bluuebunny/crossref_metadata_2025 huggingface dataset:
The active molecular form of plasma adrenomedullin is extracted in the pulmonary circulation in patients with mitral stenosis: possible role of adrenomedullin in pulmonary hypertension
Authors: NISHIKIMI Toshio , NAGATA Seiki , SASAKI Tatsuya , YOSHIHARA Fumiki , NAGAYA Noritoshi , HORIO Takeshi , MATSUO Hisayuki , MATSUOKA Hiroaki , KANGAWA Kenji
Published: August 2015

Adrenomedullin (AM), a novel hypotensive peptide, preferentially dilates pulmonary vessels rather than systemic vessels. This suggests the possibility that AM is a circulating hormone which participates in regulation of the pulmonary circulation. A recent study revealed that two molecular forms of AM, i.e. a mature, active form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly), circulate in human plasma. In the present study we investigated the production and clearance sites and pathophysiological significance of the two molecular forms of AM in the pulmonary circulation in patients with mitral stenosis. We measured the plasma levels of AM-m and total AM (AM-T; AM-m+AM-Gly) using a recently developed specific immunoradiometric assay, and thus calculated plasma AM-Gly levels, in blood samples obtained from the femoral vein, pulmonary artery, left atrium and aorta of 28 consecutive patients with mitral stenosis (20 females and eight males; age 53±10 years). Patients with mitral stenosis had significantly higher venous concentrations of AM-T, AM-Gly and AM-m than age-matched normal controls (AM-T, 15.9±2.5 and 10.6±2.1 pmol/l respectively; AM-Gly, 14.0±2.1 and 9.8±1.9 pmol/l respectively; AM-m, 1.9±0.6 and 1.1±0.3 pmol/l respectively; each P < 0.001). There was a significant decrease in the concentrations of AM-m and AM-T between the pulmonary artery and the left atrium (AM-T, 16.1±2.7 and 14.0±2.4 pmol/l respectively; AM-m, 2.0±0.6 and 0.7±0.2 pmol/l respectively; each P < 0.001); however, there were no differences in plasma AM-Gly levels between the pulmonary artery and the left atrium (14.1±2.3 and 13.5±2.3 pmol/l respectively). The venous concentrations of AM-m, AM-Gly and AM-T showed similar correlations with mean pulmonary artery pressure (AM-T, r = 0.67; AM-Gly, r = 0.63; AM-m, r = 0.59; each P < 0.001) and total pulmonary vascular resistance (AM-T, r = 0.77; AM-Gly, r = 0.70; AM-m, r = 0.75; each P < 0.001). These results suggest that the plasma concentration of AM-m is increased in parallel with those of AM-Gly and AM-T, and that the main site for clearance of AM-m from the plasma is the lung; the extracted AM-m in the lungs may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.
Regional transcapillary albumin exchange in rodent endotoxaemia: effects of fluid resuscitation and inhibition of nitric oxide synthase
Authors: SINGH Suveer , ANNING Peter B. , WINLOVE C. Peter , EVANS Timothy W.
Published: August 2015

Sepsis is characterized by increased microvascular permeability and regional variations in capillary perfusion, which may be modulated by nitric oxide (NO) and reversed by fluid resuscitation (FR). The effects of saline FR and NO synthase blockade [by NG-nitro-L-arginine methyl ester (L-NAME)] on microvascular albumin transport and perfused capillary density were assessed in anaesthetized Wistar rats with acute normodynamic endotoxaemia. Separate dual-isotope techniques were employed to measure the permeability index (PIA) and the permeability×surface area product index (PIB), which provide different and complementary information regarding blood–tissue albumin exchange. PIA represents the tissue/blood distribution volume ratio of albumin. PIB is a composite measure of endothelial permeability and the vascular surface area available for albumin exchange, and therefore takes into account the effect of altered blood volume. Capillary density was quantified by fluorescence microscopy following circulation of Evans Blue-labelled albumin. Compared with controls, PIA was reduced significantly in lipopolysaccharide (LPS)-treated animals in skeletal muscle and skin, probably due to blood volume redistribution rather than to changes in permeability. PIB was increased significantly in LPS-treated animals in the kidney, mesentery, skeletal muscle, skin and lung, and in the small bowel following FR. FR also improved the LPS-induced metabolic base deficit, but did not alter capillary density. L-NAME significantly attenuated the LPS-induced rise in PIB in the lung. In conclusion, acute endotoxaemia induces tissue-dependent variations in microvascular albumin exchange. FR improves acid–base disturbance in endotoxaemia, through mechanisms other than microvascular recruitment. NO appears to increase microvascular permeability in endotoxaemia, an effect that may be attenuated by L-NAME, particularly in the lung.
Carbon dioxide contributes to the beneficial effect of pressurization in a portable hyperbaric chamber at high altitude
Authors: IMRAY Christopher H. E. , CLARKE Timothy , FORSTER Peter J. G. , HARVEY Timothy C. , HOAR Helen , WALSH Sarah , WRIGHT Alexander D.
Published: August 2015

Regional cerebral oxygenation (rSO2) and peripheral oxygen saturation (SpO2) have been studied in subjects inside a portable hyperbaric chamber at altitude during pressurization. The effects of the accumulation of carbon dioxide within the chamber on rSO2 and SpO2 have also been investigated. Three studies of cerebral regional oxygenation were undertaken, using near-IR spectroscopy, in subjects who had ascended to 3475 m in the Alps, 4680 m in the Andes or 5005 m in the Himalayas. At 3475 m and 5005 m the effects of the removal of inspired carbon dioxide by a soda lime scavenger were also studied. On pressurization of the chamber to 19.95 kPa, inspired carbon dioxide rose within the chamber from 0.03% (0.06 kPa) ambient to over 1% (1.3 kPa). At 5005 m, SpO2 rose from a baseline of 79.5% (S.D. 4.5%) to 95.9% (2.0%) (P < 0.0001), and cerebral rSO2 rose from 64.6% (3.4%) to 69.4% (3.6%) (P < 0.0001). The introduction of a soda lime CO2 scavenger into the breathing circuit resulted in a drop in SpO2 from 95.9% (2.03%) to 93.6% (2.07%) (P < 0.001) and a fall in rSO2 from 69.4% (3.64%) to 68.5% (3.5%) (P < 0.01). Chamber pressure was maintained throughout at 19.95 kPa. Similar changes were seen at the other altitudes. Cerebral rSO2 increased rapidly following pressurization at all three altitudes. Scavenging of inspired carbon dioxide was associated with a significant fall in cerebral rSO2 and SpO2, and we estimate that the contribution of carbon dioxide may account for up to one-third of the beneficial effect of the portable hyperbaric chamber.
Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans
Authors: BÖGER Rainer H. , LENTZ Steven R. , BODE-BÖGER Stefanie M. , KNAPP Howard R. , HAYNES William G.
Published: August 2015

Hyperhomocyst(e)inaemia is associated with endothelial dysfunction in animals and humans. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inaemia are poorly understood, but may involve impaired bioavailability of endothelium-derived nitric oxide (NO). We hypothesized that acute elevation of homocyst(e)ine by oral methionine loading may stimulate the formation of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, due to a transmethylation reaction during the formation of homocyst(e)ine from methionine. We studied nine healthy human subjects (five males, four females) aged 29±2 years. Flow-mediated vasodilation (FMD) in the brachial artery (endothelium-dependent) and vasodilation induced by nitroglycerine (endothelium-independent) were measured with high-resolution ultrasound before and 8 h after oral methionine (100 mg/kg in cranberry juice) or placebo (cranberry juice), on separate days and in random order. Plasma homocyst(e)ine and ADMA concentrations were measured by specific HPLC methods. After a methionine bolus, elevation of homocyst(e)ine (28.4±3.5 µmol/l) was associated with an increased plasma concentration of ADMA (2.03±0.18 µmol/l) and reduced FMD (1.54±0.92%). Placebo had no effect on these parameters. There was a significant inverse linear relationship between ADMA concentration and FMD (r =-0.49; P < 0.05), which was stronger than the relationship between the homocyst(e)ine concentration and FMD (r =-0.36; not significant). We conclude that acute elevation of the homocyst(e)ine concentration impairs vascular endothelial function by a mechanism in which an elevated concentration of ADMA may be involved. This finding may have importance for understanding the mechanism(s) leading to homocyst(e)ine-associated vascular disease, and its potential treatment.
Iron signalling regulated directly and through oxygen: implications for sepsis and the acute respiratory distress syndrome
Authors: QUINLAN G. J. , CHEN Y. , EVANS T. W. , GUTTERIDGE J. M. C.
Published: August 2015

Reactive oxygen species produced at toxic levels are damaging species. When produced at sub-toxic levels, however, they are involved as second messengers in numerous signal transduction pathways. In addition to these findings, we can add the concept that iron (often viewed as the ‘villain’ in free radical biology) can also be considered as a signalling species. Iron is intimately involved in the regulation of its own storage, compartmentalization and turnover. During adult respiratory distress syndrome (ARDS) and sepsis, such regulation may be aberrant or altered in some predisposed way. Such changes may have profound implications for tissue damage, and for the modulation of the inflammatory response in these patients. The search for a genetic predisposition in patients that leads to the development of ARDS associated with abnormalities in iron turnover and signalling would seem to be an important and logical progression for studies into the disease. These may lead eventually to the design of effective treatment regimens that involve the control of iron.
Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat
Authors: BALLINGER Anne B. , WILLIAMS Gareth , CORDER Roger , EL-HAJ Tarek , FARTHING Michael J. G.
Published: August 2015

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30–80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.
Influence of aging on cardiac baroreflex sensitivity determined non-invasively by power spectral analysis
Authors: PICCIRILLO Gianfranco , CACCIAFESTA Mauro , VIOLA Emanuela , SANTAGADA Elvira , NOCCO Marialuce , LIONETTI Marco , BUCCA Carmela , MOISÈ Antonio , TARANTINI Sabrina , MARIGLIANO Vincenzo
Published: August 2015

Aging reduces cardiac baroreflex sensitivity. Our primary aim in the present study was to assess the effects of aging on cardiac baroreflex sensitivity, as determined by power spectral analysis (α index), in a large population of healthy subjects. We also compared the α indexes determined by power spectral analysis with cardiac baroreflex sensitivity measured by the phenylephrine method (BSphen). We studied 142 subjects (79 males/63 females; age range 9–94 years), who were subdivided into five groups according to percentiles of age (25, 50, 75 and 95). Power spectral analysis yields three α indexes: an α low-frequency (LF) index of cardiac baroreflex sensitivity that ranges around 0.1 Hz; an α high-frequency (HF) index reflecting cardiac baroreflex sensitivity corresponding to the respiratory rate; and α total frequency (α TF), a new index whose spectral window includes all power in the range 0.03–0.42 Hz. Spectra were recorded during controlled and uncontrolled respiration. Under both conditions, all three α indexes were higher in the youngest age group (⩽ 34 years old) than in the three oldest groups. Notably, α TF was significantly higher in younger subjects than in the three oldest groups [14±1 ms/mmHg compared with 9±1 (P < 0.05), 8.1±1 (P < 0.001) and 8.1±1 (P < 0.05) ms/mmHg respectively]. BSphen showed a similar pattern [12±1 ms/mmHg compared with 8±0.5 (P < 0.001), 6±0.5 (P < 0.05) and 6±1 (P < 0.05) ms/mmHg respectively]. No significant differences were found for cardiac baroreflex sensitivity among the three oldest groups. All α indexes were correlated inversely with age. The index yielding the closest correlation with BSphen was α TF (r = 0.81, P < 0.001). Cardiac baroreflex sensitivity in normotensive individuals declines with age. It falls predominantly in middle age (from approx. 48 years onwards) and remains substantially unchanged thereafter. The elderly subjects we selected for this study probably had greater resistance to cardiovascular disease that is manifested clinically, with preserved cardiac baroreceptor sensitivity.
Role of GADD153 (growth arrest- and DNA damage-inducible gene 153) in vascular smooth muscle cell apoptosis
Authors: IGASE Michiya , OKURA Takafumi , NAKAMURA Michitsugu , TAKATA Yasunori , KITAMI Yutaka , HIWADA Kunio
Published: August 2015

GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells, but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to genotoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also reported that GADD153 is directly associated with apoptosis. Recently we have reported that platelet-derived growth factor (PDGF)-BB induces apoptosis in cultured vascular smooth muscle cells (VSMC), but only when 100% confluency is reached. These results suggested that cell–cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study, we explored the role of GADD153, one of a number of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptosis, after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VSMC significantly reduced cell viability and induced apoptosis. In the carotid artery balloon injury model in rats, GADD153 protein was expressed in apoptotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanisms of VSMC apoptosis.
Insulin stimulates laser Doppler signal by rat muscle in vivo, consistent with nutritive flow recruitment
Authors: CLARK Andrew D. H. , BARRETT Eugene J. , RATTIGAN Stephen , WALLIS Michelle G. , CLARK Michael G.
Published: August 2015

Insulin-mediated increases in limb blood flow are thought to enhance glucose uptake by skeletal muscle. Using the perfused rat hindlimb, we report that macro laser Doppler flowmetry (LDF) probes positioned on the surface of muscle detect changes in muscle capillary (nutritive) flow. With this as background, we examined the effects of insulin and adrenaline (epinephrine), which are both known to increase total leg blood flow, on the LDF signals from scanning and stationary probes on the muscle surface in vivo. The aim is to assess the relationship between capillary recruitment, total limb blood flow and glucose metabolism. Glucose infusion rate, femoral arterial blood flow (FBF) and muscle LDF, using either scanning or a stationary probe positioned over the biceps femoris muscle, were measured. With scanning LDF, animals received insulin (10 m-units·min-1·kg-1), adrenaline (0.125 µg·min-1·kg-1) or saline. By 1 h, insulin had increased the glucose infusion rate from 0 to 128 µmol·min-1·kg-1 and the scanning LDF had increased by 62±8% (P < 0.05), but FBF was unaffected. Adrenaline increased FBF by 49% at 15 min, but LDF was unchanged. With saline at 1 h, neither FBF nor LDF had changed. With the stationary LDF surface probe, insulin at 1 h had increased FBF by 47% (P < 0.05) and LDF by 47% (P < 0.05) relative to saline controls. Adrenaline increased FBF (39%), but LDF was unaltered. The stimulation of LDF by insulin is consistent with capillary recruitment (nutritive flow) as part of the action of this hormone in vivo. The recruitment may be independent of changes in total flow, as adrenaline, which also increased FBF, did not increase LDF. The time of onset suggests that LDF closely parallels glucose uptake. Thus, depending on probe design, measurement of muscle haemodynamic effects mediated by insulin in normally responsive and insulin-resistant patients should be possible.
Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure
Authors: WIJEYSUNDERA Duminda N. , BUTLER Gary C. , ANDO Shin-ichi , POLLARD Michael J. , PICTON Peter , FLORAS John S.
Published: August 2015

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6±1.0 versus 7.2±1.2 mmHg; means±S.E.M., P < 0.02), HR (59±2 versus 66±3 beats/min, P < 0.05) and MSNA burst frequency (29.0±2.4 versus 39.0±3.5 bursts/min, P < 0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2±0.6 versus 8.8±1.4 bursts/100 heart beats per mmHg; P < 0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.
Effects of nitric oxide synthase inhibition on angiotensin receptors and metabolism in the pregnant hypertensive rat
Authors: YANG Y. , MACDONALD G. J. , DUGGAN K. A.
Published: August 2015

Endothelial dysfunction and a consequent decrease in nitric oxide production have been implicated in the pathogenesis of pre-eclampsia. A prominent feature of the pre-eclamptic syndrome is a loss of the pregnancy-induced refractoriness to infused pressor agents, such as angiotensin. In this study, we sought to determine whether a decrease in nitric oxide production might be linked via changes in angiotensin II receptors and angiotensin II metabolism to changes in pressor sensitivity to infused angiotensin II. Pregnant and non-pregnant spontaneously hypertensive rats (SHRs) were randomly allocated to receive 5 mg·kg-1·day-1NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water or drinking water alone from days 7 to 14 of gestation. Steady-state metabolic clearance studies of angiotensin II were then performed, or tissues were harvested for angiotensin II receptor studies. Treatment with L-NAME caused an increase in systolic pressure (P < 0.001) in both pregnant and non-pregnant rats, while urinary protein excretion increased only in the pregnant SHRs (P< 0.001). Plasma angiotensin II levels were significantly increased in the L-NAME-treated SHRs compared with controls (non-pregnant, P< 0.0005; pregnant, P < 0.01). The metabolic clearance rate of angiotensin II was decreased by L-NAME treatment in non-pregnant SHRs (P < 0.05), but was increased by L-NAME treatment in the pregnant rats (P < 0.01). In the aorta, the angiotensin II receptor number increased after treatment with L-NAME in both non-pregnant (P < 0.0005) and pregnant (P < 0.05) SHRs, and the dissociation constant increased in the non-pregnant SHRs (P < 0.005). Thus treatment of SHRs with L-NAME increased blood pressure, as well as the circulating angiotensin II concentration and vascular angiotensin II receptor expression. However, treatment with L-NAME did not affect pressor sensitivity to infused angiotensin II. We conclude, therefore, that although a decrease in nitric oxide production is associated with changes in angiotensin II concentrations and receptor numbers, it does not induce changes in pressor sensitivity to infused angiotensin II in the SHR.
Comparison of nasal pH values in black and white individuals with normal and high blood pressure
Authors: IRESON N. J. , TAIT J. S. , MACGREGOR G. A. , BAKER E. H.
Published: August 2015

Salt-sensitive hypertension is common in people of African origin, and may be caused by increased transepithelial sodium absorption. The pH of nasal secretions is negatively correlated with the difference in Na+ concentration between nasal secretions and plasma, and may be a marker of transepithelial sodium absorption. Nasal pH was measured using a probe sited under the inferior turbinate. Measurements of nasal pH were reproducible, with a coefficient of variation of 3.3% for repeated measurements on the same day and of 2.7% between measurements on different days. Nasal pH did not correlate with nasal potential difference, a measure of transepithelial sodium absorption. Nasal pH was significantly lower in 89 black individuals (24 normotensive and 65 hypertensive) than in 51 white individuals (26 normotensive and 25 hypertensive) (black normotensive. 6.44±0.08; black hypertensive, 6.62±0.05; white normotensive, 6.91±0.06; white hypertensive, 6.98±0.06), after adjustment for age, gender, current smoking status, body mass index and 24 h urinary sodium excretion (P = 0.002), but was not significantly different between the normotensive and hypertensive individuals. Nasal pH was more acidic in black than in white individuals, which may represent generalized up-regulation of sodium transport in black people. However, the lack of correlation between nasal pH and potential difference suggests that nasal pH is, at best, only weakly related to transepithelial sodium absorption. Ethnic differences in nasal pH may be of direct relevance in the airways, as many of the functions of airway surface liquid are dependent on pH.
Male pattern baldness is not associated with established cardiovascular risk factors in the general population
Authors: ELLIS Justine A. , STEBBING Margaret , HARRAP Stephen B.
Published: August 2015

A number of studies have shown an association between male pattern baldness (MPB) and cardiovascular disease. Few of these studies, however, have examined whether MPB is a novel risk factor, or is associated with abnormalities of established coronary risk factors. We have therefore performed an analysis of MPB and cardiovascular risk factors in the general population. A total of 1219 male participants aged 18–70 years from the Victorian Family Heart Study were surveyed using a validated questionnaire for degree and pattern of baldness. Carefully standardized measures of height, weight, blood pressure, pulse rate, total and high-density lipoprotein cholesterol, and plasma fibrinogen were made. Subjects were grouped according to the degree and pattern of baldness as: no baldness, frontal baldness and vertex baldness. Bald men were older than non-bald men (P < 0.0001). Age was also associated with increased levels of coronary risk factors (P < 0.0001). When multiple regression was used to adjust for age differences, the levels of coronary risk factors were not significantly different between the bald and non-bald groups. The lack of association between baldness and established coronary risk factors implies that baldness may predispose to coronary heart disease through novel mechanisms yet to be defined.
Carbohydrate and fat have different effects on plasma leptin concentrations and adipose tissue leptin production
Authors: EVANS Kevin , CLARK Mo L. , FRAYN Keith N.
Published: August 2015

Leptin is secreted by adipocytes and plays a role in the regulation of food intake. However, the regulation of leptin production by adipose tissue is unclear. We have investigated whether a mixed meal or a high-fat load given orally, or a pure fat load given intravenously, stimulates adipose tissue leptin production. Six volunteers were studied on two occasions following an overnight fast. On one occasion they consumed tomato soup containing 40 g of triacylglycerol (as Intralipid) and 9.6 g of carbohydrate; on the other occasion Intralipid was infused intravenously over 4 h to give the same fat load. A further eight subjects consumed a mixed meal (containing 37 g of fat and 100 g of carbohydrate) after an overnight fast. Paired blood samples were obtained from an arterialized hand vein and a vein draining subcutaneous adipose tissue at baseline and for 6 h following the meals or the start of the infusion. After both the intravenous and oral fat loads, the arterialized and adipose venous plasma leptin concentrations decreased over 6 h (both P< 0.001), as did the leptin veno–arterial difference (P = 0.01). Following the mixed meal, there was a slight increase in the arterialized plasma leptin concentration (P = 0.02) and a more marked increase in the adipose venous plasma leptin concentration (P = 0.03) and in the adipose tissue leptin veno–arterial difference (P = 0.01), all peaking at 240 min. We conclude that the increase in plasma leptin concentration observed after meals is not simply a result of an energy load, but is in response to a signal that is not present following a fat load without carbohydrate.
Selenite protects human endothelial cells from oxidative damage and induces thioredoxin reductase
Authors: MILLER Sue , WALKER Simon W. , ARTHUR John R. , NICOL Fergus , PICKARD Karen , LEWIN Michelle H. , HOWIE A. Forbes , BECKETT Geoffrey J.
Published: August 2015

The ability of selenium to protect cultured human coronary artery endothelial cells (HCAEC), human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells (BAEC) from oxidative damage induced by 100 μM t-butyl hydroperoxide (t-BuOOH) was compared. Preincubation of human endothelial cells for 24 h with sodium selenite at concentrations as low as 5 nM provided significant protection against the harmful effects of 100 μM t-BuOOH, with complete protection being achieved with 40 nM selenite. The preincubation period was required for selenite to exert this protective effect on endothelial cells. When compared with selenium-deficient cells, the activities of cytoplasmic glutathione peroxidase (GPX-1), phospholipid hydroperoxide glutathione peroxidase (GPX-4) and thioredoxin reductase (TR) were each induced approx. 3–4-fold by 40 nM selenite. HCAEC and HUVEC showed great similarity in their relative abilities to resist oxidative damage in the presence and absence of selenite, and the activities of TR and the GPXs were also similar in these cell types. BAEC were more susceptible to damage by 100 μM t-BuOOH than were human endothelial cells, and could not be protected completely by incubation with selenite at concentrations up to 160 nM. The activity of TR in human endothelial cells was approx. 25-fold greater than that in BAEC of a similar selenium status, but GPX-1 and GPX-4 activities were not significantly different between the human and bovine cells. These studies, although performed with a small number of cultures, show for the first time that selenium at low doses can provide significant protection of the human coronary artery endothelium against damage by oxidative stress. TR may be an important antioxidant selenoprotein in this regard, in addition to the GPXs. The data also suggest that HUVEC, but not BAEC, represent a suitable model system in which to study the effects of selenium on the endothelium of human coronary arteries.
Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction
Authors: TAYLOR Roger , FATOVICH Daniel , HITCHCOCK Thomas , MORRISON Catherine , CURTIS Lloyd
Published: August 2015

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n = 35), or matching placebo (n = 36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5×106 units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43±28 mmHg (mean±S.D.) and 40±26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to < 90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3±17.5 and 40.2±13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.
Influence of hypoglycaemia, with or without caffeine ingestion, on visual sensation and performance
Authors: OWEN G. , WATSON J. , MCGOWN A. , SHARMA S. , DEARY I. , KERR D. , BARRETT G.
Published: August 2015

Full-field visual evoked potentials and visual information processing were measured in 16 normal, healthy subjects during a hyperinsulinaemic clamp. A randomized cross-over design was used across three conditions: hypoglycaemia and caffeine; hypoglycaemia and placebo; and euglycaemia and caffeine. The latency of the P100 component of the pattern-reversal visual evoked potential increased significantly from rest to hypoglycaemia, but no effect of caffeine was found. Subjects were subsequently divided into two median groups based on the increase in P100 latency in the placebo condition (Group 1, +0.5 ms; Group 2, +5.6 ms). In the absence of caffeine, an inverse correlation between the increase in P100 latency from rest and a deterioration in visual movement detection was found for Group 2, but not for Group 1. Caffeine ingestion resulted in a further increase in P100 latency, from rest to hypoglycaemia, for subjects in Group 2. Hypoglycaemia in the absence of caffeine produces changes in visual sensation from rest to hypoglycaemia. In those subjects most sensitive to the effects of hypoglycaemia (Group 2), the increase in P100 latency was associated with poorer performance in tests of visual information processing. Caffeine ingestion produced further increases in P100 latency in these subjects.
Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability
Authors: PLAYFORD Raymond J. , MACDONALD Christopher E. , CALNAN Denis P. , FLOYD David N. , PODAS Theo , JOHNSON Wendy , WICKS Anthony C. , BASHIR O. , MARCHBANK Tania
Published: August 2015

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics but cause gastrointestinal injury. Present prophylactic measures are suboptimal and novel therapies are required. Bovine colostrum is a cheap, readily available source of growth factors, which reduces gastrointestinal injury in rats and mice. We therefore examined whether spray-dried, defatted colostrum could reduce the rise in gut permeability (a non-invasive marker of intestinal injury) caused by NSAIDs in volunteers and patients taking NSAIDs for clinical reasons. Healthy male volunteers (n = 7) participated in a randomized crossover trial comparing changes in gut permeability (lactulose/rhamnose ratios) before and after 5 days of 50 mg of indomethacin three times daily (tds) per oral with colostrum (125 ml, tds) or whey protein (control) co-administration. A second study examined the effect of colostral and control solutions (125 ml, tds for 7 days) on gut permeability in patients (n = 15) taking a substantial, regular dose of an NSAID for clinical reasons. For both studies, there was a 2 week washout period between treatment arms. In volunteers, indomethacin caused a 3-fold increase in gut permeability in the control arm (lactulose/rhamnose ratio 0.36±0.07 prior to indomethacin and 1.17±0.25 on day 5, P < 0.01), whereas no significant increase in permeability was seen when colostrum was co-administered. In patients taking long-term NSAID treatment, initial permeability ratios were low (0.13±0.02), despite continuing on the drug, and permeability was not influenced by co-administration of test solutions. These studies provide preliminary evidence that bovine colostrum, which is already currently available as an over-the-counter preparation, may provide a novel approach to the prevention of NSAID-induced gastrointestinal damage in humans.
Muscle afferent and central command contributions to the cardiovascular response to isometric exercise of postural muscle in patients with mild chronic heart failure
Authors: CARRINGTON C. A. , FISHER W. J. , DAVIES M. K. , WHITE M. J.
Published: August 2015

The roles of muscle afferent activity and central drive in controlling the compromised cardiovascular system of patients with mild chronic heart failure (CHF) during isometric exercise were examined. Blood pressure and heart rate responses were recorded in eight stable CHF patients (ejection fraction 20–40%; age 62±11 years) and in nine healthy age-matched controls during voluntary and electrically evoked isometric plantar flexion and subsequent post-exercise circulatory occlusion (PECO). During voluntary contraction, control subjects had a greater mean increase in systolic blood pressure than patients (42.4±19.2 and 23.0±10.9 mmHg respectively; P < 0.01), but this was not the case during PECO. During electrically evoked contraction, but not during PECO, the CHF group had smaller (P < 0.05) mean increases in both systolic and diastolic blood pressure than controls (13.0±5.3 compared with 25.4±14.0 mmHg and 7.6±3.0 compared with 12.9±7.2 mmHg respectively). Intra-group comparison between responses to voluntary and electrically evoked contractions revealed greater (P < 0.05) mean increases in systolic and diastolic blood pressure during the voluntary contraction in both the patients and the control subjects. These data suggest that muscle afferent drive to the pressor response from the triceps surae is low in this age group, both in control subjects and in CHF patients. Additionally, the patients may have a relatively desensitized muscle mechanoreceptor reflex.
Maximizing the success rate of minimal model insulin sensitivity measurement in humans: the importance of basal glucose levels
Authors: GODSLAND Ian F. , WALTON Christopher
Published: August 2015

Minimal model analysis of glucose and insulin concentrations in the intravenous glucose tolerance test (IVGTT) has been widely used to obtain a measure of insulin sensitivity in humans. Issues of model validity and IVGTT protocol have been explored extensively. Less attention has been paid, however, to the computer programming protocol for estimating the model parameters (programming implementation). Minimal model analysis of data from an IVGTT protocol involving a high glucose dose (0.5 g/kg) and a reduced sample schedule, employed in healthy pre- or post-menopausal women, healthy men or men with coronary heart disease or chronic heart failure (20 in each group), was undertaken according to 12 different programming implementations using a commercially available model-equation-solving program. The ability of the program to arrive at an acceptable solution to the model equations gave a success rate of between 39% and 96%, depending on the implementation. Variation in basal glucose assignment significantly affected the magnitude of estimates of insulin sensitivity. The maximum modelling success rate was achieved by introduction of an imputed glucose measurement at 360 min from the glucose injection, taking the basal glucose level as the fasting glucose concentration, and overweighting the initial glucose measurement after a delay for mixing. Use of this implementation to analyse data from a study comparing insulin sensitivities obtained using the minimal model and a euglycaemic clamp reference gave a correlation of 0.80 (P < 0.001) between the two methods. Straightforward variations in programming implementation, involving appropriate assignment of the basal glucose concentration and use of an imputed glucose measurement signifying re-establishment of basal glucose levels following the IVGTT, can considerably improve modelling success rate.
Adipose tissue thickness affects in vivo quantitative near-IR spectroscopy in human skeletal muscle
Authors: VAN BEEKVELT M. C. P. , BORGHUIS M. S. , VAN ENGELEN B. G. M. , WEVERS R. A. , COLIER W. N. J. M.
Published: August 2015

The influence of adipose tissue thickness (ATT) on near-IR spectroscopy (NIRS) measurements in vivo was studied in the human flexor digitorum superficialis muscle at rest and during sustained isometric handgrip exercise. NIRS was used for the quantitative measurement of muscle O2 consumption (mVo2) and forearm blood flow (FBF) in 78 healthy subjects. Skinfold thickness ranged from 1.4 to 8.9 mm within the group. Resting mVo2 was 0.11±0.04 ml of O2 min-1 100 g-1, and FBF was 1.28±0.82 ml min-1 100 ml-1. There was a negative correlation (r =-0.70, P ≤ 0.01), indicating a decrease in mVo2 with increasing ATT. mVo2 in the 10 leanest subjects appeared to be twice as high as that in the 10 subjects with the highest ATT. A poor correlation (r = 0.29, P ≤ 0.01) was found between ATT and FBF. The gender difference that we found for mVo2 was due to the difference in ATT between female and male subjects. No correlation was found between maximum voluntary contraction and mVo2, nor between maximum voluntary contraction and ATT, indicating that the contraction force did not confound our results. These results show that ATT has a substantial confounding influence on in vivo NIRS measurements, and that it is essential to incorporate this factor into future NIRS muscle studies in order to justify comparisons between different groups. To facilitate such comparisons, upper and lower boundaries for normal values of mVo2 and FBF in relation to ATT are presented.
Is pseudocholinesterase activity related to markers of triacylglycerol synthesis in Type II diabetes mellitus?
Authors: RUSTEMEIJER C. , SCHOUTEN J. A. , VOERMAN H. J. , BEYNEN A. C. , DONKER A. J. M. , HEINE R. J.
Published: August 2015

Hypertriglyceridaemia is a risk factor for cardiovascular disease in patients suffering from Type II diabetes mellitus, and is due to enhanced synthesis and/or impaired clearance of triacylglycerol-rich lipoproteins. In the present study we investigated whether pseudocholinesterase (PChE) activity could serve as a marker for the rate of triacylglycerol synthesis in these patients. Patients were stratified according to their apolipoprotein E (apoE) phenotype, i.e. E3E2, E3E3 or E3E4. In study I, the relationship between PChE activity and serum triacylglycerols was investigated in 224 insulin-treated patients with Type II diabetes. In study II, which had a cross-over design, PChE activity was measured in 45 dyslipidaemic, insulin-treated patients with Type II diabetes that were treated with bezafibrate or pravastatin. In study I, PChE activity was correlated positively with serum triacylglycerol concentrations, but did not differ significantly between apoE phenotypes. The strongest relationship was found in the E3E4 group (r = 0.50; P = 0.001), the phenotype for which hypertriglyceridaemia is expected to be the result of increased triacylglycerol synthesis. In a stepwise multiple regression analysis, serum triacylglycerol concentrations were found to be the strongest predictor of PChE activity in the E3E4 group. In study II, PChE activity decreased as a result of bezafibrate treatment in all three apoE groups. The decrease in PChE activity with bezafibrate treatment paralleled the decrease in serum triacylglycerol concentrations in the apoE subgroups. Pravastatin treatment did not significantly affect PChE activity. Thus the present study suggests an association between PChE activity and the rate of triacylglycerol synthesis. Measurement of PChE activity may therefore be a useful tool in the choice of drug for treatment of hypertriglyceridaemia in patients with Type II diabetes.
Effects of high-dose glucose–insulin–potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes
Authors: SZABÓ Zoltán , ARNQVIST Hans , HÅKANSON Erik , JORFELDT Lennart , SVEDJEHOLM Rolf
Published: August 2015

The effects of glucose–insulin–potassium (GIK) on cardiac metabolism have been studied previously in non-diabetic patients after cardiac surgery. Although patients with diabetes mellitus can be expected to benefit most from such treatment, the impact of GIK in diabetic patients undergoing cardiac surgery remains unexplored. Therefore the present study investigates the effects of high-dose GIK on myocardial substrate utilization after coronary surgery in patients with Type II diabetes. A total of 20 patients with Type II diabetes undergoing elective coronary surgery were randomly allocated to either post-operative high-dose GIK or standard post-operative care, including insulin infusion if necessary to keep blood glucose below 10 mmol/l. Myocardial substrate utilization was studied using the coronary sinus catheter technique. Haemodynamic state was assessed with the aid of Swan–Ganz catheters. High-dose GIK caused a shift towards carbohydrate utilization, with significant lactate uptake throughout the study period and significant uptake of glucose after 4 h. Arterial levels of non-esterified fatty acids and β-hydroxybutyric acid decreased, and after 1 h no significant uptake of these substrates was found. Increases in the cardiac index and stroke volume index were found in patients treated with high-dose GIK. A decrease in systemic vascular resistance was found both in the control group and in the high-dose GIK group. We conclude that high-dose GIK can be used in diabetic patients after cardiac surgery to promote carbohydrate uptake at the expense of non-esterified fatty acids and β-hydroxybutyric acid. This could have implications for treatment of the diabetic heart in association with surgery and ischaemia.
Relationship of maternal protein turnover and lean body mass during pregnancy and birth length
Authors: DUGGLEBY Sarah L. , JACKSON Alan A.
Published: August 2015

Epidemiological evidence shows that small size at birth is associated with an increased risk of developing cardiovascular and metabolic disease in adult life. We have examined the relationships between size at birth and maternal body composition and protein turnover in normal pregnant women. A group of 27 multiparous Caucasian women with singleton pregnancies were studied at around 18 and 28 weeks' gestation. Body composition was determined by anthropometry, and whole-body protein turnover was estimated by using a single oral dose of [15N]glycine and the end-product method. The baby's weight and length were measured within 48 h of birth. Mothers with a greater lean body mass had higher rates of protein turnover at 18 weeks' gestation. This association was largely accounted for by differences in the mother's visceral, rather than muscle, mass. Mothers who had higher protein turnover at 18 weeks' gestation had babies that were longer at birth. After adjustment for the duration of gestation and the baby's sex, 26% of the variation in length at birth was accounted for by maternal protein synthesis at 18 weeks' gestation. Maternal protein intake was not associated with the baby's birth length. Thus the mother's ability to nourish her fetus is influenced by her body composition and her rate of protein turnover. Dietary intake does not adequately characterize this ability.
Polymorphism in the gelatinase B gene and the severity of coronary arterial stenosis
Authors: WANG Jian , WARZECHA Diane , WILCKEN David , WANG Xing Li
Published: August 2015

Gelatinase B, as one of the matrix metalloproteinases, may be relevant to atherogenic plaque development and stability. Recently, a C-1562T substitution in the regulatory region of the gelatinase B gene was shown to up-regulate gelatinase B expression, which could be relevant to both the severity and stability of atherosclerotic plaques. We determined the genotype of 788 angiographically documented Caucasian patients with coronary artery disease (583 males and 205 females; age 56.7±0.4 years). The proportions of C/C (77.1%), C/T (21.4%) and T/T (1.5%) genotypes were in Hardy–Weinberg equilibrium, and did not differ between males and females (P > 0.05). The frequencies of the rare T allele in patients with angiographically documented coronary artery disease (0.123), a past history of myocardial infarction (0.128) or unstable angina (0.128) were not significantly different from those in patients without such events (0.121, 0.118 and 0.128 respectively; P > 0.05). In addition, the rare allele frequencies among patients with no (0.128), one (0.124), two (0.108) or three (0.121) significantly diseased vessels (≥ 50% luminal obstruction) were not statistically different (P = 0.932). However, the male rare T/T homozygotes had lower waist/hip ratios and levels of high-density lipoprotein cholesterol (HDL-C), and higher total cholesterol/HDL-C ratios, than C/C homozygotes (P < 0.05). In conclusion, our study in a large series of angiographically defined patients suggests that the C-1562T polymorphism may not be useful as a predictor of the presence and severity of coronary atherosclerosis.