bluuebunny/crossref_metadata_2025 huggingface dataset:
Divergent natriuretic action of calcium channel antagonists in mongrel dogs: renal haemodynamics as a determinant of natriuresis
Authors: HONDA Masanori , HAYASHI Koichi , MATSUDA Hiroto , KUBOTA Eiji , TOKUYAMA Hirobumi , OKUBO Ken , OZAWA Yuri , SARUTA Takao
Published: August 2015

This study examined the effects of different types of calcium channel antagonists on renal haemodynamics and natriuresis. The intravenous infusion of nifedipine (L-type blocker), efonidipine (L/T-type blocker) or mibefradil (predominant T-type blocker) into anaesthetized dogs elicited similar, albeit modest, reductions in blood pressure. Nifedipine (1μgċmin-1ċkg-1) increased renal plasma flow (RPF) (23±6%; P<0.05) and glomerular filtration rate (GFR) (25±5%; P<0.05) (all values are means±S.E.M., n = 7). Efonidipine (0.33μgċmin-1ċkg-1) also elevated RPF (18±6%; P<0.05), and tended to increase GFR (17±8%; P = 0.08). These antagonists exerted contrasting actions on the filtration fraction (FF), with an increase being elicited by nifedipine, whereas efonidipine had no effect. Furthermore, mibefradil (0.01-1μgċmin-1ċkg-1) slightly elevated RPF (between 5±3% and 8±3%), but failed to alter GFR, resulting in a decrease in FF. Nifedipine slightly increased urinary sodium excretion (UNaV) (29±16% increase at 1μgċmin-1ċkg-1) and fractional sodium excretion (FENa) (18±14%), whereas efonidipine (0.33μgċmin-1ċkg-1) elicited marked elevations in UNaV (110±38%; P<0.05) and FENa (102±44%; P<0.05). Mibefradil (1μgċmin-1ċkg-1) exerted a moderate natriuretic action [UNaV, +60±32% (P = 0.1); FENa, +67±20% (P<0.05)]. Furthermore, although a positive correlation was observed between UNaV and urinary nitrate/nitrite excretion, no differences were noted between the various calcium channel antagonists. Collectively, this study demonstrates that the glomerular haemodynamic and natriuretic actions of these calcium channel antagonists, which possess diverse blocking activities on L/T-type channels, vary. Based on the divergent actions on FF (i.e. increase, no change and decrease by nifedipine, efonidipine and mibefradil respectively), the natriuretic action of calcium channel antagonists is possibly attributed to the inhibition of tubular sodium reabsorption associated with increased post-glomerular blood flow, rather than increased GFR.
Influence of age, the autonomic nervous system and anxiety on QT-interval variability
Authors: PICCIRILLO Gianfranco , CACCIAFESTA Mauro , LIONETTI Marco , NOCCO Marialuce , DI GIUSEPPE Vincenza , MOISÈ Antonio , NASO Camilla , MARIGLIANO Vincenzo
Published: August 2015

As QT variability increases and heart rate variability diminishes, the QT variability index (QTVI)-a non-invasive measure of beat-to-beat fluctuations in QT interval on a single ECG lead-shows a trend towards positive values. Increased QT variability is a risk factor for sudden death. Aging lengthens the QT interval and reduces RR-interval variability. In the present study we investigated the influence of aging and the autonomic nervous system on QT-interval variability in healthy subjects. We studied 143healthy subjects, and divided them into two age ranges (younger and older than 65 years). For each subject we measured two QTVIs: from the q wave to the end of the T wave (QTeVI) and to the apex of the T wave (QTaVI). Both indexes were calculated at baseline and after sympathetic stress. In 10 non-elderly subjects, both QTVIs were determined after β-adrenoreceptor blockade induced by intravenous infusion of propranolol or sotalol. The QTVI was higher in elderly than in younger subjects (P < 0.001). QTVIs obtained during sympathetic stress remained unchanged in the elderly, but became more negative in the younger group (P < 0.05). QTeVI and QTaVI at baseline were correlated positively with age (P < 0.01) and anxiety scores (P < 0.05), but inversely with the low-frequency spectral power of RR-interval variability (P < 0.001). QTVIs were higher in subjects with higher anxiety scores. In younger subjects, sotalol infusion increased both QTVIs significantly, whereas propranolol infusion did not. In conclusion, aging increases QT-interval variability. Whether this change is associated with an increased risk of sudden death remains unclear. The association of abnormal QT-interval variability with anxiety and with reduced low-frequency spectral power of heart rate variability merits specific investigation. In healthy non-elderly subjects, acute sympathetic stress (tilt) decreases the QTVI. β-Adrenoreceptor blockade inhibits this negative trend, thus showing its sympathetic origin. Because a negative trend in QTVI induced by sympathetic stress increases only in younger subjects, it could represent a protective mechanism that is lost with aging.
Perception of bronchoconstriction in smokers with airflow limitation
Authors: OTTANELLI R. , ROSI E. , RONCHI M.C. , GRAZZINI M. , LANINI B. , STENDARDI L. , ROMAGNOLI I. , BERTINI S. , DURANTI R. , SCANO G.
Published: August 2015

To our knowledge, no data have been provided as to whether and to what extent dynamic hyperinflation, through its deleterious effect on inspiratory muscle function, affects the perception of dyspnoea during induced bronchoconstriction in patients with chronic airflow obstruction. We hypothesized that dynamic hyperinflation accounts in part for the variability in dyspnoea during acute bronchoconstriction. We therefore studied 39 consecutive clinically stable patients whose pulmonary function data were as follows (% of predicted value): vital capacity (VC), 97.8% (S.D. 16.0%); functional residual capacity, 105.0% (18.8%); actual forced expiratory volume in 1s (FEV1)/VC ratio, 56.1% (6.3%). Perception of dyspnoea using the Borg scale was assessed during a methacholine-induced fall in FEV1. The clinical score and the treatment score, the level of bronchial hyper-responsiveness and the cytological sputum differential count were also assessed. In each patient, the percentage fall in FEV1 and the concurrent Borg rating were linearly related, with the mean slope (PD slope) being 0.09 (0.06). The percentage fall in FEV1 accounted for between 41% and 94% of the variation in the Borg score. At a 20% fall in FEV1, the decrease in inspiratory capacity (ΔIC) was 0.156 (0.050) litres. Patients were divided into three subgroups according to the PD slope (arbitrary units/% fall in FEV1): subgroup I [eight hypoperceivers; PD slope 0.026 (0.005)], subgroup II [26 moderate perceivers; 0.090 (0.037)] and subgroup III [five hyperperceivers; 0.200 (0.044)]. By applying stepwise multiple regression analysis with the PD slope as the dependent variable, and other characteristics (demographic, clinical and functional characteristics, smoking history, level of bronchial hyper-responsiveness and sputum cytological profile) as independent variables, ΔIC (r2 = 45%, P < 0.00001) and to a lesser extent treatment score (r2 = 17.3%, P < 0.0006), and to an even lesser extent age (r2 = 3%, P < 0.05), independently predicted a substantial amount (r2 = 65.27%, P < 0.00001) of the variability in the Borg slope. Thus acute hyperinflation, and to a lesser extent treatment score and age, account in part for the variability in the perception of dyspnoea after accounting for changes in FEV1 during bronchoconstriction in patients with chronic airflow obstruction.
Autoantibodies against oxidized low-density lipoprotein and C-reactive protein are associated with diabetes and myocardial infarction in women
Authors: DOTEVALL Annika , HULTHE Johannes , ROSENGREN Annika , WIKLUND Olov , WILHELMSEN Lars
Published: August 2015

Women with diabetes mellitus are at high risk of myocardial infarction (MI), and it is well recognized that smoking, hypertension, hyperlipidaemia and the diabetic state itself do not fully explain this increased risk. During the last decade, growing evidence has accumulated that the immune system, with oxidized low-density lipoprotein (LDL) as a key antigen, plays an important role in the development of atherosclerosis. The aim of the present study was to explore the association between the immune response, as measured by antibody titres to malondialdehyde-treated LDL (MDA-LDL) and levels of C-reactive protein (CRP; a marker of inflammation), and diabetes mellitus and MI in women. Women (35-64 years) with diabetes (n = 18) and non-diabetic women (n = 46) who had been treated in hospital for MI were compared with diabetic women without MI (n = 35) and healthy controls (n = 70). Blood samples were collected after an overnight fast. CRP was determined with a highly sensitive immuno-enzymometric assay. IgM and IgG antibodies against MDA-LDL were analysed with a solid-phase ELISA technique. Women with diabetes but without previous MI were more similar to women with previous MI (both with and without diabetes) than to the healthy controls. Compared with healthy women, the women with diabetes and/or MI had higher IgG (P < 0.05) and lower IgM (P = 0.006) antibody titres against oxidized LDL and higher CRP levels (P < 0.001), associations that were independent of other cardiovascular risk factors. These findings might indicate a differentiated immune response against modified LDL, more pronounced inflammation and a more aggressive atherosclerotic process in women with diabetes.
Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes
Authors: VESTERGAARD Henrik , BRATHOLM Palle , CHRISTENSEN Niels Juel
Published: August 2015

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the β2-adrenoceptor (β2-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (α+β isoforms), the α/α2 isoform of GCR and β2-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n = 10) and healthy controls (n = 15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, α/α2 GCR and β2-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2m-unitsċmin-1ċkg-1) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and α/α2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06±0.30 and 1.47±0.10 amol/μg of total RNA respectively (P = 0.09); α/α2 GCR mRNA, 1.69±0.31and 0.92±0.09amol/μg of total RNA respectively (P = 0.02)], whereas mRNA levels of the β isoform of GCR (total GCR minus α/α2 GCR) were decreased (P = 0.006). β2-AR mRNA levels were comparable in diabetic patients and control subjects (0.53±0.05 and 0.45±0.02amol/μg of total RNA respectively; P = 0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P = 0.019), and during the clamp a 75% (P = 0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P = 0.005), α/α2 GCR (P = 0.005) and β2-AR (P = 0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r = 0.95, P<0.001; multiple regression analysis), and between glucose uptake and α/α2 GCRm RNA levels (r = 0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.
Differential regulation of the lysosomal, Ca2+-dependent and ubiquitin/proteasome-dependent proteolytic pathways in fast-twitch and slow-twitch rat muscle following hyperinsulinaemia
Authors: LARBAUD Daniel , BALAGE Michèle , TAILLANDIER Daniel , COMBARET Lydie , GRIZARD Jean , ATTAIX Didier
Published: August 2015

In order to characterize the poorly defined mechanisms that account for the anti-proteolytic effects of insulin in skeletal muscle, we investigated in rats the effects of a 3h systemic euglycaemic hyperinsulinaemic clamp on lysosomal, Ca2+-dependent proteolysis, and on ubiquitin/proteasome-dependent proteolysis. Proteolysis was measured in incubated fast-twitch mixed-fibre extensor digitorum longus (EDL) and slow-twitch red-fibre soleus muscles harvested at the end of insulin infusion. Insulin inhibited proteolysis (P < 0.05) in both muscles. This anti-proteolytic effect disappeared in the presence of inhibitors of the lysosomal/Ca2+-dependent proteolytic pathways in the soleus, but not in the EDL, where only the proteasome inhibitor MG 132 (benzyloxycarbonyl-leucyl-leucyl-leucinal) was effective. Furthermore, insulin depressed ubiquitin mRNA levels in the mixed-fibre tibialis anterior, but not in the red-fibre diaphragm muscle, suggesting that insulin inhibits ubiquitin/proteasome-dependent proteolysis in mixed-fibre muscles only. However, depressed ubiquitin mRNA levels in such muscles were not associated with significant decreases in the amount of ubiquitin conjugates, or in mRNA levels or protein content for the 14kDa ubiquitin-conjugating enzyme E2 and 20S proteasome subunits. Thus alternative, as yet unidentified, mechanisms are likely to contribute to inhibit the ubiquitin/proteasome system in mixed-fibre muscles.
Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients
Authors: NOUSIAINEN Tapio , VANNINEN Esko , JANTUNEN Esa , REMES Jouko , RITANEN Eira , VUOLTEENAHO Olli , HARTIKAINEN Juha
Published: August 2015

Doxorubicin-induced cardiotoxicity was used as a model to prospectively investigate neuroendocrine changes during the development of left ventricular dysfunction. Radionuclide ventriculography, frequency domain analysis of heart rate variability (HRV), and plasma noradrenaline and natriuretic peptide measurements were performed in 27 adult lymphoma patients at baseline and after cumulative doxorubicin doses of 200, 400 and 500mg/m2. The left ventricular ejection fraction (LVEF) decreased from 58.1±1.4% to 50.3±1.1% (P < 0.001) and 49.3±1.7% (P < 0.001) after cumulative doxorubicin doses of 400 and 500mg/m2 respectively. With a doxorubicin dose of up to 400mg/m2 there was an increase in sympathetic tone, characterized by a decrease in the normalized high-frequency (HFnu) power (P = 0.011), and increases in the normalized low-frequency (LFnu) power (P = 0.011), the LF/HF ratio (P = 0.021) and the plasma noradrenaline concentration (P = 0.034). The decrease in LVEF was correlated with the changes in LFnu and HFnu power (r = 0.540, P =0.012) and LF/HF ratio (r =-0.452, P =0.04). However, after the cumulative doxorubicin dose of 500mg/m2 the changes in HRV components and plasma noradrenaline levels returned towards baseline. This was accompanied by increased concentrations of plasma atrial natriuretic peptide (P = 0.004) and brain natriuretic peptide (P = 0.021). Our findings suggest that doxorubicin-induced left ventricular dysfunction is associated with an early change in sympathovagal balance towards sympathetic predominance. Along with further progression of left ventricular dysfunction, there is an attenuation of sympathetic tone, which may be attributable to sympatho-adrenal inhibition by increased secretion of natriuretic peptides.
High-density lipoprotein composition and paraoxonase activity in Type I diabetes
Authors: VALABHJI Jonathan , McCOLL Avril J. , SCHACHTER Michael , DHANJIL Surinder , RICHMOND William , ELKELES Robert S.
Published: August 2015

Type I diabetes is associated with a high incidence of coronary heart disease (CHD), despite a normal or even increased concentration of high-density lipoprotein (HDL) cholesterol. This paradox may be explained by changes in the antioxidant capacity of HDL, related to paraoxonase (PON1) activity. HDL compositional changes in subjects with Type I diabetes may result in changes in PON1 activity that are associated with a higher incidence of CHD. Single-vertical-spin density-gradient ultracentrifugation was used to isolate seven HDL fractions from serum according to density. PON1 activity was measured in serum and in the HDL fractions using phenyl acetate as substrate. The mean recovery of PON1 activity in the HDL fractions was 87% (S.D. 12%). CHD risk was assessed using B-mode ultrasound to measure carotid artery intima-media thickness (IMT). Groups of 35 subjects with Type I diabetes {duration of diabetes 18 years (12-32 years) [median (interquartile range)]; glycated haemoglobin 7.67% (1.17%)} and 24 non-diabetic control subjects were studied. Carotid IMT was greater in the diabetic subjects [0.60 (0.55-0.70) compared with 0.55 (0.45-0.64) mm; P = 0.042] and HDL cholesterol concentration was higher [1.53 (0.36) compared with 1.32(0.34)mmol/l; P = 0.031]. There were qualitative differences in HDL in subjects with Type I diabetes: HDL particles were triacylglycerol-deplete, and there were greater numbers of the larger, more buoyant HDL particles. These properties were not those found to determine PON1 activity. PON1 activity increased as HDL particle density increased and particle size decreased; the increase in PON1 activity was associated with an increase in the ratio of the two HDL surface lipid components, phospholipid and unesterified cholesterol, as particle density increased. PON1 activity was similar in diabetic and non-diabetic subjects [121 (28) and 120 (36)μmolċmin-1ċml-1 respectively; P = 0.887]. PON1 activity was not associated with carotid IMT in either group. Our results suggest that the PON1 activities of HDL particles relate to the density, size and composition of the particles. However, PON1 activity does not appear to contribute to the greater risk of CHD in subjects with Type I diabetes.
Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: a study in central obesity
Authors: WATTS G.F. , CHAN D.C.F. , BARRETT P.H.R. , MARTINS I.J. , REDGRAVE T.G.
Published: August 2015

We aimed to investigate the metabolism of chylomicron remnants in the postabsorptive state employing a new stable isotope breath test in centrally obese men without overt hyperlipidaemia. Groups of 12 centrally obese and 12 non-obese men of similar age and with similar plasma cholesterol and triacylglycerol (triglyceride) levels were studied. The catabolism of chylomicron remnants was measured using an intravenous injection of a remnant-like emulsion containing cholesteryl [13C]oleate. Isotopic enrichment of 13CO2 in breath was determined using isotope-ratio mass spectrometry, and a multi-compartmental model (SAAM II program) was used to estimate the fractional catabolic rate (FCR) of the chylomicron remnant-like particles. The plasma concentrations of low-density lipoprotein (LDL)-cholesterol, non-high-density lipoprotein (HDL)-cholesterol and insulin were significantly higher (P < 0.05) in the obese than the control subjects. The obese subjects had significantly lower HDL-cholesterol (P < 0.05) and, in particular, a decreased FCR of the remnant-like particles compared with lean subjects (0.061±0.014 and 0.201±0.048pools/h respectively; P = 0.016). In the obese group, the FCR of remnant-like particles was inversely associated with the waist/hip ratio, and with plasma triacylglycerol, cholesterol, LDL-cholesterol and non-HDL-cholesterol levels. In multiple regression analysis, the waist/hip ratio was the best predictor of the FCR of the emulsion. In conclusion, this new test suggests that postabsorptive chylomicron remnant catabolism is impaired in centrally obese subjects without overt hyperlipidaemia. This defect may be due to the degree of adiposity.
Effects of phytanic acid on the vitamin E status, lipid composition and physical properties of retinal cell membranes: implications for adult Refsum disease
Authors: YOUNG S.P. , JOHNSON A.W. , MULLER D.P.R.
Published: August 2015

Adult Refsum disease is an inherited disorder in which phytanic acid accumulates in tissues and serum. Two hypotheses have been proposed to explain the pathogenesis of this condition. The molecular distortion hypothesis suggests that phytanic acid may alter membrane composition and structure, thereby affecting membrane function(s). The anti-metabolite hypothesis suggests that an accumulation of phytanic acid in membranes may interfere with vitamin E function. These two hypotheses were investigated by studying the effects of modulating phytanic acid and α-tocopherol concentrations on the fatty acid composition and certain physical parameters of cultured retinal cells. Results showed that (a) the phospholipid fraction of retinal cells readily incorporated phytanic acid, (b) the incorporation of phytanic acid increased membrane fluidity, (c) there was no competition for uptake between phytanic acid and α-tocopherol, and (d) the incorporation of phytanic acid did not increase the susceptibility of membranes to lipid peroxidation in vitro. These results obtained with cultured retinal cells suggest that the molecular distortion hypothesis, but not the anti-metabolite hypothesis, could explain the pathogenesis of adult Refsum disease. In vitro tissue culture models can, however, only approximate to the much more complex situation that occurs in vivo.
Diabetes and the maternal resistance vasculature
Authors: ANG Christine , Ann LUMSDEN Mary
Published: August 2015

Diabetes is the most common endocrine disorder worldwide, with complications that include the development of both macro- and micro-vascular disease that contribute significantly to patient morbidity and mortality. The severity of diabetic complications is amplified during pregnancy, resulting in a higher incidence of adverse pregnancy outcomes such as pre-eclampsia, placental insufficiency and stillbirth than in non-diabetics. Vascular dysfunction is thought to underlie many of these complications, with the greatest impact occurring at the level of the resistance vasculature, where alterations in vascular reactivity can significantly affect blood flow and tissue perfusion. It is likely that problems associated with diabetic pregnancies are related, in part, to abnormal vascular function, particularly dysfunction of the vascular endothelium.
Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome
Authors: KHANI Samina , TAYEK John A.
Published: August 2015

Android obesity is associated with increased cortisol secretion. Direct effects of cortisol on gluconeogenesis and other parameters of insulin resistance were determined in normal subjects. Gluconeogenesis was determined using the reciprocal pool model of Haymond and Sunehag (HS method), and by the Cori cycle/lactate dilution method of Tayek and Katz (TK method). Glucose production (GP) and gluconeogenesis were measured after a 3h baseline infusion and after a 4-8h pituitary-pancreatic infusion of somatostatin, replacement insulin, growth hormone (GH), glucagon and a high dose of cortisol (hydrocortisone). The pituitary-pancreatic infusion maintains insulin, GH and glucagon concentrations within the fasting range, while increasing the concentration of only one hormone, cortisol. Two groups of five subjects were each given high-dose cortisol administration, and results were compared with those from a group of six ‘fasting alone’ subjects (no infusion) at 16 and 20h of fasting. Fasting GP (12h fasting) was similar in all groups, averaging 12.5±0.2μmolċmin-1ċkg-1. Gluconeogenesis, as a percentage of GP, was 35±2% using the HS method and 40±2% using the TK method. After 16h of fasting, GP had fallen (11.5±0.6μmolċmin-1ċkg-1) and gluconeogenesis had increased (55±5% and 57±5% of GP by the HS and TK methods respectively; P < 0.05). High-dose cortisol infusion for 4h increased serum cortisol (660±30nmol/l; P < 0.05), blood glucose (7.9±0.5 mmol/l; P < 0.05) and GP (14.8±0.8μmolċmin-1ċkg-1; P < 0.05). The increase in GP was due entirely to an increase in gluconeogenesis, determined by either the HS or the TK method (66±6% and 65±5% of GP respectively; P < 0.05). Thus cortisol administration in humans increases GP by stimulating gluconeogenesis. Smaller increases in serum cortisol may contribute to the abnormal glucose metabolism known to occur in the metabolic syndrome.
Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart
Authors: KATUGAMPOLA Sidath D. , DAVENPORT Anthony P.
Published: August 2015

We investigated the binding characteristics of angiotensin receptors and used this assay to determine the predominant enzyme capable of converting angiotensin I in the human left ventricle. In homogenates of human left ventricle, 125I-[Sar1,Ile8]angiotensin II bound with sub-nanomolar affinity, with a corresponding KD of 0.42±0.09nM, a Bmax of 11.2±2.3fmolċmg-1 protein and a Hill slope of 1.04±0.04. The rank order of inhibitory potency of competing ligands for the 125I-[Sar1,Ile8]angiotensin II binding site was CGP42112 > angiotensin II⩾ angiotensin III = angiotensin I > losartan. The angiotensin type II (AT2) receptor predominated in the human left ventricle over the angiotensin type I (AT1) receptor, with an approximate AT1/AT2 receptor ratio of 35:65. No specific 125I-angiotensin IV binding sites could be detected in the human left ventricle. Using competitive radioligand binding assays, we were able to demonstrate that the chymase/cathepsin G enzyme inhibitor chymostatin was more potent than the angiotensin-converting enzyme (ACE) inhibitor captopril at inhibiting the conversion of angiotensin I in the human left ventricle. Aprotonin (an inhibitor of cathepsin G but of not chymase) had no effect on angiotensin I conversion, suggesting that the majority of the conversion was mediated by chymase. Thus, although the current therapies used for the renin-angiotensin system have focused on ACE inhibitors and AT1 receptor antagonists, the left ventricle of the human heart expresses mainly AT2 receptors and the tissue-specific conversion of angiotensin I occurs predominantly via chymase rather than ACE.
Potential therapeutic uses for S-nitrosothiols
Authors: RICHARDSON G. , BENJAMIN N.
Published: August 2015

The S-nitrosothiols (RSNOs) are thought to represent a circulating endogenous reservoir of nitric oxide (NO), and may have potential as donors of NO, distinct from currently used agents. They have the general formula RSNO, and naturally occurring examples include S-nitrosocysteine, S-nitrosoglutathione and S-nitrosoalbumin, in which R is an amino acid, polypeptide and protein respectively. RSNOs have anti-platelet properties, a theoretical role in the treatment of asthma and the potential to be used as agents to treat infectious diseases ranging from the common cold to AIDS. RSNOs are relatively unstable, being degraded to release NO and the corresponding disulphide. Their stability is influenced by the properties of the R group, heat, light, the presence of transition metal ions (in particular copper) and the presence of other thiols. RSNOs participate in transnitrosation reactions in which the -NO group is transferred to another thiol to form a more stable RSNO. Thus the stability of RSNOs in vivo is difficult to predict, and this has led to the development of more stable analogues, in which the properties of R are modified. Potential interactions of RSNOs include that with ascorbic acid (vitamin C), which enhances the ability of copper to catalyse their degradation. Transnitrosation reactions with thiol-containing enzymes can influence protein function, and the intracellular thiol glutathione, levels of which are influenced by many disease states, can also influence stability. Thus, although RSNOs have many theoretically useful properties, there are also many aspects of their biochemistry that need to be addressed before their therapeutic potential can be fully realized.
The response of liver albumin synthesis to infection in rats varies with the phase of the inflammatory process
Authors: RUOT Benoît , BÉCHEREAU Fabienne , BAYLE Gérard , BREUILLÉ Denis , OBLED Christiane
Published: August 2015

To discriminate between the effects of infection and of anorexia associated with infection, liver albumin synthesis was measured in well-fed rats, in rats injected with live Escherichia coli and in pair-fed rats at different stages of the inflammatory response (1, 6 and 10 days after infection) using a large dose of l-[1-14C]valine. Albuminaemia and albumin mRNA levels were unchanged following food restriction. However, absolute albumin synthesis was decreased in pair-fed rats compared with control animals after 1 day of food restriction, and had returned to normal values by day 10 when food intake was restored. Infection was characterized by a decrease in the plasma albumin concentration (35%, 45% and 28% as compared with pair-fed rats at 1, 6 and 10 days after infection respectively). Albumin mRNA levels and relative albumin synthesis were reduced in infected rats as compared with both control and pair-fed animals at all stages of infection. However, during the early acute response, the albumin absolute synthesis rate was similar in infected rats and pair-fed rats, indicating no specific effect of infection at this stage. Later in the course of infection, the amount of albumin synthesized by the liver was lower in infected than in pair-fed rats, and hypoalbuminaemia was probably maintained due to a lack of stimulation of synthesis despite increased food intake.
Quantification of right-to-left shunt with 99mTc-labelled albumin macroaggregates and 100% oxygen in patients with hereditary haemorrhagic telangiectasia
Authors: MAGER Johannes J. , ZANEN Pieter , VERZIJLBERGEN Fred , WESTERMANN Cornelius J.J. , HAITJEMA Tjeerd , VAN HERK Gerard , LAMMERS Jan-Willem J.
Published: August 2015

Pulmonary arteriovenous malformations (PAVMs) are often associated with hereditary haemorrhagic telangiectasia (HHT). The quantification of right-to-left shunts in patients with PAVMs is important in diagnosis and follow up. Traditionally, this shunt is measured by the 100% oxygen method, in which the value for the arteriovenous difference in oxygen content, Cao2-Co2 (where Cao2 is the oxygen content of arterial blood and Co2 is the oxygen content of mixed venous blood) is estimated. Alternative methods consist of measurement of the systemic or renal uptake of 99mTc-labelled macroaggregates of albumin (MAA), which are trapped in pulmonary capillaries, but pass through PAVMs. We first measured Cao2-Co2 in 12 HHT patients before and after embolization of PAVMs. We obtained a mean value of 4.4ml/100ml, instead of the usual 5ml/100ml. Subsequently, we measured right-to-left shunt in 21 HHT patients using the 100% oxygen method and with two different methods involving 99mTc. We used the kidney-lung method (K/L method), in which it is assumed that the right kidney receives 10% of the cardiac output, and we also used a method with two tracers (HSA/MAA method): (1) 99mTc-labelled human serum albumin (HSA) (which passes through pulmonary capillaries) to measure the fraction of the cardiac output perfusing the kidneys, and (2) MAA to measure the shunt fraction. In 35 shunt measurements we evaluated this new technique and the K/L method, by comparing the results with those from the 100% oxygen method. There was poor agreement between the 100% oxygen method and the K/L method, with 95% limits of agreement for the shunt fraction of -15.2% to +15.2%. There was moderate agreement between the 100% oxygen method and the HSA/MAA method, with limits of agreement of -8.3% to +7.7%. We conclude that the different methods cannot replace each other, because the limits of agreement are too wide for clinical use.
Adenosine inhibits thrombin-induced expression of tissue factor on endothelial cells by a nitric oxide-mediated mechanism
Authors: GABAZZA Esteban C. , HAYASHI Tatsuya , IDO Masaru , ADACHI Yukihiko , SUZUKI Koji
Published: August 2015

Enhanced expression of tissue factor (TF) is associated with the occurrence of coronary disease, strokes and arterial thrombosis. We demonstrated previously that adenosine inhibits TF expression in human umbilical vein endothelial cells (HUVECs) stimulated with inflammatory mediators. In the present study, we evaluated the mechanism of adenosine-induced inhibition of TF expression in HUVECs. The adenosine inhibitory activity on thrombin-induced TF expression in HUVECs was potentiated by the NO precursor, l-arginine, but it was significantly suppressed by the NO scavenger, 2(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, and by endothelial NO synthase inhibitors, NG-monomethyl-l-arginine and NG-nitro-l-arginine methyl ester, in a dose-dependent manner. The concentrations of nitrites, cGMP and cAMP in the culture medium of HUVECs treated with a mixture of thrombin and adenosine were significantly higher compared with the culture medium of HUVECs treated with thrombin alone. Northern blotting showed that thrombin decreases and adenosine increases the eNOS mRNA expression in HUVECs. A cAMP-dependent protein kinase inhibitor suppressed NO-mediated TF inhibition in a dose-dependent manner. Overall, these results suggest that adenosine inhibits thrombin-induced TF expression in endothelial cells by a NO-mediated mechanism, and that increased intracellular formation of cAMP is implicated in this inhibitory activity of NO.
Regular ingestion of black tea improves brachial artery vasodilator function
Authors: HODGSON Jonathan M. , PUDDEY Ian B. , BURKE Valerie , WATTS Gerald F. , BEILIN Lawrence J.
Published: August 2015

A higher intake of black tea has been associated with lower cardiovascular disease risk. The antioxidant effects of tea polyphenols may enhance endothelial function and thereby reduce the risk of coronary events. The objective of the present study was to determine whether regular ingestion of black tea can improve brachial artery vasodilator function. The effects of regular ingestion of 5 cups per day of black tea for 4 weeks were compared with control conditions (hot water ingestion) in 21 subjects with mild elevations in serum cholesterol or triacylglycerol (triglyceride) concentrations in a parallel designed study. Endothelial function of the brachial artery was assessed ultrasonographically by measurement of post-ischaemic (endothelium-dependent) dilatation of the brachial artery. Endothelium-independent dilatation of the brachial artery was measured following administration of 400μg of sublingual glyceryl trinitrate. Regular ingestion of black tea resulted in a significant and consistent increase in endothelium-dependent dilatation (2.3%; P = 0.008) and in a significant increase in endothelium-independent dilatation (4.2%; P = 0.03), compared with ingestion of hot water. These differences remained after adjustment for age, sex and body mass index. These results suggest that one mechanism by which black tea may reduce cardiovascular risk is via improved vasodilator function of conduit arteries.
Are the reductions in triacylglycerol and insulin levels after exercise related?
Authors: GILL Jason M.R. , HERD Sara L. , TSETSONIS Natassa V. , HARDMAN Adrianne E.
Published: August 2015

Moderate exercise improves insulin sensitivity and reduces triacylglycerol (triglyceride; TG) concentrations. We hypothesized that changes in insulin sensitivity are an important determinant of exercise-induced changes in postprandial TG concentrations. Altogether, 38 men and 43 women, all of whom were normotriglyceridaemic and normoglycaemic, each underwent two oral fat tolerance tests with different pre-conditions: control (no exercise) and prior exercise (90min of exercise at 60% of maximal O2 uptake the day before). Venous blood samples were obtained in the fasting state and for 6h after a high-fat mixed meal. In the control trial there were significant correlations between log fasting TG concentration and log fasting insulin concentration (r = 0.42, P < 0.0005) and between log postprandial TG response (area under the curve) and log postprandial insulin response (r = 0.48, P < 0.0005). Prior exercise reduced the fasting TG concentration by 18.2±2.2% (mean±S.E.M.) (P < 0.0005), the postprandial TG response by 21.5±1.9% (P < 0.0005), the fasting insulin concentration by 3.8±3.1% (P < 0.01) and the postprandial insulin response by 11.9±2.5% (P < 0.0005). However, there was no relationship between the exercise-induced changes in log fasting TG and log fasting insulin (r = 0.08, P = 0.50), nor between the exercise-induced changes in log postprandial TG response and log postprandial insulin response (r = 0.04, P = 0.70). These data suggest that the reductions in fasting and postprandial TG levels elicited by a session of moderate-intensity exercise are not mediated by an increase in insulin sensitivity.
Effects of ornithine 2-oxoglutarate on neutrophils in stressed rats: evidence for the involvement of nitric oxide and polyamines
Authors: MOINARD Christophe , CALDEFIE Florence , WALRAND Stephane , TRIDON Arlette , CHASSAGNE Jacques , VASSON Marie-Paule , CYNOBER Luc
Published: August 2015

Diets enriched in ornithine 2-oxoglutarate (ornithine α-ketoglutarate; OKG) improve immune status during stress. We described previously the ability of OKG to increase the respiratory burst in polymorphonuclear neutrophils (PMNs), but the underlying mechanisms remain unclear. OKG is usually recognized as generating glutamine, arginine and polyamines. The aim of the present study was first to determine the effects of OKG on PMN bactericidal functions (chemotaxis and respiratory burst) in stressed rats, and whether these effects could be reproduced by glutamine- or arginine-enriched diets. Secondly, we investigated the metabolic pathway involved in these actions, using three metabolic inhibitors: methionine sulphoximine (an inhibitor of glutamine synthetase), S-methylthiourea (an inhibitor of inducible nitric oxide synthase) and difluoromethylornithine (an inhibitor of ornithine decarboxylase). OKG, arginine and glutamine all increased the production of reactive oxygen species (evaluated by chemiluminescence, ferricytochrome c reduction and flow cytometry). Only OKG markedly enhanced the chemotaxis index (5-fold). Inhibition of glutamine synthetase showed that glutamine production was not involved in the action of OKG. The use of S-methylthiourea and difluoromethylornithine demonstrated that OKG modulated the respiratory burst via nitric oxide (NO·) and polyamine generation. Moreover, OKG stimulated PMN migration via NO·, but arginine administration failed to reproduce this effect. These data suggest that OKG (or its metabolites) and arginine are channelled differently in PMNs. This hypothesis deserves further study.
Vascular KATP channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes
Authors: ABBINK E.J. , PICKKERS P. , VAN ROSENDAAL A. Jansen , LUTTERMAN J.A. , TACK C.J. , RUSSEL F.G.M. , SMITS P.
Published: August 2015

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (KATP) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of KATP opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to KATP channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10mgċday-1) followed by 8 weeks of treatment with acarbose (300mgċday-1), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290±58% and 561±101% respectively; P < 0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to KATP opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of KATP channel activation.
Response of tumour necrosis factor-α to delayed in vitro monocyte stimulation in patients with septic shock is related to outcome
Authors: APPOLONI Olivier , VINCENT Jean-Louis , DUCHATEAU Jean
Published: August 2015

We hypothesized that cytokine production following delayed in vitro cell stimulation (to reproduce physiological cellular status at baseline) may be related to outcome in patients with septic shock. A total of 20 patients were included in a prospective clinical study, conducted in a medico-surgical intensive care unit in a university hospital. Blood samples were obtained at the onset of septic shock; these were treated to retain the cells, but to wash out autologous plasma (containing potential inflammatory stimuli such as cytokines, bacterial products and drugs) and replace it with foetal calf serum. Each treated sample was divided into two sets of four aliquots, to be stimulated either immediately or after an overnight period of resting incubation at 37°C. The rest period was to allow recovery from potentially reversible endogenous or pharmacologically induced alterations in cellular response, in order to reproduce a near physiological state at baseline. In vitro cellular challenges used low-dose (0.2ng/ml) or high-dose (1ng/ml) CD14-dependent lipopolysaccharide and CD14-independent pokeweed mitogen to induce the production of tumour necrosis factor-α (TNF-α), and interleukins-1β and -10. Levels of TNF-α, interleukin-1β and interleukin-10 were significantly higher (P < 0.05) when cell stimulation was delayed for 16h, indicating a functional down-regulation of cells during septic shock. Moreover, TNF-α responses obtained with high-dose lipopolysaccharide were significantly greater in cells from patients who subsequently survived septic shock (n = 13; median value 1392pg/ml; range 592-2048pg/ml) than in cells from non-survivors (n = 7; median value 708 pg/ml; range 520-1344pg/ml). These observations support the existence of individual differences in the inflammatory response that could influence patient outcome following septic shock.
Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis
Authors: BÖHM Felix , AHLBORG Gunvor , PERNOW John
Published: August 2015

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ETA receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60min intra-arterial infusion of ET-1 (n = 10) significantly blunted EDV in young healthy males (33±13% compared with 271±74% increase in FBF induced by 10μg/min acetylcholine; P < 0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60min intra-arterial infusion of the selective ETA receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n = 10; 109±45% compared with 255±101% increase in FBF induced by 10μg/min acetylcholine; P < 0.01), whereas no significant change was observed in healthy age-matched controls (n = 9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ETA receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ETA-receptor-mediated mechanism.
Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine
Authors: MARKLEY Michele A. , PIERRO Agostino , EATON Simon
Published: August 2015

Glutamine has beneficial effects on enterocytes and the immune system in sepsis, but its effects on hepatic metabolism remain unknown. The aim of the present study was to determine the effects of glutamine on hepatocyte energy metabolism under conditions of neonatal endotoxaemia. Suckling Wistar rats were injected intraperitoneally with 200μg/kg lipopolysaccharide. Oxygen consumption was measured polarographically in hepatocytes respiring on either palmitate (0.5mM) or palmitate plus glutamine (10mM). Total hepatocyte oxygen consumption was similar in hepatocytes from control and endotoxic rats, but this was due to a decrease in intramitochondrial and an increase in extramitochondrial oxygen consumption in the cells from endotoxic animals. The addition of glutamine to hepatocytes from endotoxic rats restored intramitochondrial oxygen consumption to control levels. Although glutamine did not reverse the inhibition of the thermogenic proton leak observed in endotoxaemia, it significantly increased oxygen consumption due to mitochondrial ATP synthesis (P = 0.03). Glutamine significantly increased the hepatocyte ATP/ADP ratio (P = 0.02 compared with hepatocytes from endotoxic rats). Electron microscopy revealed morphological damage to the mitochondria of hepatocytes from endotoxic rats, and a return to a normal appearance with the addition of glutamine. We conclude that glutamine reverses the inhibition of mitochondrial metabolism that is observed in endotoxaemia. The effect is primarily at the level of ATP synthesis.