bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo
Authors: CHU Z. M. , CROFT K. D. , KINGSBURY D. A. , FALCK J. R. , REDDY K. M. , BEILIN L. J. 
Published: August 2015

We have investigated the role of cytochrome P450 (CYP-450) metabolites of arachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthetized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inhibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substantially suppressed mesenteric vasoconstrictor responses to angiotensin II in SHR, but had no effect on responses to noradrenaline or sympathetic nerve stimulation. In normotensive Wistar–Kyoto (WKY) rats, miconazole caused only a modest suppression of vasoconstrictor responses to angiotensin II. N-Methylsulphonyl-12,12-dibromododec-11-enamide (DDMS), a new selective inhibitor of CYP-450 ω-hydroxylase activity, decreased mean intra-arterial blood pressure and significantly attenuated mesenteric angiotensin II-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize 14C-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The results from the present studies combined with the existing evidence that angiotensin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachidonic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin II-induced vasoconstriction. However, the development of more sensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.
Effects of prolonged hypobaric hypoxia on human skeletal muscle function and electromyographic events
Authors: CAQUELARD F. , BURNET H. , TAGLIARINI F. , CAUCHY E. , RICHALET J. P. , JAMMES Y. 
Published: August 2015

This study tested the hypothesis that a prolonged decrease in arterial oxygen pressure in resting or contracting skeletal muscles alters their ability to develop force through an impairment of energy-dependent metabolic processes and also through an alteration of electrophysiological events. The experiment was conducted during a 32-day simulated ascent of Mt. Everest (8848 m altitude) (Everest III Comex '97), which also allowed testing of the effects of re-oxygenation on muscle function. Maximal voluntary contractions (MVCs) of the flexor digitorum, and static handgrips sustained at 60% of MVC, were performed by eight subjects before the ascent (control), then during the stays at simulated altitudes of 5000 m, 6000 m and 7000 m, and finally 1 day after the return to 0 m. The evoked muscle compound action potential (M-wave) was recorded at rest and during the manoeuvres at 60% of MVC. The changes in median frequency of electromyographic (EMG) power spectra were also studied during the contraction at 60% of MVC. In four individuals, transient re-oxygenation during the ascent allowed us to test the reversibility of hypoxia-induced MVC and M-wave changes. At rest, a significant decrease in M-wave amplitude was noted at 5000 m. This effect was associated with a prolonged M-wave conduction time at 6000 m and an increased M-wave duration at 7000 m, and persisted after the return to 0 m. Re-oxygenation did not modify the changes in M-wave characteristics. A significant decrease in MVC was measured only during the ascent (-10 to -24%) in the non-dominant forearm of subjects who underwent re-oxygenation; this intervention slightly improved muscle strength at 6000 m and 7000 m. During the ascent and after the return to 0 m, there was a significant reduction of the median frequency decrease throughout contraction at 60% of MVC compared with the EMG changes measured before the ascent. It is concluded that prolonged exposure to hypoxia slows the propagation of myopotentials and alters sensorimotor control during sustained effort. Re-oxygenation did not affect the hypoxia-induced EMG changes and had a modest influence on muscle strength.
Tumour necrosis factor-α gene expression and production in human umbilical arterial endothelial cells
Authors: NEUHAUS Thomas , TOTZKE Gudrun , GRUENEWALD Elisabeth , JUESTEN Hans-Peter , SACHINIDIS Agapios , VETTER Hans , KO Yon 
Published: August 2015

Endothelial cells act as an interface between the blood and tissues, and are known to be involved in inflammatory processes. These cells are responsive to and produce different cytokines. Tumour necrosis factor-α (TNF-α) not only is one of the most important inflammatory peptides, but also can be induced by lipopolysaccharide (LPS). The focus of the present study was on TNF-α gene expression and production in human umbilical arterial endothelial cells (HUAEC), including the kinetics of this process. Interleukin-1α (IL-1α), LPS and TNF-α, which are all known to be elevated in septic shock, were used as stimulators at concentrations commonly found in patients with sepsis. Through the use of reverse transcriptase/PCR, immunohistochemical reactions and ELISA techniques, we showed that, in HUAEC, all three stimuli were able to induce gene expression and production of TNF-α. Furthermore, this induction by IL-1α, LPS and TNF-α occurred in a time- and concentration-dependent manner in these cells. TNF-α expression and production was induced by all three agents at concentrations commonly found in patients with sepsis. TNF-α mRNA was observed within 30 min regardless of the stimulus used, but the levels peaked at different times. Since it is well established that TNF-α is able to induce the synthesis of IL-1α in endothelial cells and, as shown in the present study, TNF-α and IL-1α are themselves able to induce the synthesis of TNF-α in endothelial cells, an autocrine potentiation of cytokine release in sepsis can be proposed. This situation could lead to a locally acting ‘vicious cycle’ which, when considered in addition to the known ability of TNF-α to induce apoptosis, could mean that various organs will be damaged, a condition associated with sepsis. Thus these results provide further evidence for the important role played by the endothelium in inflammation.
Plasma soluble adhesion molecules and endothelium-dependent vasodilation in early human atherosclerosis
Authors: JOHN Stefan , JACOBI Johannes , DELLES Christian , SCHLAICH Markus P. , ALTER Ortrun , SCHMIEDER Roland E. 
Published: August 2015

Levels of soluble cellular adhesion molecules are increased in patients with atherosclerosis, and have been found to predict coronary heart disease. Therefore these molecules have been suggested to represent laboratory markers for inflammation and activation of endothelial cells. Impaired endothelium-dependent vasodilation has been demonstrated to be an early marker of atherosclerosis. We hypothesized that soluble adhesion molecules are related to impaired endothelium-dependent vasodilation and may serve as an early marker of atherosclerosis. Patients (n = 52) with moderate and uncomplicated hypercholesterolaemia [low-density lipoprotein (LDL)-cholesterol 4.89±1.26 mmol/l] were compared with healthy controls (n = 43; LDL-cholesterol 2.44±0.79 mmol/l). Endothelium-dependent vasodilation of the forearm vasculature was assessed by intra-arterial infusion of acetylcholine (12 and 48 µg/min). Forearm blood flow was measured by venous occlusion plethysmography. Plasma concentrations of the soluble forms of ICAM-1 (intercellular cell adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and E-selectin were measured by ELISA. Hypercholesterolaemic patients had impaired endothelium-dependent vasodilation in comparison with healthy controls (forearm blood flow after 48 µg/min acetylcholine: 21.3±10.6 and 30.4±16.3 ml·min-1·100 ml-1 respectively; P = 0.002). Plasma concentrations of soluble adhesion molecules were not different between hypercholesterolaemic patients and controls (ICAM-1, 196±56 and 180±38 ng/ml respectively; VCAM-1, 431±137 and 405±65 ng/ml respectively; E-selectin, 39±17 and 37±12 ng/ml respectively). Moreover, levels of soluble adhesion molecules were not correlated with endothelium-dependent vasodilation. Thus, in hypercholesterolaemic patients without clinical atherosclerosis, levels of soluble adhesion molecules were not elevated in comparison with healthy controls. In addition, these markers of endothelial inflammation were not related to impaired endothelium-dependent vasodilation. Our data indicate that measurement of levels of soluble adhesion molecules cannot replace assessment of endothelium-dependent vasodilation in detection of early hypercholesterolaemic atherosclerosis.
Prolongation of the QT interval in heart failure occurs at low but not at high heart rates
Authors: DAVEY P. P. , BARLOW C. , HART G. 
Published: August 2015

Abnormal left ventricular structure and function as in, for example, left ventricular hypertrophy or chronic heart failure, is associated with sudden cardiac death and, when the ejection fraction is depressed, with prolongation of the QT interval. The dependence on heart rate of QT interval prolongation in these conditions, and the relationship of any abnormalities either to deranged autonomic nervous system function or to an adverse prognosis, has not been well studied. We therefore investigated (1) the dependence on heart rate of the QT interval, and (2) the relationship between both QT interval and the QT/heart rate slope and markers of adverse prognosis in these two conditions. The QT interval was measured at rest and during exercise in 34 subjects with heart failure, 16 subjects with left ventricular hypertrophy and 16 age-matched controls with normal left ventricular structure and function. QTc (corrected QT) intervals at rest were significantly longer in heart failure patients (471±10 ms) than in controls (421±6 ms) or in subjects with hypertrophy (420±6 ms) (P < 0.05). At peak exercise, despite the attainment of similar heart rates, the QT intervals no longer differed from each other, being 281±7 ms for controls, 296±11 ms in hypertrophy and 303±10 ms in heart failure (no significant difference). The QT/heart rate slope was significantly increased in heart failure [2.3±0.1 ms·(beats/min)-1] compared with controls [1.55±0.06 ms·(beats/min)-1] and hypertrophy [1.66±0.1 ms·(beats/min)-1] (P < 0.001). In left ventricular hypertrophy, despite animal data suggesting that QT interval prolongation should occur, no abnormalities were found in QT intervals at rest or during exercise. The QT/heart rate slope did not relate to any markers for an adverse prognosis, except that of prolongation of QT interval. Long QT intervals were associated principally with impairment of left ventricular systolic function. Our data emphasize the dynamic nature of the QT interval abnormalities found in heart failure.
Persistent, progressive hypophosphataemia after voluntary hyperventilation
Authors: PALEOLOGOS M. , STONE E. , BRAUDE S. 
Published: August 2015

Hyperventilation (HV) and respiratory alkalosis are associated with hypophosphataemia, although the extent and duration of HV required to produce changes in serum phosphate levels are not known. We sought to characterize the effects of HV, with or without dextrose loading, on serum phosphate levels and other biochemical parameters. HV was monitored by controlling the end-tidal partial pressure of carbon dioxide (Petco2). The effect of dextrose was studied because infusion of a glucose load is known to promote a fall in serum phosphate via stimulation of glycolysis. Eight healthy volunteers were enrolled in four study protocols: (1) HV for 20 min to a Petco2 of 25–30 mmHg (mild); (2) HV for 20 min to a Petco2 of 15–20 mmHg (severe); (3) mild HV with intravenous dextrose loading, and (4) dextrose loading alone. Periodic measurements of serum phosphate, venous pH, serum 2,3-diphosphoglycerate (2,3-DPG) and other parameters were made. Serum phosphate fell during HV and continued to decline after cessation of HV. Dextrose loading alone caused a fall in serum phosphate that continued for at least 30 min after cessation of the infusion (P < 0.0002). HV combined with dextrose resulted in a greater decline in serum phosphate than either variable alone (P = 0.003). The maximal decline in serum phosphate occurred in severe HV, with a mean decrease of 0.38 mmol/l at 20 min after cessation of HV (P < 0.0001). Serum phosphate was still significantly lowered compared with baseline at 90 min after cessation of HV (P = 0.001). Other significant changes seen with HV included a decrease in serum glucose (P < 0.01), a decrease in serum potassium (P < 0.05) and an increase in venous pH (P < 0.007). Serum 2,3-DPG levels did not change significantly in any study protocol. Thus relatively mild acute HV produces significant changes in serum phosphate. In both mild and severe HV this effect is progressive after cessation of HV. This phenomenon has not been shown before, and may have significant clinical implications.
Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism?
Authors: MCCANN Gerald P. , CAHILL Helen , KNIPE Stephen , MUIR Douglas F. , MACINTYRE Paul D. , HILLS W. Stewart 
Published: August 2015

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the perception of exercise-induced fatigue. Sumatriptan is a selective 5-HT1B/D receptor agonist which does not cross the blood–brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 28.4±10.8 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively; 95% confidence interval (CI) of difference 12.1 s, 59.1 s; P = 0.008]. There was no significant effect on peak oxygen consumption (placebo, 50.6±6.3 ml·min-1·kg-1; sumatriptan, 51.7±7.6 ml·min-1·kg-1). Sumatriptan administration resulted in decreases in both heart rate (sumatriptan, 188±14 beats/min, placebo, 196±12 beats/min; 95% CI of difference 12.6, 2.6; P = 0.008) and respiratory exchange ratio (sumatriptan, 1.23±0.06; placebo, 1.26±0.07; 95% CI of difference 0.05, 0.01; P = 0.01) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation.
Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer
Authors: AGTERESCH H. J. , LEIJ-HALFWERK S. , VAN DEN BERG J. W. O. , HORDIJK-LUIJK C. H. , WILSON J. H. P. , DAGNELIE P. C. 
Published: August 2015

Cancer cachexia is associated with elevated lipolysis, proteolysis and gluconeogenesis. ATP infusion has been found to significantly inhibit loss of body weight, fat mass and fat-free mass in patients with advanced lung cancer. The present study was aimed at exploring the effects of ATP on whole-body glucose turnover, alanine turnover and gluconeogenesis from alanine. Twelve patients with advanced non-small-cell lung cancer (NSCLC) were studied 1 week before and during 22–24 h of continuous ATP infusion. After an overnight fast, turnover rates of glucose and alanine, and gluconeogenesis from alanine, were determined using primed constant infusions of [6,6-2H2]glucose and [3-13C]alanine. Thirteen NSCLC patients and eleven healthy subjects were studied as control groups without ATP infusion. During high-dose ATP infusion (75 µg·min-1·kg-1), glucose turnover was 0.62±0.07 mmol·h-1·kg-1, compared with 0.44±0.13 mmol·h-1·kg-1 at baseline (P = 0.04). For gluconeogenesis a similar, but non-significant, trend was observed [baseline, 0.30±0.16 mmol·h-1·kg-1; during ATP, 0.37±0.13 mmol·h-1·kg-1 (P = 0.08)]. At lower ATP doses (37–50 µg·min-1·kg-1) these effects were not detected. The relative increase in glucose turnover during ATP infusion compared with baseline showed a significant correlation with the ATP dose (r = 0.58, P = 0.02). No change in alanine turnover was observed at any ATP dose. The results of this study indicate an increase in glucose turnover during high-dose ATP infusion compared with baseline levels. During high-dose ATP infusion, glucose turnover was similar to that during low-dose ATP infusion and to that in control NSCLC patients. Between ATP infusions, however, glucose turnover in patients treated with high-dose ATP was significantly lower than that in the low-dose and control NSCLC patients (P = 0.04 and P = 0.03 respectively), and similar to that in healthy subjects. This would suggest that repeated high-dose ATP infusions may inhibit glucose turnover between infusion periods.
Myocardial infarction with and without reperfusion in sheep: early cardiac and neurohumoral changes
Authors: CHARLES Christopher J. , ELLIOTT John M. , NICHOLLS M. Gary , RADEMAKER Miriam T. , RICHARDS Mark 
Published: August 2015

There are few stable and reproducible large-animal models of chronic heart failure produced by ischaemic damage to the myocardium. Here we characterize a novel method of inducing myocardial damage in closed-chest sheep by catheter delivery of thrombogenic coils, and compare this with a newly described open-artery model of cardiac injury in sheep. Sham controls were compared with animals subjected to (a) 90 min of coronary artery occlusion/reperfusion by PTCA (percutaneous transluminal coronary angioplasty) balloon, and (b) permanent coronary artery occlusion induced by catheter delivery of thrombogenic coils (seven sheep/group). Both balloon occlusion/reperfusion and permanent coil occlusion resulted in well-defined anteroapical infarcts, as documented by ECG changes, significant rises in creatine kinase (both groups P < 0.001) and troponin-T (both groups P < 0.05), and post-mortem examination. Washout of enzymes was much more rapid in the reperfused group (P < 0.01). Infarction resulted in significant reductions in left ventricular (LV) ejection fraction (both groups P < 0.01) and regional wall abnormalities. Ejection fraction 7 days post-coil (21.3±4.2%) was significantly lower (P < 0.01) than that 7 days post-balloon (38.8±4.5%). Coil-induced infarction was associated with acutely reduced arterial pressure (P < 0.05), and increases in heart rate (P < 0.05), atrial pressures (P < 0.05), plasma brain natriuretic peptide levels (P < 0.05) and adrenaline levels (P < 0.05). Rises seen in plasma endothelin levels in sham controls were blunted in the coil group (P < 0.001). Haemodynamic changes were less marked in the balloon group. In conclusion, restriction of coronary artery occlusion to 90 min results in infarction, but less LV dysfunction with reduced early remodelling, compared with permanent occlusion. Acute changes in biochemical markers, haemodynamics, neurohormones and LV function confirm that these are excellent models of open- and closed-artery myocardial infarction leading to asymptomatic LV dysfunction.
Baroreflex sensitivity in the elderly: influence of age, breathing and spectral methods
Authors: GERRITSEN J. , TENVOORDE B. J. , DEKKER J. M. , KOSTENSE P. J. , BOUTER L. M. , HEETHAAR R. M. 
Published: August 2015

Baroreflex sensitivity (BRS) has been proposed as a diagnostic parameter for neurological disorders and as a survival-prognosis parameter in diabetic and cardiac patients. Therefore reference values and the reproducibility of BRS were assessed, taking into account the possible influence of age, gender, test conditions and some analysis variants. Healthy subjects (n = 191) were randomly selected from the 50–75-year-old general population (the Hoorn Study). Variations in blood pressure and heart rate were recorded non-invasively during three breathing modes: spontaneous (3 min), slow metronome (1 min; 6 breaths/min = 0.1 Hz) and fast metronome (1 min; 15 breaths/min = 0.25 Hz), all in a supine position. From these recordings, BRS was assessed as the transfer gain between changes in blood pressure and heart period, and as the α coefficient. BRS values ranged from 5.0 to 8.9 ms·mmHg-1. Slow metronome breathing resulted in higher BRS values than fast breathing, while during spontaneous breathing BRS in the low-frequency band was lower than that in the high-frequency band (respiratory origin). BRS values decreased with lower coherence criteria. BRS-α was significantly higher than BRS-gain. While regression analysis showed no gender differences, BRS decreased with age. Therefore age-specific reference values were calculated. The reproducibility of BRS values was in general moderate, with reliability coefficients ranging from 43 to 81% and coefficients of variation ranging from 34 to 59%. In conclusion, this study shows age, breathing mode, frequency and coherence threshold to affect measures of BRS. Therefore these factors should be considered in clinical studies; appropriate reference values are given.
Dexamethasone and pentastarch produce additive attenuation of ischaemia/reperfusion lung injury
Authors: CHIANG Chi-Huei , WU Chin-Pyng , PERNG Wann-Cherng , YAN Horng-Chin , YU Cheng-Ping 
Published: August 2015

The choice of an intravenous solution for the attenuation of ischaemia/reperfusion (I/R) lung injury is still a difficult one. Although 10% (w/v) pentastarch has been used in ICU settings, its use in I/R lung injury has not been well explored. We hypothesized that this synthetic colloid substance, which maintains colloid osmotic pressure and potentially ‘seals’ capillary leaks, in combination with an anti-inflammatory agent (i.e. dexamethasone), would ameliorate I/R lung injury. After 60 min of lung ischaemia in an isolated rat lung model, lungs were reperfused for 60 min in a closed circulating system with one of the following solutions: (1) NS (0.9% normal saline), (2) NS+Dex (dexamethasone), (3) NS+Penta (pentastarch), or (4) NS+Penta+Dex. Haemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc) and lung pathology were analysed. Results showed significantly lower values of Kfc and LWG in pentastarch- or dexamethasone-perfused groups as compared with those in the NS group. Dexamethasone as an additive to NS+Penta further decreased Kfc and LWG. Histopathological studies showed similar decreases in injury profiles. We conclude that reperfusion with dexamethasone and pentastarch can attenuate I/R lung injury, and that dexamethasone and pentastarch have additive effects. Our data thus suggest that the combination of a colloid substance with ‘sealing effects’ and an anti-inflammatory agent may provide a better reperfusion solution for patients with I/R lung injury or for lungs stored for transplant.