecal bupivacaine (15mg) alone, prior to caesarean section. The two groups were comparable demographically. Altogether, ten samples of 4.5ml of blood (taken every 60 s) were obtained before and ten samples were obtained after the intrathecal administration of the drug and establishment of the T6 block, and plasma oxytocin concentrations were assayed for each subject. Oxytocin was measured by RIA. We found no significant differences in plasma oxytocin concentrations of individual subjects before and after intrathecal injection. In addition, there were no significant differences in plasma oxytocin concentrations between the two groups when pooled samples from the subjects were compared for the pre- and post-intrathecal injection phases. We conclude that the spinal intrathecal administration of fentanyl does not suppress oxytocin secretion in pregnant women who are not in labour at term.
Evaluation of mechanical arterial properties: clinical, experimental and therapeutic aspects
Authors: MCVEIGH Gary E. , HAMILTON Paul K. , MORGAN David R.
Published: August 2015

Ageing and disease states associated with an increase in cardiovascular events alter the physical characteristics of blood vessel walls and impair the pulsatile function of arteries. An accumulating body of evidence indicates that impaired pulsatile function of arteries provides important prognostic and therapeutic information beyond that provided by traditional blood pressure measurements. A variety of techniques are currently employed to evaluate the mechanical properties of arteries. All techniques have theoretical, technical and practical limitations that impact on their widespread application in the clinical setting and use as measurement tools to improve cardiovascular risk stratification. A detailed discussion of these issues forms the basis of this review.
Threshold for adrenomedullary activation and increased cardiac work during mild core hypothermia
Authors: FRANK Steven M. , CATTANEO Christine G. , WIENEKE-BRADY Mary Beth , EL-RAHMANY Hossam , GUPTA Neeraj , LIMA Joao A.C. , GOLDSTEIN David S.
Published: August 2015

Postoperative hypothermia increases the incidence of ischaemic cardiac events in patients at risk, but the underlying mechanism is unclear. One possibility is increased cardiac work related to the sympathoneural or adrenomedullary hormonal responses. In awake human volunteers, the present study assessed the effects of mild core hypothermia on these responses, and on the associated changes in indices of cardiac work. A total of 11healthy men were studied on two separate days. On one day, core temperature (Tc) was decreased by the intravenous infusion of cold normal saline (4°C; 60ml/kg over 30min) through a central venous catheter. On the other day (normothermic control), warm normal saline (37°C; 60ml/kg over 30min) was given intravenously. Transthoracic echocardiograms, the sympathoneural response (noradrenaline) and the adrenomedullary response (adrenaline) were evaluated before, during and after the intravenous infusions. Echocardiography was used to measure left ventricular function and cardiac output. Compared with the normothermic control treatment, core cooling of 0.7°C was associated with increased plasma noradrenaline (220% increase; P = 0.001), whereas adrenaline, cardiac output, heart rate and the rate-pressure product were unchanged. After core cooling of 1.0°C, increases in noradrenaline (by 230%; P = 0.001), adrenaline (by 68%; P = 0.05), cardiac output (by 23%; P = 0.04), heart rate (by 16%; P = 0.04) and rate-pressure product (by 25%; P = 0.007) were all significant compared with the normothermic control treatment. In conclusion, there is a Tc threshold, below which an adrenomedullary (adrenaline) response is triggered in addition to the sympathoneural (noradrenaline) response. This Tc threshold (≈ 1°C below the normothermic baseline) is also associated with an increase in haemodynamic indices of cardiac work. Mild core hypothermia therefore constitutes a catecholamine-mediated cardiovascular ‘stress test’.
Tibolone does not affect muscle power and functional ability in healthy postmenopausal women
Authors: MEEUWSEN Ingrid B.A.E. , SAMSON Monique M. , DUURSMA Sijmen A. , VERHAAR Harald J.J.
Published: August 2015

Maintenance of neuromuscular function into old age is critical to maintain normal daily activity and functional independence. Maximal muscle strength declines with age, and the age-related loss in power might be even greater. An accelerated loss of muscle strength and power has been observed in women around the time of the menopause. The aim of the present study was to examine the effects of tibolone, a synthetic steroid with oestrogenic, progestogenic and androgenic activities, on muscle power, endurance and functional ability. A total of 85 healthy women, between 1 and 15 years postmenopausal, were recuited from local paper advertisements. Participants were randomly assigned to 2.5mg of tibolone or to placebo pills of identical appearance; pills were taken daily for 12 months, orally in the morning. Muscle power was assessed as explosive leg extensor power. Endurance was measured on a 2min walk test and a 3.5m walk. Functional ability was determined with the timed Get Up and Go test and a Postural/Locomotor/Manual test. No significant between-group differences were observed for any of the parameters. Possible explanations for this lack of effect are either the absence of an effect of tibolone on muscle power and functional ability, or that our participants were too far above their strength-related functional limits to derive benefit from intervention. Further research is required to resolve this issue.
Holmium as a faecal marker for copper absorption studies in adults
Authors: HARVEY Linda J. , MAJSAK-NEWMAN Gosia , DAINTY Jack R. , WHARF S. Gabrielle , REID Martin D. , BEATTIE John H. , FAIRWEATHER-TAIT Susan J.
Published: August 2015

The objective of the present study was to investigate the validity of using holmium as a faecal marker in a copper absorption study using a highly enriched 65Cu stable isotope label. Ten volunteers (nine female, one male) aged 24-55 years were recruited from the Norwich area to take part in a free-living study. The study was conducted in the Human Nutrition Unit at the Institute of Food Research, Norwich, U.K., and involved feeding breakfast test meals containing foods labelled intrinsically or extrinsically with a highly enriched 65Cu stable isotope label. A 1mg oral dose of the rare earth element holmium was administered to volunteers simultaneously with an oral dose of highly enriched 65Cu stable isotope as a label in the breakfast test meal. Complete faecal collections were made for 10 days after dosing, and the mean percentage holmium recovery (±S.D.) was 105±15%. After correcting for re-excreted copper label, the labelled copper and holmium had similar excretory profiles. It was concluded that holmium is a valid faecal marker in adult human copper absorption studies using stable isotopes.
Non-invasive measurement of cardiac output in heart failure patients using a new foreign gas rebreathing technique
Authors: GABRIELSEN Anders , VIDEBÆK Regitze , SCHOU Morten , DAMGAARD Morten , KASTRUP Jens , NORSK Peter
Published: August 2015

Values of effective pulmonary blood flow (QEP) and cardiac output, determined by a non-invasive foreign gas rebreathing method (CORB) using a new infrared photoacoustic gas analysing system, were compared with measurements of cardiac output obtained by the direct Fick (COFICK) and thermodilution (COTD) methods in patients with heart failure or pulmonary hypertension. In 11 patients, of which three had shunt flow through areas without significant gas exchange, the mean difference (bias) and limits of agreement (±2S.D.) were 0.6±1.2litreċmin-1 when comparing COFICK and QEP, and -0.8±1.3litreċmin-1 when comparing COFICK and COTD. When correction for intrapulmonary shunt flow was applied (i.e. calculation of CORB) in all 11 patients, the bias between COFICK and CORB was 0.1±0.9litreċmin-1, primarily because agreement improved in the three patients with significant shunt flow. In the eight patients without significant shunt flow, the agreement between QEP and COFICK was 0.3±0.9litreċmin-1. In conclusion, a foreign gas rebreathing method with a new infrared photoacoustic gas analyser provided at least as reliable a measure of cardiac output as did thermodilution. In the absence of significant shunt flow, measurement of QEP itself provides a reliable estimate of cardiac output in heart failure patients. The infrared photoacoustic gas analyser markedly facilitates clinical use of the rebreathing method in general, which makes the method available to a larger group of clinicians working with patients with cardiovascular diseases.
Relationship between cardiomyocyte cell death and cardiac function during hypertensive cardiac remodelling in Dahl rats
Authors: IKEDA Shuntaro , HAMADA Mareomi , QU Peng , HIASA Go , HASHIDA Hidetoshi , SHIGEMATSU Yuji , HIWADA Kunio
Published: August 2015

The exact mechanisms responsible for the progression of heart failure remain unclear. We investigated the in vivo relationship between the incidence of apoptotic cell death and left ventricular function serially from the beginning of hypertension to decompensated heart failure in Dahl salt-sensitive rats. Dahl salt-resistant and Dahl salt-sensitive rats were fed on a high-salt diet from 6 weeks of age. Systolic blood pressure was recorded by the tail-cuff method every week. Cardiac function in vivo was evaluated by echocardiography and cardiac catheterization. Cardiomyocyte apoptosis was detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) method. The gene expression of Bax, Bcl-2 and Bcl-xL was analysed by Northern blotting. The TUNEL method revealed that the incidence of cardiomyocyte apoptosis was significantly increased in the hearts of 18-week-old Dahl salt-sensitive rats (apoptotic index 1.3±0.1%). Northern blot analysis revealed that the Bcl-xL mRNA level increased gradually during the progression towards heart failure. In conclusion, these data suggest that cardiomyocyte apoptosis is a terminal event, and plays a role as an aggravating factor in the vicious cycle of heart failure.
Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin–proteasome pathway, are increased in patients with lung cancer referred for thoracotomy
Authors: JAGOE R. Thomas , REDFERN Christopher P.F. , ROBERTS Russell G. , GIBSON G. John , GOODSHIP Timothy H.J.
Published: August 2015

Muscle wasting is a common and prominent feature of advanced cancer, including lung cancer. Evidence from animal experiments suggests that accelerated proteolysis via the ubiquitin-proteasome pathway is the primary cause of cancer-related cachexia. However, there are few data on the role of this pathway in determining muscle wasting in human cancer. The present study was designed to measure whether skeletal muscle gene expression of components of the ubiquitin-proteasome pathway and/or the lysosomal proteolytic pathway was increased in patients with early lung cancer. A total of 36 patients with lung cancer referred for curative resection and 10 control subjects had biopsies of latissimus dorsi muscle taken at operation. mRNA levels of four components of the ubiquitin-proteasome pathway, i.e. polyubiquitin, C2α proteasome subunit, 14kDa ubiquitin-carrier protein and ubiquitin-activating protein, and of two lysosomal proteolytic enzymes, i.e. cathepsin B and cathepsin D, were measured using quantitative Northern blotting. mRNA levels for cathepsin B, but not for components of the ubiquitin-proteasome pathway, were higher in patients with cancer compared with controls (P = 0.01). Among lung cancer patients, cathepsin B mRNA levels correlated with fat-free mass index (r =-0.57, P = 0.003) and tumour stage (rs = 0.45, P = 0.03), and were higher in smokers (P = 0.04). Thus gene expression of the lysosomal protease cathepsin B is increased in the skeletal muscle of patients with early lung cancer, and the strong inverse relationship with fat-free mass suggests that cathepsin B may have a role in inducing muscle wasting in the early stages of lung cancer.
Circadian variation in vascular tone and endothelial cell function in normal males
Authors: ELHERIK Khalid , KHAN Faisel , MCLAREN Margaret , KENNEDY Gwen , BELCH Jill J.F.
Published: August 2015

The existence of circadian rhythms in the time of onset of acute cardiovascular events has been described previously. This report describes the circadian variation in endothelial cell products, such as nitric oxide (NO) and endothelin-1 (ET-1) levels, and endothelium-dependent and -independent vasodilation in normal males. Plasma ET-1 and NO were measured every 4h in nine subjects (20-41 years old) over a 24h period. Endothelium-dependent and -independent vascular responses were measured in the forearm skin every 4h using laser Doppler imaging after iontophoresis of increasing doses of acetylcholine (ACh) and sodium nitroprusside respectively. A statistically significant circadian variation was demonstrated for the mean ACh response (P = 0.0001, ANOVA). The peak response [in arbitrary perfusion units (AU)] occurred at 16.00 hours (8.90±1.91 AU) and the lowest response at 08.00 hours (4.57±0.66 AU). A significant circadian variation was also seen for the highest dose of sodium nitroprusside (P = 0.036, ANOVA), the peak occurred at 16.00 hours (3.97±1.80 AU), and the lowest at 04.00 hours (2.62±0.58 AU) and 08.00 hours (2.58±1.16 AU). There was a significant circadian variation in the ET-1 levels (P = 0.04) with two peaks, one at 20.00 hours (0.80±0.28pg/ml) and the other at 08.00 hours (0.84±0.15pg/ml). The lowest value occurred at 16.00 hours (0.61±0.24pg/ml). There was also a borderline trend for a circadian variation in NO levels (P = 0.06), with higher levels at 20.00 hours (15.53±8.42μmol/l), and low levels at 04.00 hours (10.87±4.70μmol/l) and 08.00 hours (9.82±3.15μmol/l). ACh responses were significantly correlated with ET-1 (r = -0.3, P = 0.02) and NO (r = 0.30, P = 0.02) levels. Our findings suggest that endothelial activity has a circadian variation with attenuation in the morning. These circadian variations in endothelial activity might play an important role in the occurrence of acute cardiovascular events at this time, which are precipitated through the interplay between ET-1, NO and vascular function.