bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenosine induces histamine release from human bronchoalveolar lavage mast cells
Authors: FORSYTHE P. , MCGARVEY L. P. A. , HEANEY L. G. , MACMAHON J. , ENNIS M.
Published: August 2015

Previous studies have shown that in vitroadenosine enhances histamine release from activated human lung mast cells obtained by enzymic dispersion of lung parenchyma. However, adenosine alone has no effect on histamine release from these cells. Given the evidence for direct activation of mast cells after endobronchial challenge with adenosine and previous studies indicating that mast cells obtained at bronchoalveolar lavage are a better model for asthma studies than those obtained by enzymic dispersion of lung tissue, the histamine-releasing effect of adenosine was examined on lavage mast cells. Bronchoalveolar lavage fluid was obtained from patients attending hospital for routine bronchoscopy (n = 54). Lavage cells were challenged with adenosine or adenosine receptor agonists (20 min, 37 °C) and histamine release determined using an automated fluorometric assay. Endogenous adenosine levels were also measured in lavage fluid (n = 9) via an HPLC method. Adenosine alone caused histamine release from lavage mast cells in 37 of 54 patients with a maximal histamine release of 20.56±2.52% (range 5.2–61%). The adenosine receptor agonists (R)-N6-(2-phenylisopropyl)adenosine, 5'-N-ethylcarboxamidoadenosine and CGS21680 also induced histamine release from lavage mast cells. Preincubation of lavage mast cells with the adenosine receptor antagonist xanthine amine congener caused significant inhibition of the response to adenosine (P = 0.007). There was an inverse correlation between endogenous adenosine levels in the lavage fluid and the maximal response to in vitro adenosine challenge of the lavage cells. The findings of the present study indicate a means by which adenosine challenge of the airways can induce bronchoconstriction and support a role for adenosine in the pathophysiology of asthma. The results also suggest that cells obtained from bronchoalveolar lavage fluid may provide the ideal model for the testing of novel, adenosine receptor, targeted therapies for asthma.
Influence of posture and handgrip on the QT interval in left ventricular hypertrophy and in chronic heart failure
Authors: DAVEY Patrick
Published: August 2015

In certain disease states prolongation of the QT interval has been shown to be arrhythmogenic. Whether QTc interval changes with position and thus whether certain positions are more arrhythmogenic than others is not known for different diseases that predispose to arrhythmias, and was therefore studied. Patients with left ventricular hypertrophy and heart failure, and the appropriate matched controls, were recruited. Subjects were studied in the lying, sitting, standing and squatting positions and had QT intervals determined by computer algorithm 2 min after each position change. After resting, QT interval was determined while the subjects performed maximum handgrip exercise with their dominant hand. QT intervals were rate-corrected using Bazett's method. QTc interval is prolonged in heart failure patients compared with either left ventricular hypertrophy or control subjects in the lying and sitting position, but not in the standing or squatting position. The QTc intervals for heart failure and control subjects were, respectively, 443±7 ms versus 421±6 ms when lying (P< 0.05), 451±10 ms versus 419±6 ms when sitting (P< 0.05), 429±10 versus 414±7 ms when standing (P not significant) and 437±10 versus 419±8 ms when squatting (P not significant). The values for patients with hypertrophy did not differ from control values. Maximum handgrip does not affect the QTc interval in heart failure, but prolongs it in both the hypertrophy and control groups. Position and static exercise are important modifiers of QTc interval and their effect depends on the condition of the left ventricle.
Relationship between mucosal levels of Helicobacter pylori-specific IgA, interleukin-8 and gastric inflammation
Authors: ZHANG Q. B. , ETOLHI G. , DAWODU J. B. , GEMMELL C. G. , RUSSELL R. I.
Published: August 2015

Mucosal IgA is important in local immune defence. Helicobacter pylori induces a specific IgA response in antral mucosa, but its immunopathology is unknown. Interleukin-8 (IL-8) has been suggested to be important in H. pylori-induced inflammation. Current information on the relationship between H. pylori-induced IgA and mucosal inflammation is limited. To investigate possible associations between mucosal-specific IgA, the toxinogenicity of H. pylori, mucosal levels of IL-8 and gastric inflammation, 52 endoscoped patients were studied. These comprised 28 patients with peptic ulcer and 24 with non-ulcer dyspepsia. Of these patients, 38 had H. pylori infection: 28 with peptic ulcer and 10 with non-ulcer dyspepsia. Antral biopsies were taken for histology, H. pylori culture and measurement of mucosal levels of IL-8 (pg/mg) and specific IgA (A450×1000) by ELISA. Mucosal H. pylori IgA was detectable in 35 out of 38 patients with H. pylori infection, with a median (interquartile) level of 220 (147, 531) units. There was no significant difference in mucosal levels of the IgA antibodies between patients infected with cytotoxin-positive or cagA-positive strains of H. pylori and those with toxin-negative or cagA-negative strains. The IgA levels in those patients with severe neutrophil infiltration were lower than in those with mild or moderate infiltration (P< 0.05). There was a weak inverse correlation between antral mucosal IgA and IL-8 in infected patients (r = -0.36; P = 0.04). H. pylori infection induced a significant local mucosal IgA response in most infected patients. The level of IgA antibodies does not appear to be correlated with the toxinogenicity of H. pylori. However, patients with severe active inflammation appear to have decreased levels of IgA. An inverse correlation between mucosal IL-8 and IgA may suggest that IL-8-induced inflammation compromises the mucosal IgA defence and renders the mucosa susceptible to further damage.
Lysophosphatidic acid and mesangial cells: implications for renal diseases
Authors: INOUE Chiyoko N. , EPSTEIN Murray , FORSTER Hayley G. , HOTTA Osamu , KONDO Yoshiaki , IINUMA Kazuie
Published: August 2015

The last decade has witnessed a phenomenal increase in our understanding of the biological role of lysophosphatidic acid (LPA) and has led to an appreciation of this critical serum-derived growth factor released from platelets. We herein summarize recent observations that collectively support the hypothesis that LPA may play a key role in the pathogenesis of initiation and progression of proliferative glomerulonephritis. LPA synergistically stimulates mesangial cell proliferation in combination with platelet-derived growth factor in primary culture. The mechanism of co-mitogenesis is likely to be mediated by the prolonged activation of mitogen-activated protein kinase which is stimulated by platelet-derived growth factor and LPA through different mechanisms. LPA contracts cultured mesangial cells and has properties in common with other pressor molecules including mobilization of intracellular Ca2+ and promotion of Ca2+ entry through dihydropyridine-sensitive calcium channels. LPA receptor mRNA has been identified in isolated glomeruli dissected from renal biopsy samples of patients with IgA nephropathy. All of these facts have led us to postulate that LPA is produced within glomeruli and that LPA's mitogenic as well as haemodynamic action contribute to the pathological process of mesangial proliferative glomerulonephritis. The possible production of LPA as an autocrine factor from mesangial cells themselves has also been discussed.
Lisinopril improves arterial function in hyperlipidaemia
Authors: LEE Alison F. C. , DICK John B. C. , BONNAR Clare E. , STRUTHERS Allan D.
Published: August 2015

Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n = 20), or placebo (n = 20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145±4 to 128±4 mmHg (P< 0.001); diastolic: 84±2 to 74±2 mmHg (P< 0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33±0.3 (pre) versus 4.45±0.48 (post) at 30 μg/ml (P< 0.03), and also to nitroprusside, e.g. 3.0±0.2 (pre) versus 3.86±0.3 (post) at 3.2 μg/ml (P< 0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia.
Salt-sensitivity classification in normotensive adults
Authors: MATTES Richard D. , FALKNER Bonita
Published: August 2015

The objectives of this study were to assess the reliability, sensitivity and specificity of salt-sensitivity classification in normotensive adults and to determine the predictive power of four clinical indices for salt-sensitivity. A total of 66 healthy, normotensive, free-living adults were administered 11-day salt-sensitivity diagnostic dietary salt challenges on two occasions to permit assessment of classification test–retest reliability. An oral glucose tolerance test, an acute saline loading test, gustatory testing and determination of salivary flow and sodium concentration were carried out to assess (by correlation analysis) their predictive power for salt-sensitivity. Following these procedures, 21 participants followed a reduced-sodium diet for 4 months, during which blood pressure was monitored monthly to allow evaluation of salt-sensitivity classification sensitivity and specificity. Regression was used to develop a predictive model for salt-sensitivity. Salt-sensitivity classification was not highly reliable (κ-value = 0.38), sensitive (0.73) or specific (0.60). No single index was highly predictive of classification status, but a model composed of five indices accounted for 92% of the variance in blood pressure response to acute salt challenge. The dietary salt challenge procedure used here for salt-sensitivity classification of normotensive adults had low test–retest reliability. While a battery of easily measured attributes may facilitate rapid salt-sensitivity classification, such a diagnosis provides only limited insight regarding blood pressure responsiveness to chronic dietary salt restriction in normotensive adults.
Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex
Authors: PAPADOPOULOS M. C. , LAMB F. J. , MOSS R. F. , DAVIES D. C. , TIGHE D. , BENNETT E. D.
Published: August 2015

Encephalopathy is a common complication of sepsis. However, little is known about the morphological changes that occur in the brain during sepsis. Faecal peritonitis was induced in pigs that were killed 8 h later and frontal cortex samples were taken immediately after death. The tissue was investigated using light and electron microscopy and compared with frontal cortex samples taken from sham-operated controls. Septic pigs had 49.5% more perimicrovessel oedema than sham pigs. However, the tight junctions between cerebral microvessel endothelial cells appeared morphologically intact in both septic and sham pigs. Sepsis also resulted in neuronal injury, disruption of astrocytic end-feet and swollen, rounded erythrocytes. These morphological changes may be sufficient to underlie the clinical features seen in septic encephalopathy.
Co-expression of prepro-adrenomedullin with a putative adrenomedullin receptor gene in vascular smooth muscle
Authors: AUTELITANO Dominic J. , TANG F.
Published: August 2015

The prepro-adrenomedullin (prepro-AM) gene encodes several biologically active peptides, including the potent vasodilator AM. At least part of the vasodilator action of AM appears to be mediated via interactions with receptors on vascular smooth muscle cells (VSMC); however, the specific receptors involved are not known. The aim of the present study was to identify putative AM receptor genes that are co-expressed with AM in cultured rat aortic VSMC that may mediate the actions of AM. AM mRNA was shown to be expressed in rat aortic VSMC cultures. In acute (4 h) secretion studies, only 20% of the total immunoreactive AM was intracellular, with the majority (80%) found in the medium, indicating active release of AM peptide from VSMC. Using highly specific ribonuclease protection analysis, mRNAs encoding three putative AM receptors [L1, calcitonin-receptor-like receptor (CRLR) and RDC1] were shown to be present at high concentrations in RNA extracts from lung. In cultured VSMC, however, whereas RDC1 mRNA was expressed at relatively high concentrations, transcripts encoding CRLR and L1 were not detected. The co-expression of prepro-AM mRNA with the RDC1 receptor implies that AM may act in a localized manner via this receptor to modulate VSMC function.
Dyspnoea, peripheral airway involvement and respiratory muscle effort in patients with Type I diabetes mellitus under good metabolic control
Authors: SCANO Giorgio , SEGHIERI Giuseppe , MANCINI Marco , FILIPPELLI Mario , DURANTI Roberto , FABBRI Alessandro , INNOCENTI Fabio , IANDELLI Iacopo , MISURI Gianni
Published: August 2015

Dyspnoea and pulmonary dysfunction have recently been associated with Type I (insulin-dependent) diabetes mellitus. The putative role of altered pulmonary mechanics and of performance of inspiratory muscles in inducing dyspnoea has not been yet assessed in Type I diabetes. To better focus on this topic we evaluated nine patients with Type I diabetes mellitus, aged 19 to 48 years with good and stable metabolic control, without a history of smoking and microvascular complications, alongside a group of 14 healthy control subjects. In each subject, pulmonary volumes, static and dynamic compliance, pleural pressure swings (Pplsw), maximal inspiratory pressures (Pplsn), Pplsw(%Pplsn), a measure of respiratory muscle effort, and tension–time index [TTI = TI/TTOT×Pplsw(%Pplsn)] were measured (TI = inspiratory time;TTOT = total time of the respiratory cycle). All subjects were studied at baseline and during hypoxic rebreathing. Patients had normal pulmonary volumes. During hypoxic rebreathing, a normal change in respiratory muscle effort [ΔPplsw(%Pplsn)/ΔSaO2] and ΔTTI/ΔSaO2, and a lower change in tidal volume versus change in oxygen saturation [ΔVT(% vital capacity)/ΔSaO2], resulted in a higher ratio of respiratory effort to tidal volume [Pplsw(%Pplsn)/VT(% vital capacity)], a measure of neuroventilatory dissociation of the respiratory pump. Hypoxic dyspnoea, assessed by a modified Borg scale, showed a greater rate of rise (ΔBorg/ΔSaO2) and a greater increase for a given level of respiratory effort in patients. Moreover, neuroventilatory dissociation related to the expression of peripheral airway involvement, as assessed in terms of low dynamic compliance, and to concurrent change in dyspnoea sensation. Patients with Type I diabetes mellitus under good metabolic control and with normal lung volumes may have abnormal peripheral airway function. The latter is thought to be responsible for the association between dyspnoea sensation and neuroventilatory dissociation.
Effects in vivo of decreased plasma and intracellular muscle glutamine concentration on whole-body and hindquarter protein kinetics in rats
Authors: OLDE DAMINK Steven W. M. , DE BLAAUW Ivo , DEUTZ Nicolaas E. P. , SOETERS Peter B.
Published: August 2015

Glutamine is considered to be a ‘conditionally’ essential amino acid. During situations of severe stress like sepsis or after trauma there is a fall in plasma glutamine levels, enhanced glutamine turnover and intracellular muscle glutamine depletion. Under these conditions, decreased intramuscular glutamine concentration correlates with reduced rates of protein synthesis. It has therefore been hypothesized that intracellular muscle glutamine levels have a regulatory role in muscle protein turnover rates. Administration of the glutamine synthetase inhibitor methionine sulphoximine (MSO) was used to decrease glutamine levels in male Wistar rats. Immediately after the MSO treatment (t = 0 h), and at t = 6 h and t = 12 h, rats received intraperitoneal injections (10 ml/100 g body weight) with glutamine (200 mM) to test whether this attenuated the fall in plasma and intracellular muscle glutamine. Control animals received alanine and saline after MSO treatment, while saline was also given to a group of normal rats. At t = 18 h rats received a primed constant infusion of l-[2,6-3H]phenylalanine. A three-pool compartment tracer model was used to measure whole-body protein turnover and muscle protein kinetics. Administration of MSO resulted in a 40% decrease in plasma glutamine and a 60% decrease in intracellular muscle glutamine, both of which were successfully attenuated by glutamine infusions. The decreased intracellular muscle glutamine levels had no effect on whole-body protein turnover or muscle protein kinetics. Also, glutamine supplementation did not alter these parameters. Alanine supplementation increased both hindquarter protein synthesis and breakdown but the net balance of phenylalanine remained unchanged. In conclusion, our results show that decreased plasma and muscle glutamine levels have no effect on whole-body protein turnover or muscle protein kinetics. Therefore, it is unlikely that, in vivo, the intracellular muscle concentration of glutamine is a major regulating factor in muscle protein kinetics.
Interleukin-4 and interleukin-4 receptor polymorphisms in minimal change nephropathy
Authors: PARRY R. G. , GILLESPIE K. M. , PARNHAM A. , CLARK A. G. B. , MATHIESON P. W.
Published: August 2015

Minimal change nephropathy (MCN) is an important cause of nephrotic syndrome, especially in children, that is strongly associated with atopy and IgE production. The immunogenetics of MCN are poorly understood. Interleukin-4 (IL-4) is the critical cytokine involved in the development of atopy. Polymorphic regions in the genes encoding IL-4 itself and the IL-4 receptor have been demonstrated that may predispose to increased activity. We have analysed these polymorphisms in 149 patients with MCN and 73 controls to test the hypothesis that these loci are involved in genetic predisposition to MCN. In our populations there were no polymorphisms in the IL-4 promoter. We did confirm allelic variation in a dinucleotide repeat in the second intron of the IL-4 gene, but there was no significant difference between allele distributions in MCN and controls. Similarly, allele frequencies for the IL-4 receptor α chain polymorphism were similar in patients and controls. Genetic loci which are believed to influence IL-4 responsiveness and to predispose to atopy do not appear to be associated with susceptibility to MCN.
Weight fluctuations could increase blood pressure in android obese women
Authors: GUAGNANO M. T. , PACE-PALITTI V. , CARRABS C. , MERLITTI D. , SENSI S.
Published: August 2015

Recent studies have documented a relationship between increased morbidity and mortality from cardiovascular diseases and a history of weight cycling (WC) in obese subjects. We performed a cross-sectional analysis in 96 weight-cycling android obese women, matched with 96 non-weight-cycling android obese women by age, body mass index (BMI) and waist-to-hip ratio (WHR), to evaluate any increase in blood pressure (BP) levels in association with WC. The patients were all between 20 and 45 years old, were non-menopausal, did not smoke, did not take any medication, had normal glucose tolerance and were otherwise healthy. A history of WC was established on the basis of at least five weight losses in the previous 5 years due to dieting, with a weight loss of at least 4.5 kg per cycle. We documented higher levels of casual BP in the weight-cycling obese compared with the non-weight-cycling subjects: 147±12/90±8 mmHg versus 125±14/79±8 mmHg (P < 0.001). The women with WC showed a statistically significant positive correlation between BP and age, weight, BMI, waist circumference, WHR, total weight regained and weight cycling index (WCI). However, in a multiple regression model only the WHR and WCI contributed significantly to the BP variability. These findings could support the hypothesis that it is the combined exposure of central-type obesity and WC that strongly raises the prediction of hypertension.
Role of nitric oxide in the regulation of cardiovascular autonomic control
Authors: CHOWDHARY Saqib , TOWNEND Jonathan N.
Published: August 2015

Alteration in function of the cardiac autonomic nervous system has proved to be a powerful predictor of cardiac death or serious arrhythmia in patients with cardiac disease, yet little is known about the mechanisms by which this system is regulated. Recent evidence suggests that the gaseous molecule nitric oxide (NO) may act as an important mediator in this pathway. Histochemical staining techniques have identified neuronal populations that contain NO synthase within medullary cardio-regulatory sites and their peripheral autonomic pathways. Drugs that modulate the NO pathway (administered both systemically and into the central nervous system) cause changes in pre- and post-ganglionic sympathetic nerve activity that imply that NO serves to inhibit central sympathetic outflow. There is also evidence that NO may attenuate cardiovascular end-organ responses to sympathetic stimulation. Studies suggest that NO modulates cardiac vagal control, increasing the activity of central vagal motoneurons and, more contentiously, contributing to the bradycardic effects of vagal stimulation. NO also modulates so-called ‘indirect’ vagal inhibition of sympathetic cardiac responses. Additionally, central attenuation of baroreflex-mediated vagal control has been described. There is relatively little information available on the importance of NO in the regulation of human cardiovascular autonomic control. Further well-controlled studies are required.
Activation of haemostasis by exercise, mental stress and adrenaline: effects on platelet sensitivity to thrombin and thrombin generation
Authors: WALLÉN N. Håkan , GOODALL Alison H. , LI Nailin , HJEMDAHL Paul
Published: August 2015

Stress-induced activation of haemostasis may be involved in the triggering of acute coronary syndromes. We compared the effects of mental stress, dynamic exercise and adrenaline infusion on platelet sensitivity to thrombin using flow-cytometric analysis of platelet fibrinogen binding in whole blood, and platelet aggregability using filtragometry ex vivo, in healthy volunteers. Furthermore, we assessed thrombin generation [prothrombin fragment 1+2 (F1+2) and thrombin–antithrombin complexes in plasma] and thrombin activity (fibrinopeptide A in plasma). Exercise (bicycle ergometry) enhanced thrombin-induced platelet fibrinogen binding (P< 0.05) and platelet aggregability (P< 0.01), and elevated F1+2, thrombin–antithrombin complexes and fibrinopeptide A (P< 0.05 for all three). Adrenaline infusion enhanced thrombin-induced platelet fibrinogen binding and platelet aggregability (P< 0.05), and elevated thrombin–antithrombin complexes (P< 0.05), whereas F1+2 and fibrinopeptide A levels were not significantly affected. Mental stress increased platelet sensitivity to high concentrations of thrombin only, and produced small increases in levels of thrombin–antithrombin complexes. Time control experiments showed no important changes with repeated measurements during rest. Platelet responses to exercise and adrenaline were reversible, with recovery 60 min later. Thus, heavy exercise and high levels of adrenaline reversibly increased platelet aggregability and platelet sensitivity to thrombin, and enhanced thrombin formation; the effects were most pronounced during exercise. Mental stress only weakly affected these parameters.
Effect of nebulized epoprostenol (prostacyclin) on exhaled nitric oxide in patients with pulmonary hypertension due to congenital heart disease and in normal controls
Authors: FORREST Ian A. , SMALL Therese , CORRIS Paul A.
Published: August 2015

Inhaled epoprostenol (prostacyclin) may be used in the treatment of severe pulmonary hypertension, improving oxygenation and reducing pulmonary artery pressures. We have observed symptomatic benefits of epoprostenol in patients with congenital heart disease that extend beyond acute haemodynamic effects of the drug, which has a short biological half-life. The aim of this study was to examine the effects of epoprostenol in patients and normal subjects on exhaled nitric oxide (eNO), based on the hypothesis that the drug may alter the resting vasoconstrictor/vasodilator balance. Nine patients with pulmonary hypertension complicating left-to-right cardiac shunts and nine healthy controls received 100 µg of nebulized epoprostenol. Exhaled eNO was measured, using a chemiluminescence method, before, immediately after and 18 h after nebulization. There was no significant difference between the two groups in baseline eNO or eNO immediately following nebulized epoprostenol. Epoprostenol produced a delayed elevation in eNO 18 h after nebulization in patients, but not in normal controls. This study supports the concept that epoprostenol, while having no effect on the normal pulmonary circulation, acts on the hypertensive circulation via a mechanism that may result in a delayed alteration of vasoconstrictor/vasodilator balance.
Altered cardiovascular haemodynamics and baroreceptor–heart rate reflex in adult sheep after prenatal exposure to dexamethasone
Authors: DODIC M. , PEERS A. , COGHLAN J. P. , MAY C. N. , LUMBERS E. , YU Z.-Y. , WINTOUR E. M.
Published: August 2015

Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset of cardiovascular and metabolic diseases later in life. We were the first to show that sheep exposed to dexamethasone (0.28 mg⋅kg-1⋅day-1 for only 2 days) at the end of the first month of pregnancy (PTG1), but not those exposed at the end of the second month of pregnancy (PTG2), had a higher basal mean arterial pressure (MAP) 19 months after birth. In the present study we report the MAP, cardiovascular haemodynamics and baroreflex sensitivity in these animals at 40 months of age. MAP in the PTG1 group was significantly higher than in the control group (91±1 mmHg and 81±1 mmHg respectively; P< 0.001) and also when compared with the PTG2 group (82±1 mmHg; P< 0.001). There was a significant increase in cardiac output in the PTG1 group compared with the control group (108±2 and 96±4 ml⋅min-1⋅kg-1 respectively; P< 0.05). The increase in cardiac output in the PTG1 group was due to an increase in stroke volume (1.82±0.08 ml⋅kg-1⋅beat-1, compared with 1.46±0.06 ml⋅kg-1⋅beat-1 in the control group; P< 0.05), but not in heart rate. In the hypertensive group of animals (PTG1), there was a rightward shift of the baroreflex curve. In group PTG2 (the normotensive group of animals), a lower gain was found before and during propranolol treatment. The decrease in gain of the baroreflex was not associated with changes in heart rate range, suggesting an impairment in the central processing of the baroreceptor signals. Thus sheep fetuses exposed to dexamethasone for only 2 days at the end of the first month of gestation have high blood pressure (dependent upon the increase in cardiac output) and a reset of the baroreflex at 40 months of age. Animals that have received prenatal dexamethasone closer to mid-gestation, although normotensive with normal cardiac output, showed an altered baroreceptor-heart rate response.
Basal nitric oxide production is impaired in offspring of patients with essential hypertension
Authors: McALLISTER A. S. , ATKINSON A. B. , JOHNSTON G. D. , HADDEN D.R. , BELL P. M. , McCANCE D. R.
Published: August 2015

There is considerable evidence that endothelium-dependent nitric oxide (NO)-mediated vasodilatation in response to acetylcholine is impaired in essential hypertension, whereas the endothelium-independent response to sodium nitroprusside is normal. More limited data have suggested that there is also reduced vasoconstriction in response to NG-monomethyl-⌊-arginine (⌊-NMMA), a competitive inhibitor of basal NO release. As it is not known whether endothelial dysfunction in hypertension, if indeed present, is a cause or consequence of the condition, we have studied the normotensive offspring of parents with essential hypertension. Both basal and stimulated vascular responses were examined in 12 normotensive offspring [mean age (°S.E.M.) 26.1°1.4 years] of parents with essential hypertension and compared with those in 12 age-matched offspring (mean age 25.6°1.1 years) of normotensive subjects. Forearm blood flow was measured simultaneously in both arms by venous occlusion plethysmography, both at baseline and during intra-arterial brachial infusion of increasing doses of acetylcholine, sodium nitroprusside, noradrenaline and ⌊-NMMA. There were no significant differences between the groups in the responses to acetylcholine, sodium nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to l-NMMA was significantly blunted in the offspring of hypertensive parents compared with that in the offspring of normotensive parents (P = 0.005). Thus endothelial dysfunction, as demonstrated by impaired basal production of NO, is present in subjects at high risk of essential hypertension, and does not occur simply as a consequence of the condition.
Plasma endothelin-1 and total insulin exposure in diabetes mellitus
Authors: WOLLESEN Flemming , BERGLUND Lars , BERNE Christian
Published: August 2015

Insulin stimulates endothelin-1 (ET-1) expression in a dose-response relationship, and ET-1 effects on vascular wall structure are similar to the long-term complications of diabetes. We therefore determined whether the plasma ET-1 concentration in patients with diabetes is associated with their total insulin exposure to see if plasma ET-1 might be a link between insulin exposure and long-term complications of diabetes. We studied 69 patients with Type I and 40 patients with Type II diabetes mellitus in equally tight glycaemic control for 2 years in a cross-sectional design. We measured basal and glucagon-stimulated plasma C-peptide, abdominal sagittal diameter, skinfold thickness, glomerular filtration rate, albumin excretion rate and standard clinical characteristics. Mean HbA1c was 6.4% in Type I and 6.3% in Type II diabetes. Patients with an albumin excretion rate > 300 μg/min were excluded. Adjusted mean plasma ET-1 was 4.11 (S.E.M. 0.39) pg/ml in 21 normal subjects, 3.47 (0.19) pg/ml in Type I diabetes and 4.84 (0.26) pg/ml in Type II diabetes (P = 0.0001). In all patients with measurable plasma C-peptide, plasma ET-1 was associated with basal plasma C-peptide (r = 0.5018, P < 0.0001), with stimulated plasma C-peptide (r = 0.5379, P < 0.0001), and with total daily insulin dose (r = 0.2219, P = 0.00851). Abdominal obesity, metabolic abnormalities, blood pressure and glomerular filtration rate were not associated with plasma ET-1, when corrected for C-peptide and daily insulin dose. Our study shows that the plasma concentration of ET-1 is closely associated with insulin secretion and insulin dose in patients with diabetes. Plasma ET-1 is higher in Type II diabetes than in Type I diabetes. Increased insulin exposure in patients with diabetes may have long-term effects on vascular wall structure through its stimulation of ET-1 expression.
Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link
Authors: GOETZ Regina M. , HOLTZ Juergen
Published: August 2015

Endothelial vasomotor function is impaired in a variety of disorders representing both early and late stages of atherosclerosis. There is experimental evidence for enhanced vascular angiotensin-converting enzyme (ACE) activity in these disorders. We explored whether enhanced vascular ACE activity accounts for endothelial dysfunction in experimental hypertension. Hypertension was induced in rats by coarctation of the aorta. At 2 weeks post-operation, the animals were randomly divided into groups receiving the ACE inhibitor quinapril (2.0 mgċkg-1ċday-1), the angiotensin type-1 receptor antagonist losartan (3.0 mgċkg-1ċday-1), the B2 kinin receptor antagonist icatibant (0.4 mgċkg-1ċday-1), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were performed 4 weeks post-operation. None of the drug treatments had any significant effect on blood pressure. ACE activity was nearly doubled in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril reduced ACE activity in aortae from hypertensive rats by 75%, losartan caused a 40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide-mediated vasodilator responses studied in vitro were impaired by 40% in aortae from untreated hypertensive rats as compared with sham-operated rats. Both quinapril and losartan restored endothelial vasomotor function in aortae from hypertensive rats. Co-applied icatibant negated the effects of quinapril, but not those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by competitive RNA PCR was decreased by half in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril induced an increase in the eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co-applied icatibant. Losartan restored eNOS mRNA expression in aortae from hypertensive rats to normal levels, and this effect was not modified by co-applied icatibant. These findings suggest that enhanced vascular ACE activity accounts for endothelial vasomotor dysfunction by impairing the bioavailability of endothelium-derived NO. Both enhanced formation of angiotensin II and enhanced metabolism of bradykinin might account for a vascular deficiency of bioactive NO.
Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute-phase response, resting energy expenditure, and catabolic and anabolic hormones
Authors: SIMONS Jean Paul F. H. A. , SCHOLS Annemie M. W. J. , BUURMAN Wim A. , WOUTERS Emiel F. M.
Published: August 2015

The aim of the present study was to investigate, in human lung cancer, the relationship between weight loss and the existence of a low body cell mass (BCM) on the one hand, and the putative presence of systemic inflammation, an increased acute-phase response, anorexia, hypermetabolism and changes in circulating levels of several anabolic and catabolic hormones on the other. In 20 male lung cancer patients, pre-stratified by weight loss of ⩾ 10% (n = 10) or of < 10% (n = 10), the following measurements were performed: BCM (by dual-energy X-ray absorptiometry/bromide dilution), circulating levels of sTNF-R55 and sTNF-R75 (soluble tumour necrosis factor receptors of molecular masses 55 and 75 kDa respectively), interleukin-6, lipopolysaccharide-binding protein, albumin, appetite (scale of 0–10), resting energy expenditure (by indirect calorimetry) and circulating levels of catabolic (cortisol) and anabolic [testosterone, insulin-like growth factor-I (IGF-I)] hormones. Compared with the patients with a weight loss of < 10%, those with a weight loss of ⩾ 10% were characterized by higher levels of sTNF-R55 (trend towards significance; P = 0.06), and lower levels of albumin (27.4 compared with 34.4 mmol/l; P = 0.02), testosterone (13.2 compared with 21.5 nmol/l; P = 0.01) and IGF-I (119 compared with 184 ng/ml; P = 0.004). In the patient group as a whole, the percentage weight loss was significantly correlated with sTNF-R55 (r = 0.59, P = 0.02), albumin (r =-0.63, P = 0.006) and IGF-I (r =-0.50, P = 0.02) levels. Height-adjusted BCM was significantly correlated with sTNF-R55 (r =-0.57, P = 0.03), sTNF-R75 (r =-0.50, P = 0.04), lipopolysaccharide-binding protein (r =-0.50, P = 0.04), albumin (r = 0.56, P = 0.02) and resting energy expenditure/BCM (r =-0.54, P = 0.03), and there was a trend towards a correlation with IGF-I concentration (r = 0.44, P = 0.06). We conclude that, in human lung cancer, weight loss and the presence of a low BCM are associated with systemic inflammation, an increased acute-phase response and decreased levels of IGF-I. In addition, a decreased BCM is associated with hypermetabolism.
Ramipril prevents basal arterial constriction and enhanced myogenic tone in the femoral artery in mildly uraemic normotensive rats
Authors: SAVAGE Tessa , MCMAHON Aisling C. , MULLEN Adrian , TRIBE Rachel M. , YAQOOB Magdi M.
Published: August 2015

Some aspects of vascular reactivity are altered in mild experimental uraemia, as shown by increased myogenic tone and a reduced lumen diameter in the femoral artery. This study was conducted to investigate the prevention of these uraemia-induced vascular abnormalities by the angiotensin-converting enzyme inhibitor (ACE-I) Ramipril. Ten male Wistar rats were rendered uraemic (U) by 5/6th nephrectomy, and 10 control (C) rats were concurrently sham-operated. After 4 weeks, both groups were given daily subcutaneous injections of 3 μg of Ramipril for a further 4 weeks. Tail-cuff systolic blood pressure was then recorded and the rat was killed. Isolated femoral arteries were mounted on a pressure myograph and pressurized at 40 mmHg for baseline measurements of the lumen internal diameter. Myogenic tone was then assessed over a range of intravascular pressures from 40 to 160 mmHg. Biochemically, serum urea and creatinine were significantly higher in the uraemic (U) group [urea: U, 23±3 mmol/l; C, 6±1 mmol/l (P < 0.001); creatinine: U, 147±17 mmol/l, C, 72±11 mmol/l (P < 0.01)]. Systolic blood pressure was the same in both groups (U, 127±7 mmHg; C, 127±3 mmHg). The mean baseline internal diameter was the same in both groups (U, 756±22 μm; C, 721±34 μm, not significant), as was mean myogenic tone (U, 4.7±1%; C, 3.4±1%). In conclusion, there were no differences in baseline lumen diameter or myogenic tone in uraemic compared with control femoral arteries of rats treated with Ramipril, which suggests that Ramipril may prevent the development of elevated myogenic tone and decreased lumen diameter previously observed in this model of uraemia. These results suggest that these specific vascular abnormalities in uraemia may be mediated by renin or bradykinin, or by the direct action of angiotensin II on vascular smooth muscle.
Relationship between vascular reactivity in vitro and blood flows in rats with cirrhosis
Authors: PATERON Dominique , OBERTI Frédéric , LEFILLIATRE Pascale , VEAL Nary , TAZI Khalid A. , SOGNI Philippe , POIREL Odile , HELLER Jörg , MOREAU Richard , CALES Paul , LEBREC Didier
Published: August 2015

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10-9–10-4 M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by Nω-nitro-l-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to Nω-nitro-l-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.
Effects of acidosis on leptin secretion from 3T3-L1 adipocytes and on serum leptin in the uraemic rat
Authors: TETA Daniel , BEVINGTON Alan , BROWN Jeremy , THROSSELL David , HARRIS Kevin P. G. , WALLS John
Published: August 2015

Marked hyperleptinaemia and metabolic acidosis are common findings in patients with chronic renal failure. In animal models, both leptin administration and acidosis reduce food intake. However, leptin causes loss of body fat, while acidosis induces muscle wasting. Whether a low pH and leptin production are related has not been studied. Leptin secretion was measured in cultured 3T3-L1 adipocytes exposed to acid or control pH for up to 96 h. In addition, serum leptin was compared between acidotic and bicarbonate-treated uraemic Wistar rats using the remnant model. Leptin levels in the culture medium were decreased at an acid pH of 7.1 compared with a control pH of 7.5 at 96 h (562±78 and 831±103 pg·48 h-1·well-1 respectively; mean±S.E.M.; P = 0.037). Similarly, serum leptin in uraemic rats was found to be lower in the acidotic group than in the bicarbonate-treated group, although this observation fell just short of statistical significance (1273±171 compared with 2059±376 pg/ml; P = 0.07). In conclusion, acidosis decreases leptin secretion from cultured adipocytes. Accordingly, acidotic uraemic rats seem to exhibit lower serum leptin levels than their bicarbonate-supplemented counterparts. This study is the first report providing a link between acidosis and leptin levels.
Decreased activity of the red blood cell ATPase-dependent Na+ pump in patients with cardiac syndrome X
Authors: FERRI Claudio , DESIDERI Giovambattista , de MATTIA Giancarlo , BELLINI Cesare , GENTILE Marco , GIOFFRÈ Pieragostino , SANTUCCI Anna , GASPARDONE Achille
Published: August 2015

Marked Na+/Li+ countertransport hyperactivity and post-load hyperinsulinaemia have been described in 93% of patients with cardiac syndrome X. We hypothesized that more complex abnormalities in Na+ traffic across the cell membrane are present in these patients. The aim of the present study was to evaluate the activities of the two main transporters responsible for transmembrane Na+ transport, i.e. the ATPase-dependent Na+ pump and the Na+–K+–2Cl- co-transporter, in a selected group of patients with cardiac syndrome X. We evaluated 19 patients with cardiac syndrome X and 14 control subjects. The ATPase-dependent Na+ pump and Na+–K+–2Cl- co-transport activities were assessed from Na+-loaded red blood cells by using nystatine, in the presence of furosemide and ouabain, as appropriate. Erythrocyte Na+/Li+ countertransport activity, serum lipid and post-load (75 g of oral glucose) insulin levels were also evaluated. The Vmax of Na+/Li+ countertransport (P = 0.0001) and post-load insulin levels (120 min; P = 0.001) were confirmed to be higher in patients with syndrome X than in controls. The Vmax of Na+–K+–2Cl- co-transport was similar in patients and controls. By contrast, the Vmax of the ATPase-dependent Na+ pump was significantly lower (P = 0.002) in syndrome X patients (3.13±0.87 mmol·h-1·l-1) than in controls (4.28±1.10 mmol·h-1·l-1). Serum total cholesterol and triacylglycerol concentrations were also higher in patients with syndrome X than in control subjects (P < 0.0001). Thus decreased activity of the ATPase-dependent Na+ pump was present in patients with cardiac syndrome X. Such an abnormality has the biological potential to augment microvascular tone and the response to constrictor stimuli via increased intracellular free Ca2+. Of note, syndrome X patients also manifested Na+/Li+ countertransport hyperactivity which, in turn, is known to induce peripheral insulin resistance and consequent abnormalities in insulin secretion and lipid turnover. Thus cardiac syndrome X appears as a multifaceted syndrome presenting with either metabolic or cardiovascular symptoms, or both, based on the expression of complex abnormalities in Na+ traffic across the cell membrane.
Up-regulation of nitric oxide production by interferon-γ in cultured peritoneal macrophages from patients with cirrhosis
Authors: BORIES P. N. , CAMPILLO B. , SCHERMAN E.
Published: August 2015

We previously described a long-lasting overproduction of nitric oxide (NO) in cirrhotic patients with spontaneous bacterial peritonitis. The aim of the present study was to investigate the presence of the inducible NO pathway in peritoneal macrophages. Ascitic fluids were collected from 29 patients with cirrhosis, aged between 35 and 82 years. Peritoneal macrophages were isolated and cultured in the presence or absence of 1 μg/ml lipopolysaccharide and/or 500 units/ml interferon-γ (IFN-γ) for 6 days. NO production was measured as nitrate+nitrite (NOx), inducible NO synthase (iNOS) protein expression was analysed by immunocytochemistry and Western blot analysis using a specific anti-(human iNOS) antibody, and the catalytic activity of NOS was revealed by cytochemical staining for NADPH-dependent diaphorase. Cultured macrophages spontaneously released small amounts of NOx [median (10–90th percentile) of 18 separate experiments: 3.3 (0–8) μmol/l]. Addition of lipopolysaccharide alone or in combination with IFN-γ to the culture medium did not change the levels of NOx, while IFN-γ alone dramatically increased NO production [13.4 (3.5–28.3) μmol/l; P< 0.001]. Macrophages were stimulated by IFN-γ to a greater extent in patients with recent spontaneous bacterial peritonitis (n = 13) than in those in a stable clinical condition (n = 18) [19.8 (10.5–30.1) and 10.0 (3.2–14.5) μmol/l respectively; P< 0.001]. Macrophages freshly isolated or stimulated with IFN-γ expressed iNOS protein, as shown by Western blot and immunocytochemical analysis, and stained for NADPH diaphorase. Our findings demonstrate the presence of iNOS protein in peritoneal macrophages from cirrhotic patients. The role of IFN-γ appears to be a determinant for the up-regulation of NO production, particularly under conditions of infection. Therefore peritoneal macrophages producing large amounts of NO at the site of infection may contribute to maintaining splanchnic vasodilation in these patients.