bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of adenosine receptor antagonists on the responses to contrast media in the isolated rat kidney
Authors: OLDROYD Simon D. , FANG Lu , HAYLOR John L. , YATES Michael S. , EL NAHAS A. Meguid , MORCOS Sameh K.
Published: August 2015

Contrast media can induce both a decrease in renal blood flow and a reduction in glomerular filtration rate (GFR) when administered to both experimental animals and humans. In the present study we have examined the role of adenosine in mediating these effects using the isolated perfused rat kidney. Kidneys were perfused with a 6.7%-(w/v)-albumin-based perfusate supplemented with glucose and amino acids (n = 6 per group). They were exposed to diatrizoate [20 mg of iodine (mgI)/ml; osmolality 1650 mOsm/kg of water] or iotrolan (20 mgI/ml; osmolality 320 mOsm/kg of water) in the presence or absence of theophylline (10.8 µg/ml), or to diatrizoate in the presence or absence of a specific adenosine A1 receptor antagonist (KW-3902; 2 µg/ml) or a specific A2 receptor antagonist (KF17837; 6 µg/ml). Diatrizoate (n = 6) produced a fall in GFR from 0.65±0.04 to 0.42±0.03 ml·min-1·g-1 (P < 0.05); renal perfusate flow (RPF) also declined, from 36.5±3.8 to 22.0±3.2 ml·min-1·g-1 (P < 0.05). Iotrolan (n = 6) produced a fall in GFR from 0.64±0.02 to 0.48±0.04 ml·min-1·g-1 (P < 0.05) and in RPF from 33.3±3.8 to 24.0±3.0 ml·min-1·g-1 (P < 0.05). Theophylline (10.8 µg/ml) prevented the fall in GFR caused by either diatrizoate (baseline, 0.63±0.05 ml·min-1·g-1; diatrizoate+theophylline, 0.60±0.04 ml·min-1·g-1) or iotrolan (basline, 0.64±0.04 ml·min-1·g-1; iotrolan+theophylline, 0.67±0.05 ml·min-1·g-1), but did not affect the decreases in RPF caused by either agent. KW-3902 (2 µg/ml) also prevented the fall in GFR produced by diatrizoate (baseline, 0.66±0.05 ml·min-1·g-1; diatrizoate+KW-3902, 0.61±0.05 ml·min-1·g-1), while the fall in RPF remained unaffected. KF17837 (6 µg/ml) had no effect on the decreases in either GFR or RPF induced by diatrizoate (n = 6 per group). The results suggest a role for adenosine acting at the A1 receptor in mediating the decrease in GFR induced by contrast media. This effect is independent of a change in renal vascular resistance, and possibly secondary to mesangial cell contraction causing a decrease in the ultrafiltration coefficient.
Does a high concentration of calcium in the urine cause an important renal concentrating defect in human subjects?
Authors: LAM George S. S. , ASPLIN John R. , HALPERIN Mitchell L.
Published: August 2015

The objective of this study was to evaluate the hypothesis that a high concentration of ionized calcium in the lumen of the medullary collecting duct causes an osmole-free water diuresis. The urine flow rate and osmolality were measured in normal human subjects, as well as in patients with a history of nephrolithiasis who excreted more than 5 mmol of calcium per 24 h. There was an inverse relationship between the concentration of calcium in the urine and the 24 h urine volume both in normal subjects and in patients with a history of nephrolithiasis. When the concentration of calcium in the urine was greater than 5 mmol/l, the urine volume was less than 1 litre per day in the majority of subjects. After 16 h of water deprivation, when the concentration of calcium in the urine was as high as 17 mmol/l (ionized calcium 7.4 mmol/l), urine osmolality was 1258 mOsm/kg of water and the urine flow rate was 0.30 ml/min. We conclude that, although a calcium receptor may be present in the lumen of the medullary collecting duct in human subjects, an extremely high concentration of urinary total and ionized calcium does not cause a clinically important defect in the renal concentrating process.
Myocardial tissue oxygen supply and utilization during coronary artery bypass surgery: evidence of microvascular no-reflow
Authors: AL-OBAIDI Mohamed K. , ETHERINGTON Philip J. , BARRON David J. , WINLOVE Peter C. , PEPPER John R.
Published: August 2015

The supply and utilization of oxygen by the myocardium reflect the dynamic efficiency of the microcirculation. The present study examines these parameters during coronary artery bypass surgery. We used a voltammetric microelectrode technique to assess regional variations in myocardial tissue partial pressure of oxygen (PO2) and myocardial tissue perfusion (MTP) in patients undergoing coronary artery bypass surgery. A total of 29 myocardial regions were studied in 17 patients to assay tissue PO2, and 13 regions in 10 patients to measure MTP. There was an increase in MTP from 53±9 ml·min-1·100 g-1 before cardiopulmonary bypass to 72±13 ml·min-1·100 g-1 after (means±S.E.M.; P = 0.05). Tissue PO2 showed an overall increase from a baseline level of 45±8 mmHg to a final level of 88±10 mmHg (P< 0.0001). Following release of the aortic cross-clamp there was a variable time delay before a change in tissue PO2 was observed. There was an immediate response in five regions, whereas in 20 regions the response was delayed by between 0.5 and 32 min. In the remaining four regions there was no change in tissue PO2. The duration of the delay in response was correlated positively with the cross-clamp time (r = 0.45, P < 0.05) and negatively with the final tissue PO2 (r =-0.5, P < 0.05). Voltammetric methods for monitoring changes in oxygen supply and utilization offer new insights into the changes that occur during ischaemia and reperfusion. A delay in the delivery of oxygen to the myocardium occurs in many patients following coronary artery bypass surgery.
Effects of pre- and post-absorptive factors on the lactulose/rhamnose gut permeability test
Authors: VAN NIEUWENHOVEN M. A. , DE SWART E. A. M. , VAN EIJK H. M. , DEUTZ N. E. P. , BROUNS F. , M. BRUMMER R.-J.
Published: August 2015

It is assumed that the outcome of the lactulose/rhamnose gut permeability test is not influenced by pre- or post-absorptive factors. The aim of our study was to investigate the role of a pre-absorptive factor, i.e. small-intestinal transit, and a post-absorptive factor, i.e. renal clearance. Ten healthy male subjects were studied. Urinary lactulose and rhamnose excretion was measured after intraduodenal administration of lactulose and rhamnose following induction of increased intestinal permeability using chenodeoxycholic acid (chenodiol), in the absence and in the presence of accelerated intestinal transit. Urinary sugar excretion was measured after intravenous administration of either a regular dose (50 mg/50 mg) or a high dose (250 mg/250 mg) of lactulose/rhamnose. The intraduodenal experiments showed that a combination of accelerated small-bowel transit and increased permeability did not lead to significant differences in the recovery of lactulose (P = 0.647) or rhamnose (P = 0.889), or in the lactulose/rhamnose ratio, compared with those under conditions of increased permeability alone (P = 0.68). However, lactulose recovery was significantly lower (P = 0.025) after intravenous administration of a high dose of the sugars. There was no significant difference in urinary rhamnose recovery (P = 0.575) between the high and the regular doses. This resulted in a significantly lower lactulose/rhamnose ratio (P = 0.021) after intravenous administration of a high dose, compared with a regular dose, of the sugars. In conclusion, the assumption that post-absorptive processes do not influence the outcome of the lactulose/rhamnose permeability test appears not to be valid.
The hyperinsulinaemic–euglycaemic glucose clamp: reproducibility and metabolic effects of prolonged insulin infusion in healthy subjects
Authors: SOOP Mattias , NYGREN Jonas , BRISMAR Kerstin , THORELL Anders , LJUNGQVIST Olle
Published: August 2015

To examine the reproducibility of the hyperinsulinaemic–euglycaemic clamp technique at mid-physiological hyperinsulinaemia, seven healthy subjects {age 50 (25, 59) years [median (range)], body mass index 23.1 (20.8, 25.5) kg·m-2} were investigated with three 2 h hyperinsulinaemic (60 µmol·l-1)–euglycaemic (4.5 mmol·l-1) clamps performed 48 h and 14 days apart respectively. The third clamp was prolonged to 8 h in order to examine effects on glucose disposal during prolonged clamps. The glucose infusion rates (GIRs) during the three 2 h clamps were 7.41 (4.28, 10.96), 7.26 (5.38, 11.02) and 6.63 (4.42, 10.3) mg·kg-1·min-1, with a median intra-individual coefficient of variation of 5.8 (2.6, 22) %. During the 8 h clamp a highly variable gradual increase in GIR was observed, reaching a plateau between 4 and 5 h at 32 (5, 101) % above the GIR between 1 and 2 h (P < 0.05). This increase was correlated inversely with the GIR between 1 and 2 h (r = -0.82; P < 0.05), and directly with age (r = 0.86; P < 0.05). Carbohydrate oxidation measured by indirect calorimetry was stable during the repeated 2 h clamps and the 8 h clamp. Endogenous glucose production measured by infusion of [6,6-2H2]glucose was suppressed during the 8 h clamp. The 2 h hyperinsulinaemic–euglycaemic clamp is reproducible at a mid-physiological range of hyperinsulinaemia. If prolonged, it results in a delayed increase in non-oxidative glucose disposal, which is most pronounced in subjects with low insulin sensitivity. The findings underline the importance of selecting age-matched controls in studies of insulin resistance.
Ethanol effects on cardiomyocyte contractility
Authors: DELBRIDGE Leanne M. D. , CONNELL Pamela J. , HARRIS Peter J. , MORGAN Trefor O.
Published: August 2015

Little is known about the direct cardiac effects of socially common sub-intoxication levels of ethanol. Previous studies evaluating the responses of normal cardiomyocytes to short-term ethanol exposure have utilized ethanol concentrations equivalent to extreme intoxication or lethal levels in vivo. The purpose of the present study was to investigate the contractile responses of isolated rat ventricular cardiomyocytes during exposure to relatively low concentrations of ethanol in the range 0.05–0.5% (v/v) (8.6–86 mM) under physiological conditions (3 Hz stimulation; 36 °C; BSA vehicle). High-speed imaging techniques were used to study the kinetics of myocyte contraction, and shortening parameters were calculated for mechanistic evaluation. The concentration–response relationship was not linear and exhibited two plateau phases, suggesting at least two mechanisms of action of ethanol on cardiomyocyte contraction. At 0.05% (8.6 mM), ethanol treatment produced a 14.4% decrease in maximum myocyte shortening. The maximum rates of cell shortening and lengthening were similarly impaired, but there was no effect on contraction cycle timing at this low concentration. At 0.30% (51 mM), ethanol reduced maximum shortening by 40.2%, prolonged excitation–contraction coupling latency and abbreviated the contraction cycle time by 38%. The inotropic modulatory effect of ethanol was exaggerated in the absence of protein in the superfusion buffer. This is the first report which identifies ethanol at 0.05% (v/v) as a modulator of cardiac contractility. Kinetic analyses indicate that the mechanism of action involves disturbance of sarcoplasmic reticulum function, and this may contribute to arrhythmogenic vulnerability – especially in an in vivo context of heightened compensatory sympathetic drive.
α2-Macroglobulin, the main serum antiprotease, binds β2-microglobulin, the light chain of the class I major histocompatibility complex, which is involved in human disease
Authors: GOUIN-CHARNET Annie , LAUNE Daniel , GRANIER Claude , MANI Jean-Claude , PAU Bernard , MOURAD Georges , ARGILÉS Àngel
Published: August 2015

β2-Microglobulin, a 12 kDa protein forming part of the class I HLA (histocompatibility locus antigen) major histocompatibility complex, has been used as a prognosis factor for multiple myeloma and as a marker of renal function, and has been shown to be involved in the pathogenesis of dialysis-related amyloidosis. α2-Macroglobulin has the ability to bind a wide range of physiologically important molecules, thereby influencing their metabolic impact. In this study we show by Western blotting analysis that β2-microglobulin binds to α2-macroglobulin in vitro. This binding was confirmed by BIAcore analysis, and was shown by ELISA to be concentration-dependent. The sequences of the binding peptides in the mature β2-microglobulin molecule were identified by Spot multiple peptide synthesis and α2-macroglobulin binding studies. In conclusion, β2-microglobulin interacts specifically with the universal antiprotease a2-macroglobulin. The identification of this interaction brings into question some of the axioms on the metabolism of β2-microglobulin, and may help to explain the clinical findings observed in b2-microglobulin-related diseases.
Vitamin C modifies the cardiovascular and microvascular responses to cigarette smoke inhalation in man
Authors: GAMBLE J. , GREWAL P. S. , GARTSIDE I. B.
Published: August 2015

Both neutrophil margination and increases in the non-invasively assessed parameter, isovolumetric venous congestion cuff pressure (Pvi), are symptomatic of some inflammatory diseases. Neutrophil margination occurs primarily, though not exclusively, at the post-capillary endothelial surface. The local haemodynamic changes resulting from margination may be responsible for the observed increases in Pvi. Smoke inhalation has been shown in animal studies to cause an increase in post-capillary neutrophil margination by mechanisms that can be blocked by oral vitamin C administration. We looked for indices of a relationship between margination and Pvi in man, using cigarette smoke inhalation as a pathophysiological challenge. We also examined the effect of prophylactic vitamin C on the response. Smoke inhalation was associated with highly significant increases in both Pvi and heart rate. After vitamin C pre-treatment, no increase in Pvi was observed in response to the smoke inhalation; however, whilst heart rate still increased significantly, the duration of this response was attenuated. The results suggest that vitamin C affords protection against some of the cardiovascular and microvascular changes associated with cigarette smoke inhalation in man. They also support the notion that non-invasive assessment of changes in Pvi may provide a measurable index of systemic changes in inflammatory conditions.
Comparative physiological study of arbutamine with exercise in humans
Authors: LOVELL Sharon L. , MAGUIRE Suzanne M. , TURTLE Frances , McDOWELL Garry , CAMPBELL Norman P. S. , RILEY Marshall S. , NICHOLLS D. Paul
Published: August 2015

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols.The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO2 [35.1 (S.D. 3.1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (VD/VT) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml·min-1·beat-1; exercise, 4.7 (1.4) to 16.1 (4.6) ml·min-1·beat-1 (P < 0.0001 compared with baseline); difference between peak responses: P < 0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.
Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease
Authors: CLELAND Stephen J. , SATTAR Naveed , PETRIE John R. , FOROUHI Nita G. , ELLIOTT Henry L. , CONNELL John M. C.
Published: August 2015

Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Endothelial cell activation is an early event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentration. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in nine healthy subjects (mean age 53±8.1 years; body mass index 27±3.2 kg/m2; mean arterial blood pressure 101±9.0 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of NG-monomethyl-l-arginine (l-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with (i) the percentage decrease in forearm blood flow (FBF) during l-NMMA infusion (r = 0.85, P = 0.004); and (ii) the serum leptin concentration (r = 0.65, P = 0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to l-NMMA remained significant when age and leptin (t = 2.65, P = 0.045), age and BMI (t = 3.69, P = 0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol (t = 3.37, P = 0.044), were included in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.
A new treatment for unresectable liver tumours: long-term studies of electrolytic lesions in the pig liver
Authors: WEMYSS-HOLDEN Simon A. , ROBERTSON Gavin S. M. , DENNISON Ashley R. , VANDERZON Paula S. , M. HALL Pauline de la , MADDERN Guy J.
Published: August 2015

The majority of liver tumours are inoperable and an alternative treatment to surgical resection is urgently needed. Electrolysis has been investigated in a rat model and the procedure is safe, with accurate and predictable effects. The necrosis produced has also been shown to cause destruction of tumour deposits in the rat liver. A similar evaluation in a large animal model was necessary before clinical trials could commence. Using platinum electrodes connected to a d.c. generator, areas of hepatic necrosis were created in the pig liver. Animals were killed at various time points after treatment to assess the extent of healing. Treatment was uneventful and all animals made a full recovery. No animal died from the treatment or had to be killed prematurely. After 2 days of treatment, healing was minimal but at successive time points there was progressive evidence of healing, such that after 4 months, the original electrolytic lesion was greatly reduced in size and the large area of necrosis seen at the early time points was largely replaced by a fibrous scar with only small islands of necrotic tissue. In a large animal model, electrolysis is a safe method for creating areas of hepatic necrosis. The lesions heal with time and are associated with minimal morbidity. The results support a trial of electrolysis in patients with unresectable liver tumours.
Muscle function during fatigue in myoadenylate deaminase-deficient Dutch subjects
Authors: DE RUITER C. J. , VAN ENGELEN B. G. M. , WEVERS R. A. , DE HAAN A.
Published: August 2015

Myoadenylate deaminase (MAD) is an enzyme active in skeletal muscle, probably during exercise of moderate intensity but certainly during vigorous exercise, when the deamination of AMP leads to increased levels of IMP and ammonia. There is controversy about the clinical significance of MAD deficiency. The main objective of the present study was to investigate the extent to which genetically confirmed MAD deficiency affects muscle function under conditions of maximal short-term electrically induced activation. The left hand was immobilized and adductor pollicis muscle function was investigated. To exclude the influence of central factors, such as the patient's motivation, the ulnar nerve was maximally electrically activated and force output was measured at the thumb. Sixty rapid shortening contractions resulted in a decrease of maximal power to 34.2±5.4% and 33.3±6.3% (means±S.D.) of the values for unfatigued muscle in the control and MAD-deficient subjects respectively (P > 0.05; n = 7). Maximal isometric forces and shortening velocities did not differ between groups in unfatigued, fatigued or recovered muscle. None of the subjects experienced exercise-related muscle aches or cramps. In conclusion, MAD deficiency does not appear to affect adductor pollicis muscle force, shortening velocity and relaxation, either during or after maximal short-term activation.
The increase in sympathetic nerve activity after glucose ingestion is reduced in type I diabetes
Authors: FAGIUS Jan , BERNE Christian
Published: August 2015

Food intake is followed by an increase in baroreflex-governed sympathetic outflow to muscle vessels. It is established that insulin contributes to this stimulation; however, the increase occurs (to a lesser degree) even in the absence of enhanced insulin secretion. To further elucidate the role of insulin, muscle nerve sympathetic activity was recorded by microneurography, and the increase after an oral 100-g glucose load in eight C-peptide-negative patients with type I diabetes without any signs of neuropathy was compared with that in 16 healthy control subjects. The level of sympathetic activity at rest was similar in the two groups (type I diabetes patients, 19.5±2.4 bursts/min; controls, 20.4±4.8 bursts/min; means±S.D.). Following glucose intake there was a significant increase in activity in both groups, with maximum values at 30 min of 24.3±3.7 bursts/min for type I diabetes patients and 34.4±9.1 bursts/min for controls. The summarized response (during 90 min) of the diabetic patients was less than half that of the control subjects (P = 0.0003). It is concluded that the response of muscle nerve sympathetic activity to glucose ingestion is reduced to about half of its normal strength in the absence of insulin, and that there is no difference in sympathetic outflow at rest between healthy subjects and diabetic patients without polyneuropathy.
Alveolar–capillary membrane dysfunction in chronic heart failure: pathophysiology and therapeutic implications
Authors: GUAZZI Marco
Published: August 2015

Chronic heart failure (CHF) disturbs the alveolar–capillary interface and increases the resistance to gas transfer. Alveolar–capillary membrane conductance (DM) and capillary blood volume (Vc) are subcomponents of the lung diffusion capacity. Elevation of the capillary pressure causes alveolar–capillary membrane stress failure (i.e. increase in capillary permeability to water and ions, and disruption of local regulatory mechanisms for gas exchange), leading to a decrease in DM, an increase in Vc and subsequent impairment of diffusion capacity. Renewed recent interest in abnormalities in lung diffusion in patients with CHF has brought about new pathophysiological insights. A significant contribution of the altered gas transfer to the pathogenesis of exercise limitation and ventilatory abnormalities has been reported, and DM has been identified as the best lung function predictor of oxygen uptake at peak exercise. This review examines the pathophysiological and clinical significance of assessing lung diffusion capacity in patients with CHF.
Fatigue in chronic disease
Authors: SWAIN Mark G.
Published: August 2015

Fatigue is an extremely common complaint among patients with chronic disease. However, because of the subjective nature of fatigue, and the lack of effective therapeutics with which to treat fatigue, this symptom is often ignored by clinicians, who instead focus on hard, objective disease end-points. Recently, the symptom of fatigue has received greater attention as part of overall health-related quality of life assessments in patients with chronic disease. Furthermore, new methods are being developed to help quantify fatigue, and are being utilized more frequently in the clinical setting. Moreover, studies in patients and using animal models of disease have provided some insight into changes within the brain which appear to be linked to the genesis of central fatigue. This review focuses on fatigue in chronic disease and outlines possible mechanisms which may give rise to central fatigue in chronic disease. Moreover, methods for measuring fatigue and an approach to the fatigued patient are discussed. Hopefully, a broader understanding of this distressing symptom will lead to the development of specific therapies for treating fatigue in these patients.
Molecular basis of human natural killer cell recognition of HLA-E (human leucocyte antigen-E) and its relevance to clearance of pathogen-infected and tumour cells
Authors: O'CALLAGHAN Christopher A.
Published: August 2015

HLA-E (human leucocyte antigen-E) is a conserved class I major histocompatibility molecule which has only limited polymorphism. It binds to the leader peptide derived from the polymorphic classical major histocompatibility molecules HLA-A, HLA-B and HLA-C. This peptide binding is highly specific and stabilizes the HLA-E protein, allowing it to migrate to the cell surface. A functioning TAP (transporter associated with antigen processing) molecule is required to transport these peptides into the endoplasmic reticulum, where they can interact with HLA-E. HLA-E then migrates to the cell surface, where it interacts with CD94/NKG2A receptors on natural killer cells. This interaction inhibits natural killer cell-mediated lysis of a cell displaying HLA-E. If the leader peptide is not present in the endoplasmic reticulum, HLA-E is unstable and is degraded before it reaches the cell surface. In damaged cells, such as virally infected or tumour cells, down-regulation of HLA-A, HLA-B and HLA-C production or inhibition of TAP prevents stabilization of HLA-E by the leader peptide. Under these circumstances, HLA-E does not reach the cell surface and the cell is then vulnerable to lysis by natural killer cells. The molecular mechanisms underlying this function of HLA-E have been revealed by crystallographic studies of the structure of HLA-E.
First clinical trial with etomoxir in patients with chronic congestive heart failure
Authors: SCHMIDT-SCHWEDA Stephan , HOLUBARSCH Christian
Published: August 2015

In the failing human myocardium, both impaired calcium homoeostasis and alterations in the levels of contractile proteins have been observed, which may be responsible for reduced contractility as well as diastolic dysfunction. In addition, levels of a key protein in calcium cycling, i.e. the sarcoplasmic reticulum Ca2+-ATPase, and of the α-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltransferase inhibitor, in normal and pressure-overloaded rat myocardium. We therefore studied, for the first time, the influence of long-term oral application of etomoxir on cardiac function in patients with chronic heart failure. A dose of 80 mg of etomoxir was given once daily to 10 patients suffering from heart failure (NYHA functional class II–III; mean age 55±4 years; one patient with ischaemic heart disease and nine patients with dilated idiopathic cardiomyopathy; all male), in addition to standard therapy. The left ventricular ejection fraction was measured echocardiographically before and after a 3-month period of treatment. Central haemodynamics at rest and exercise (supine position bicycle) were defined by means of a pulmonary artery catheter and thermodilution. All 10 patients improved clinically; no patient had to stop taking the study medication because of side effects; and no patient died during the 3-month period. Maximum cardiac output during exercise increased from 9.72±1.25 l/min before to 13.44±1.50 l/min after treatment (P < 0.01); this increase was mainly due to an increased stroke volume [84±7 ml before and 109±9 ml after treatment (P < 0.01)]. Resting heart rate was slightly reduced (not statistically significant). During exercise, for any given heart rate, stroke volume was significantly enhanced (P < 0.05). The left ventricular ejection fraction increased significantly from 21.5±2.6% to 27.0±2.3% (P < 0.01). In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties. Thus, although the results of this small pilot study are not placebo-controlled, all patients seem to have benefitted from etomoxir treatment. Etomoxir, which has no acute inotropic or vasodilatory properties and is thought to increase gene expression of the sarcoplasmic reticulum Ca2+-ATPase and the α-myosin heavy chain, improved clinical status, central haemodynamics at rest and during exercise, and left ventricular ejection fraction.
Very-low-frequency oscillations in heart rate and blood pressure in periodic breathing: role of the cardiovascular limb of the hypoxic chemoreflex
Authors: FRANCIS Darrel P. , DAVIES L. Ceri , WILLSON Keith , PONIKOWSKI Piotr , COATS Andrew J. S. , PIEPOLI Massimo
Published: August 2015

In chronic heart failure, very-low-frequency (VLF) oscillations (0.01–0.04 Hz) in heart rate and blood pressure may be related to periodic breathing, although the mechanism has not been fully characterized. Groups of ten patients with chronic heart failure and ten healthy controls performed voluntary periodic breathing with computer guidance, while ventilation, oxygen saturation, non-invasive blood pressure and RR interval were measured. In air, voluntary periodic breathing induced periodic desaturation and prominent VLF oscillations when compared with free breathing in both patients [RR interval spectral power from 179 to 358 ms2 (P < 0.05); systolic blood pressure (SBP) spectral power from 3.44 to 6.25 mmHg2 (P < 0.05)] and controls [RR spectral power from 1040 to 2307 ms2 (P < 0.05); SBP spectral power from 3.40 to 9.38 mmHg2 (P < 0.05)]. The peak in RR interval occurred 16–26 s before that in SBP, an anti-baroreflex pattern. When the patients followed an identical breathing pattern in hyperoxic conditions to prevent desaturation, the VLF RR interval spectral power was 50% lower (179.0±51.7 ms2; P < 0.01) and the VLF SBP spectral power was 44% lower (3.51±0.77 mmHg2; P < 0.01); similar effects were seen in controls (VLF RR power 20% lower, at 1847±899 ms2, P < 0.05; VLF SBP power 61% lower, at 3.68±0.92 mmHg2, P = 0.01). Low- and high-frequency spectral powers were not significantly affected. Thus periodic breathing causes oxygen-sensitive (and by implication chemoreflex-related) anti-baroreflex VLF oscillations in RR interval and blood pressure in both patients with chronic heart failure and normal controls.
Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae
Authors: OPGAARD Ole SAETRUM , MÖLLER Sebastian , DE VRIES René , EDVINSSON Lars , SAXENA Pramod R.
Published: August 2015

The aim of the present study was to determine possible inotropic effects mediated by endothelin ETA and ETB receptors in human myocardial trabeculae from the right atrium and the left ventricle. Isolated trabeculae from human hearts were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 (ET-1) and ET-3 had a strong positive inotropic effect in all trabeculae. ET-1 was significantly more potent than ET-3 in both atrial (P < 0.001) and ventricular (P < 0.05) trabeculae. Preincubation with the ETA receptor antagonist FR139317 (1 μM) decreased significantly (P < 0.005) the potency of ET-1 in both atrial and ventricular trabeculae, without any significant changes in Emax (maximum effect obtained with an agonist). The ETB receptor agonist IRL 1620 had a positive inotropic effect only in some trabeculae, and the ETB receptor antagonist BQ 788 (1 μM) almost completely blocked this effect. These results suggest that both ETA and ETB receptors mediate positive inotropic responses at both the atrial and ventricular level in the human heart.
Vasoconstriction to endogenous endothelin-1 is impaired in patients with Type II diabetes mellitus
Authors: MCAULEY Daniel F. , NUGENT Ailish G. , MCGURK Colm , MAGUIRE Suzanne , HAYES J. Randal , JOHNSTON G. Dennis
Published: August 2015

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P < 0.001). Diabetic subjects, however, showed no significant response (P > 0.05). There was a significant difference between the diabetic and control groups (P < 0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.
Inhibition of muscle glutamine formation in hypercatabolic patients
Authors: BIOLO Gianni , FLEMING R. Y. Declan , MAGGI Sergio P. , NGUYEN Thuan T. , HERNDON David N. , WOLFE Robert R.
Published: August 2015

Glutamine is synthesized primarily in skeletal muscle, and enables transfer of nitrogen to the liver, as well as serving other functions. There is increasing evidence for beneficial clinical effects of glutamine supplementation in critically ill patients. However, the response of endogenous glutamine formation to severe stress is poorly understood. The rates of net protein balance, leucine oxidative decarboxylation, and alanine and glutamine synthesis de novo were determined in leg skeletal muscle of 20 severely burned patients and 19 normal controls in the post-absorptive state. Patients were studied at 14±5 days post-burn, and their mean burn size was 66±18% of total body surface area. Methods were based on the leg arteriovenous balance technique in combination with biopsies of the vastus lateralis muscle. In the post-absorptive state, patients with severe burns, as compared with healthy control subjects, exhibited accelerated muscle loss (+150%) (i.e. proteolysis minus synthesis) and leucine oxidative decarboxylation (+117%), and depletion of the intramuscular free glutamine pool (-63%). The average rate of glutamine synthesis de novo was decreased by 48%, whereas net alanine synthesis de novo was increased by 174%, in skeletal muscle of burned patients. In conclusion, in severely hypercatabolic burned patients, muscle glutamine formation was suppressed, whereas alanine was the major vehicle for inter-organ nitrogen transport. These changes account for a decreased glutamine availability during prolonged severe stress.
Renal synthesis of dopamine in asymptomatic post-infarction left ventricular systolic dysfunction
Authors: FERREIRA António , BETTENCOURT Paulo , PESTANA Manuel , OLIVEIRA Nuno , SERRÃO Paula , MACIEL Maria Júlia , CERQUEIRA-GOMES Mário , SOARES-DA-SILVA Patrício
Published: August 2015

Left ventricular systolic dysfunction (LVSD) following acute myocardial infarction (AMI), by decreasing renal blood flow, may interfere with renal L-DOPA availability and, consequently, dopamine synthesis. Dopamine of renal origin exerts local natriuretic effects. We studied 17 post-AMI patients with asymptomatic LVSD (ejection fraction < 40%) and 14 without (ejection fraction ⩾ 40%), measuring 24-h urinary excretions of L-DOPA, dopamine and its metabolites, and plasma levels of the amines, amine derivatives and type-B natriuretic peptide (BNP). Baseline characteristics were well balanced between the two groups. No differences were observed in urinary volume and sodium and creatinine excretions. The group with asymptomatic LVSD presented lower urinary excretion of L-DOPA (66.8±10.1 versus 115.3±21.9 nmolċday-1, P = 0.04), whereas plasma levels of L-DOPA were identical in both groups. Urinary dopamine was similar in the two groups (1124.2±172.4 versus 1049.0±146.4 nmolċday-1, P = 0.86), resulting in higher urinary dopamine/L-DOPA ratios in patients with asymptomatic LVSD (20.4±3.0 versus 9.9±0.8, P < 0.001). Plasma levels of BNP were higher in the asymptomatic LVSD group (348.5±47.3 versus 146.8±21.9 pgċml-1, P = 0.003). Ejection fraction was negatively correlated with both plasma levels of BNP and urinary dopamine/L-DOPA ratios. Renal dopamine production is well preserved in patients with asymptomatic LVSD and increased neurohumoral activation, despite reduced urinary excretion of its precursor. This suggests that renal uptake and/or decarboxylation of L-DOPA is enhanced in this condition, as a compensatory mechanism, contributing to preservation of urinary sodium excretion.
Vasoactive intestinal peptide down-regulates the intrahepatic renin–angiotensin system in the anaesthetized rat
Authors: YE V. Z. C. , DUGGAN K. A.
Published: August 2015

Gastric sodium loading results in an increase in the portal venous concentration of vasoactive intestinal peptide (VIP) and down-regulation of both the intrahepatic and circulating renin–angiotensin systems. In the present study we sought to determine whether an increase in the concentration of VIP in the portal circulation might act to down-regulate the intrahepatic and/or circulating renin–angiotensin systems. Male Sprague–Dawley rats were infused intraportally with haemaccel vehicle or VIP in haemaccel for 60 min. Livers were harvested and blood was sampled. Angiotensin-converting enzyme (ACE) activity and angiotensinogen, angiotensin I, angiotensin II and renin concentrations were measured. VIP infusion decreased hepatic ACE activity (P < 0.05), the hepatic angiotensinogen concentration (P < 0.001) and the hepatic angiotensin I concentration (P < 0.05). The plasma angiotensinogen concentration and serum ACE activity were also decreased by intraportal VIP infusion (P < 0.05 for each). Plasma renin, angiotensin I and angiotensin II concentrations were unchanged by VIP infusion. We conclude that an increase in the portal venous VIP concentration down-regulates the intrahepatic renin–angiotensin system. These changes are similar to those reported after gastric sodium loading, and we suggest, therefore, that the increase in portal venous VIP that occurs after gastric sodium is the means by which the gastric sodium sensor signals the liver to effect these changes in the renin–angiotensin system.
The gain-of-function G389R variant of the β1-adrenoceptor does not influence blood pressure or heart rate response to β-blockade in hypertensive subjects
Authors: O'SHAUGHNESSY Kevin M. , FU Beiyuan , DICKERSON Claire , THURSTON Denise , BROWN Morris J.
Published: August 2015

Mutation scanning of the β1-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to β-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a β1-selective β-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1±3.5/13.9±2.7 mmHg (systolic/diastolic blood pressure), 18.4±2.2 beats/min; GR, 20.0±2.2/15.0±1.3 mmHg, 16.5±1.5 beats/min; RR, 20.8±2.3/13.4±1.1 mmHg, 16.0±1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0±4.3/11.2±3.4 mmHg, 12.0±3.5 beats/min; GR, 16.6±1.8/14.4±1.1 mmHg, 13.1±2.1 beats/min; RR, 18.0±1.6/13.0±1.4 mmHg, 14.4±1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic β1-adrenoceptor blockade.
Occlusion cuff position is an important determinant of the time course and magnitude of human brachial artery flow-mediated dilation
Authors: BERRY Karen L. , SKYRME-JONES R. Andrew P. , MEREDITH Ian T.
Published: August 2015

Non-invasive ultrasound techniques to assess flow-mediated vasodilation (FMD) are frequently used to assess arterial endothelial vasodilator function. However, the range of normal values varies considerably, possibly due to differences in methodological factors. We sought to determine the effect of occlusion cuff position on the time course and magnitude of brachial artery blood flow and flow-mediated dilation. Twelve healthy subjects underwent measurements of forearm blood flow using venous occlusion plethysmography (VOP) before and after 5 min of susprasystolic cuff inflation, using two randomly assigned occlusion cuff positions (upper arm and forearm). An additional 16 subjects underwent two brachial ultrasound studies, using the two cuff positions, to assess the extent and time course of changes in brachial artery diameter and blood flow. Maximum increase in blood flow (peak reactive hyperaemia), measured by VOP, occurred immediately upon each cuff deflation, but was greater after upper arm compared with forearm arterial occlusion (33.1±3.1 versus 22.8±2.2 ml/min per forearm tissue, P = 0.001). Maximal brachial artery FMD was significantly greater following upper arm occlusion (9.0±1.2%, mean±S.E.M.) compared with forearm occlusion (5.9±0.7%, P = 0.01). The time course of the change in brachial artery diameter was affected differently in response to each protocol. The time to peak dilation following upper arm occlusion was delayed by 22 s compared with forearm occlusion. Occlusion cuff position is thus a powerful determinant of peak reactive hyperaemia, volume repaid and the extent and time course of brachial artery FMD. Positioning the cuff on the upper arm produces a greater FMD. These results highlight the need for comparisons between FMD studies to be made with care.
Effects of balloon mitral valvuloplasty on systemic and regional left atrial levels of prothrombin fragment 1+2 in mitral stenosis
Authors: PEVERILL Roger E. , HARPER Richard W. , GAN T. Eng , SMOLICH Joseph J.
Published: August 2015

A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n = 22) and those with increased (group 2; n = 15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P < 0.005) and left atrial (P < 0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial–venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P < 0.005); however, in contrast with group 1, the left atrial level decreased (P < 0.03) and as a result the left-atrial–venous difference fell (P < 0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial–venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.
Insulin sensitivity of glucose and fat metabolism in severe sepsis
Authors: CHAMBRIER Cécile , LAVILLE Martine , BERRADA Khalid RHZIOUAL , ODEON Michelle , BOULÉTREAU Paul , BEYLOT Michel
Published: August 2015

In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit. The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-unitsċmin-1ċkg-1) were measured using the isoglycaemic clamp technique. Total glucose turnover was determined with D-[6,6-2H2]glucose. In each group, plasma glucose was maintained at basal levels (control subjects, 4.32±0.22 mmolċl-1; patients with sepsis, 7.10±2.29 mmolċl-1; P < 0.05). Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unitċmin-1ċkg-1 for controls and 0.5 m-unitċmin-1ċkg-1 for patients with sepsis, but differed following infusion at 2 m-unitċmin-1ċkg-1 (control subjects, 102±13.4 m-unitsċl-1; patients with sepsis, 124.8±19.7 m-unitsċl-1; P < 0.05). Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unitċmin-1ċkg-1), but was only suppressed during infusion at 1 m-unitċmin-1ċkg-1 insulin in patients with sepsis. The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis. Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis. In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis. Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study. Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects.