bluuebunny/crossref_metadata_2025 huggingface dataset:
Catamenial Variations in Erythrocyte Sodium–Lithium Countertransport and Blood Pressure
Authors: Adebayo G. I. , Hemeryck L. , Hall M. , Gasparro D. , Sinnott M. , Feely J.
Published: August 2015

1. We undertook a temporal study of external sodium-stimulated lithium efflux (sodium—lithium countertransport) in erythrocytes and blood pressure by measuring these two parameters in three phases of the menstrual cycle (menstrual, midcycle and luteal phases) in 22 healthy, non-medicated females with regular menstrual cycles. Plasma oestradiol and progesterone levels were also determined.

2. Sodium—lithium countertransport activity (activity in 140 mmol/1 external NaCl) in the midcycle phase (0.176 ± 0.017 mmol h−1 l−1 of cells) was lower than in the menstrual (0.192 ± 0.016 mmol h−1 l−1 of cells, P < 0.030) and luteal (0.203 ± 0.018 mmol h−1 l−1 of cells, P < 0.030) phases. The Vmax of the transporter changed similarly but the Km was unaltered.

3. The plasma oestradiol level was 628.9 ± 39.1 pmol/1 in the midcycle phase, higher than in the menstrual (232 ± 18.5 pmol/1, P < 0.001) and luteal (372.5 ± 28.1 pmol/1, P < 0.001) phases. The progesterone level was 28.6 ± 2.1 nmol/1 in the luteal phase, and values were lower in the menstrual (2.5 ± 0.3 nmol/1, P < 0.001) and midcycle (2.8 ± 0.4 nmol/1, P < 0.001) phases.

4. There was no correlation between plasma oestradiol and sodium—lithium countertransport activity or Vmax during the menstrual cycle, but plasma progesterone was positively correlated with sodium—lithium countertransport activity (r = 0.478, P < 0.025, n = 22) and Vmax (r = 0.551, P < 0.045, n = 14) in the luteal phase.

5. Systolic blood pressure did not change significantly during the menstrual cycle. However, the diastolic pressure showed variation similar to that in sodium—lithium countertransport activity/Vmax, its midcycle value of 66.6 ± 1.4 mmHg being lower than that in the luteal (71.6 ± 1.3 mmHg, P < 0.025) and menstrual (70.6 ± 1.4 mmHg, P < 0.025) phases.

6. We conclude that sodium—lithium countertransport activity exhibits catamenial variation. Therefore we suggest, given this observation, that blood sampling for the assessment of the state of activity of the transport system be standardized in relation to a phase of the menstrual cycle in future studies involving females.
Protein Degradation during Renal Passage in Normal Kidneys is Inhibited in Experimental Albuminuria
Authors: Osicka Tanya M. , Comper Wayne D.
Published: August 2015

1. Tritium labelled proteins, namely bovine serum albumin ([3H]BSA), rat serum albumin ([3H]RSA), anionic horseradish peroxidase ([3H]aHRP) and immunoglobulin present in urine fractions from rat filtration studies in vivo and isolated perfused rat kidneys (IPKs) have been shown by gel chromatographic analysis to be severely degraded to small peptides. The degradation of RSA and BSA in vivo has been shown to be similar.

2. Degradation of proteins in the urine from IPK experiments was inhibited by including 150 mmol/l lysine in the perfusate. Similarly, [3H]BSA and [3H]aHRP excreted from rats with puromycin aminonucleoside nephrosis was again essentially intact for both IPK and in vivo experiments.

3. It appears that the degradation of proteins observed in urine obtained from control kidneys is due, in part, to proteolytic activity associated with the proximal tubule. Inhibition of proximal tubule function, which occurs for both lysine and puromycin aminonucleoside treatments (as calibrated by lysozyme uptake), results in inhibition of the degradation observed. Glomerular epithelial cells could also contribute to the degradation.

4. There was no generation of low-molecular-weight material in the perfusate or plasma arising from breakdown of circulating proteins or recycling of potential degradation products from the tubules.
Hepatic Preservation with Histidine—Tryptophan—Ketoglutarate Solution in Living-Related and Cadaveric Liver Transplantation
Authors: Hatano Etsuro , Kiuchi Tetsuya , Tanaka Akira , Shinohara Hisashi , Kitai Toshiyuki , Satoh Seiji , Inomoto Takuya , Egawa Hiroto , Uemoto Shinji , Inomata Yukihiro , Lang Hauke , Oldhafer Karl J , Ringe Bruckhardt , Pichlmayr Rudolf , Tanaka Koichi , Yamaoka Yoshio
Published: August 2015

1. Living-related liver transplantation has some advantages in the evaluation of novel clinical protocols, since many complicated factors affecting initial graft function are almost uniform in grafts obtained from healthy donors.

2. To compare histidine—tryptophan—ketoglutarate (HTK) and University of Wisconsin (UW) solution in terms of tissue oxygenation in living-related liver transplantation, oxygen saturation of haemoglobin (SO2) in hepatic tissue and its heterogeneity (CV, coefficient of variation) were measured by near-infrared spectroscopy. The HTK and UW groups consisted of 15 and 49 successful transplants respectively, in which no statistical differences in background were observed.

3. In the HTK group, hepatic SO2 after portal vein reflow was higher (P<0.01) than that in the UW group, as was that after hepatic artery reflow (P<0.05). In the UW group, hepatic SO2 remained at the lower level at the end of the operation.

4. Furthermore, the increase in CV after portal vein reflow was normalized after hepatic artery reflow in the HTK group. However, the CV remained at a high level at the end of the operation in the UW group.

5. Postoperative peak aspartate aminotransferase level in the HTK group was lower than that in the UW group (P<0.05).

6. In cadaveric liver transplantation, higher hepatic SO2 and lower CV of hepatic SO2 in the early phase after reperfusion compared with the UW group (n = 18) were also observed in the HTK group (n = 30) (P<0.05).

7. In conclusion, recovery of tissue oxygenation and its heterogeneity after reperfusion in HTK-preserved livers were more rapid and homogeneous than in UW-preserved livers in living-related liver transplantation. Accordingly, HTK solution may be a potential alternative to UW solution.
A Simple Versatile Method for Measuring Tail Cuff Systolic Blood Pressure in Conscious Rats
Authors: Widdop Robert E. , Li Xiao C.
Published: August 2015

1. The non-invasive measurement of tail cuff systolic blood pressure in conscious rats is routinely used in long-term cardiovascular studies. There are a number of commercially available tail cuff systems, however, these apparatus are generally expensive and are dedicated for single-task operations. In the present study, a simple method for measuring systolic blood pressure, which requires only minor modifications to the existing hardware found in most cardiovascular laboratories, is described.

2. Systolic blood pressure measurements were made in the conventional manner by determining the systolic blood pressure which coincided with the restoration of the caudal artery pulse. This was achieved by using an inexpensive piezo-electric pulse transducer to detect the pulse, and this was coupled to a standard data-aquisition system (MacLab®, ADInstruments) normally set up to record blood pressure. This method was compared with another established tail cuff method, as well as with direct intra-arterial recordings.

3. It was found that the results obtained using both tail cuff systems were in good agreement when systolic blood pressure was measured in Wistar—Kyoto rats and spontaneously hypertensive rats. In addition, systolic blood pressure was measured over 4 weeks in 2K1C rats and sham-operated rats, with both tail cuff methods producing similar results, which were not significantly different from direct intra-arterial recordings in the same animals.

4. Thus, in the present study, with only minor modifications, the same equipment was used for both direct and indirect determinations of systolic blood pressure. This situation differs from other conventional tail cuff systems since these items are designed for a single purpose. Therefore, the current method using piezo-electric sensor/MacLab®-technology should be viewed as a relatively simple, flexible and cheap alternative method to measure tail cuff systolic blood pressure in conscious rats.
Nitric Oxide and Vascular Reactivity in Pregnant Rats with Adriamycin Nephropathy
Authors: Rathaus Mauro , Podjarny Eduardo , Benchetrit Sydney , Green Janice , Bernheim Jacques
Published: August 2015

1. In previous studies we have shown that, after the administration of adriamycin, hypertension developed in rats who became pregnant (adriamycin-pregnant rats), whereas virgin animals remained normotensive. Subsequently, we showed that this hypertension was prevented by administration of l-arginine, suggesting that deficient synthesis of nitric oxide may be pathogenetic in this model.

2. To further assess the role of nitric oxide in this model, we measured mean arterial blood pressure after administration of l-arginine to adriamycin-pregnant rats or of NG-nitro-l-arginine-methyl ester (l-NAME) to normal pregnant rats. In other experiments, we assessed the response of isolated perfused arterial mesenteric vessels, precontracted with noradrenaline, to acetylcholine, l-arginine or l-NAME.

3. Blood pressure was decreased in normal pregnant rats, whereas it was elevated in adriamycin-pregnant rats. l-NAME treatment increased blood pressure in normal pregnant rats and l-arginine decreased it in adriamycin-pregnant rats.

4. Mesenteric vessels of adriamycin-pregnant rats exibited an exaggerated vasoconstrictory response to noradrenaline, when compared with the blunted response observed in normal pregnancy. The addition of l-NAME in vitro induced a further contraction, significantly greater in normal pregnant rats. The vasodilatory response to acetylcholine and l-arginine was greater in vessels from adriamycin-pregnant rats. In contrast, responses to either nitroprusside or diazoxide were similar in all groups.

5. The results suggest a state of reduced nitric oxide synthesis in rats with adriamycin nephropathy, leading to vascular maladaption and hypertension in pregnancy.
Evidence for an R(+)-[(dihydroindenyl)oxy]alkanoic Acid-Sensitive K+/Cl− co-Transporter in Human Platelets and its Interaction with the Na+/K+/2Cl− co-transporter
Authors: de Silva H. A. , Aronson J. K.
Published: August 2015

1. The K+/Cl− co-transport system is activated by a number of interventions, such as cell swelling and stimulation with N-ethylmaleimide. It is specifically inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid and requires the presence of K+ and Cl− on the same side of the cell membrane. This co-transporter has been studied extensively, mainly in erythrocytes of many species, in which it plays a key role in cell volume regulation. Here we present evidence that human platelets contain K+/Cl− co-transporters.

2. We have studied the efflux of 86Rb+ (a marker for K+) from 86Rb+-loaded human platelets, and have defined their response to stimulation by N-ethylmaleimide.

3. N-Ethylmaleimide (0.5 and 1 mmol/l) stimulated an increase in cumulative 86Rb+ efflux in a concentration-dependent manner. This efflux was inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid (10 μmol/l) but was insensitive to bumetanide. It also required the presence of external Cl−.

4. These observations suggest that 86Rb+ efflux from the platelets stimulated by N-ethylmaleimide occurs via K+/Cl− co-transport.

5. When the K+/Cl− co-transporter was stimulated by N-ethylmaleimide we were unable to stimulate the Na+/K+/2Cl− co-transporter with a high external concentration of KCl or inhibit 86Rb+ efflux with bumetanide. Together with other evidence, this suggests that when the K+/Cl− co-transporter is stimulated with N-ethylmaleimide, the Na+/K+/2Cl− co-transporter is inhibited.
Age, Gender and Fractal Scaling in Heart Rate Variability
Authors: Otsuka Kuniaki , Cornelissen Germaine , Halberg Franz
Published: August 2015

1. The fractal scaling of heart rate variability, gauged by the correlation dimension (CD), is hypothesized to be characterized by a time structure (chronome), which in health shows differences as a function of gender and age.

2. From 24 h Holter records of 44 clinically healthy male subjects in four age groups (5–10, 20–25, 40–45 and 60–65 years; n = 11 in each group), 500 s sections at 4 h intervals for 24 h were analysed for smoothed R-R intervals sampled at 4 Hz. Using an algorithm modified from Grassberger and Procaccia (Physica D 1983; 9: 189–208), the correlation integral was estimated for embedding dimensions from 1 to 20 with a 1.0 s time lag for each section. Nightly (02.00 hours-06.00 hours) ECG records were similarly analysed in 72 additional clinically healthy subjects of both genders, 5–70 years of age. The single cosinor assessed the circadian characteristics; one- and two-way analyses of variance and linear regression were used to examine changes as a function of gender and age.

3. The 24 h average of CD is largest in the 20–25-year-old men and decreases with age thereafter (P < 0.05). These changes apply in particular to the nightly CD values, which are higher in female than in male subjects (P < 0.001). Increasing age is associated with a decrease in the amplitude and an advance in the phase of the circadian rhythm in CD (P < 0.05).

4. A chaotic end-point from fractal scaling, yielding a non-linear index, such as the correlation integral, undergoes a circadian rhythm and changes with gender and age. This assessment in the chronome represents an added diagnostic tool in cardiology, and provides new end-points for the study of coherence among internal variables of autonomic mechanisms and of influences by external environmental variables upon them.
Impaired Nitric Oxide-Mediated Vasodilatation and Total Body Nitric Oxide Production in Healthy Old Age
Authors: Lyons Declan , Roy Suzanne , Patel Mahesh , Benjamin Nigel , Swift Cameron G.
Published: August 2015

1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years.

2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA; 1, 2 and 4 μmol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to l-NMMA and noradrenaline in both groups.

3. The mean age and blood pressure of the elderly subjects was 76 (range 66–82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20–35) years and 131/72 (4/3) mmHg respectively. l-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. l-NMMA (4 μmol/min) produced less vasoconstriction in the elderly than in the young (−37.7 ± 2.6 versus −48.3 ± 4.2%; P = 0.017). The mean slope of the l-NMMA dose-response curves in the elderly was significantly less than the younger group (−35.2 ± 3.1 versus −63.7 ± 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (−22.8 ± 2.9 versus −35.3 ± 5.0%; P = 0.029) although the slopes of the dose—response curves did not differ significantly.

4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 ± 97.7 versus 205.9 ± 64.8 μmol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of l-NMMA (r = 0.5, P = 0.046).

5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.
Fractional Clearance of Albumin is Influenced by its Degradation during Renal Passage
Authors: Osicka Tanya M. , Panagiotopoulos Sianna , Jerums George , Comper Wayne D.
Published: August 2015

1. The fractional clearance of intact albumin as determined by fractionation of urine by gel chromatography gave a value of 3.9 ± 1.6 × 10−4 for the isolated perfused kidney and 2.1 ± 0.6 × 10−4in vivo using ALZET osmotic pumps.

2. Albumin fractional clearance as measured by detection of the tritium label on the albumin molecule by radioactivity analysis gave a value of 7.5 ± 3.9 × 10−3 for the isolated perfused kidney and 2.3 ± 0.9 × 10−3in vivo.

3. The major differences between assays that detect intact albumin compared with non-specific assays in the estimates of the fractional clearance of albumin can be explained by the degradation of approx. 90% of albumin to small peptides during its renal passage. This has been demonstrated by size exclusion chromatography of urine samples from experiments where (i) exogenous tritium-labelled albumin was used in isolated perfused kidneys, (ii) exogenous tritium-labelled albumin was administered intravenously and (iii) analysis was made with metabolically labelled endogenous albumin in vivo.
Bicarbonate Therapy and Intracellular Acidosis
Authors: Goldsmith D. J. A. , Forni L. G. , Hilton P. J.
Published: August 2015

1. The correction of metabolic acidosis with sodium bicarbonate remains controversial. Experiments in vitro have suggested possible deleterious effects after alkalinization of the extracellular fluid. Disequilibrium of carbon dioxide and bicarbonate across cell membranes after alkali administration, leading to the phenomenon of ‘paradoxical’ intracellular acidosis, has been held responsible for some of these adverse effects.

2. Changes in intracellular pH in suspensions of leucocytes from healthy volunteers were monitored using a fluorescent intracellular dye. The effect in vitro of increasing extracellular pH with sodium bicarbonate was studied at different sodium bicarbonate concentrations. Lactic acid and propionic acid were added to the extracellular buffer to mimic conditions of metabolic acidosis.

3. The addition of a large bolus of sodium bicarbonate caused intracellular acidification as has been observed previously. The extent of the intracellular acidosis was dependent on several factors, being most evident at higher starting intracellular pH. When sodium bicarbonate was added as a series of small boluses the reduction in intracellular pH was small. Under conditions of initial acidosis this was rapidly followed by intracellular alkalinization.

4. Although intracellular acidification occurs after addition of sodium bicarbonate to a suspension of human leucocytes in vitro, the effect is minimal when the conditions approximate those seen in clinical practice. We suggest that the observed small and transient lowering of intracellular pH is insufficient grounds in itself to abandon the use of sodium bicarbonate in human acidosis.
Plasma Oxygen during Cardiopulmonary Bypass: A Comparison of Blood Oxygen Levels with Oxygen Present in Plasma Lipid
Authors: Petyaev I. M. , Vuylsteke A. , Bethune D. W. , Hunt J. V.
Published: August 2015

1. Although not often appreciated, it is a fact that molecular oxygen is more soluble in lipids than in aqueous solution. We have recently developed a method to monitor oxygen within the lipid content of plasma. Monitoring plasma oxygen is one essential element during open heart surgery using a cardiopulmonary bypass pump and oxygenator. Currently oxygen is monitored electrochemically and is based upon monitoring the partial pressure of oxygen in a gas equilibrated with whole blood.

2. To determine the relative importance of lipid-associated oxygen in blood and assess the potential use of such a measurement we present comparisons of changes in oxygen associated with whole blood and lipid content of plasma before, during and after cardiac surgery.

3. In a limited number of patients studied (n = 28), aged between 34 and 86 years, oxygen in lipid increased with decreased extracorporeal blood temperature during cardiopulmonary bypass, increased in proportion to oxygen supplied and appeared to be a better monitor of oxygen than conventional electrochemical systems currently in use. Oxygen associated with whole blood and plasma lipid was markedly below normal on aortic declamping after cardiopulmonary bypass, suggesting an hypoxic episode at this point. Levels of oxygen in the lipid phase of plasma returned to normal presurgical values 6–8 h after surgery.

4. Calculation of the concentration of lipid-associated oxygen present in plasma suggests that plasma lipids contain up to 25% of that typically ascribed to haemoglobin. Thus, we suggest that monitoring lipid-associated oxygen may prove a better alternative to current methods of measuring oxygen status. Furthermore, we suggest that plasma lipid is a hitherto unsuspected pool of circulating oxygen which may play a significant role in tissue oxygen supply.
Plasma Levels of Adrenomedullin in Patients with Acute Myocardial Infarction
Authors: Yoshitomi Yuji , Nishikimi Toshio , Kojima Shunichi , Kuramochi Morio , Takishita Shuichi , Matsuoka Hiroaki , Miyata Atsuro , Matsuo Hisayuki , Kangawa Kenji
Published: August 2015

1. Adrenomedullin, a newly identified vasorelaxant peptide, participates in the regulation of the cardiovascular system. To investigate the pathophysiological significance of adrenomedullin in patients with acute myocardial infarction, we measured plasma levels of adrenomedullin.

2. Cardiac catheterization was performed on admission, after 1 day, and after 4 weeks in 36 patients with acute myocardial infarction. We measured plasma levels of adrenomedullin, atrial natriuretic peptide and brain natriuretic peptide in the right atrium, pulmonary artery and aorta.

3. Plasma levels of adrenomedullin in the right atrium (mean ± SEM) were significantly increased on admission (4.2 ± 2.6 h) in patients with acute myocardial infarction (10.6 ± 1.0 pmol/l) compared with controls (5.2 ± 0.3 pmol/l, P < 0.01). In addition, plasma levels of adrenomedullin were further elevated in patients with congestive heart failure (12.3 ± 1.4 pmol/l) compared with patients without congestive heart failure (7.8 ± 0.6 pmol/l, P < 0.01). In patients with congestive heart failure, plasma adrenomedullin on admission significantly correlated with atrial natriuretic peptide and brain natriuretic peptide.

4. These results suggest that plasma adrenomedullin increases in the early phase of acute myocardial infarction and that volume expansion may be one of the additional stimuli for the release of adrenomedullin in patients with acute myocardial infarction complicated by congestive heart failure.
Nitric Oxide Modulation of Coronary Artery Myogenic Tone in Spontaneously Hypertensive and Wistar—Kyoto Rats
Authors: Garcia Susana R. , Bund Stuart J.
Published: August 2015

1. The endothelium contributes substantially to the modulation of myogenic tone in coronary arteries from spontaneously hypertensive rats (SHR) and Wistar—Kyoto rats (WKY). This study has addressed the contributions of endothelium-derived nitric oxide and cyclo-oxygenase products to this modulation in small coronary arteries (approximately 200 μm internal diameter) from 20-week-old SHR and WKY under pressurized, no-flow conditions in an arteriograph.

2. Active pressure—diameter relationships were uninfluenced by the cyclo-oxygenase inhibitor indomethacin (10 μmol/l) in either rat strain. In the presence of indomethacin and the nitric oxide synthase inhibitor Nω-nitro-l-arginine (l-NNA, 0.1 mmol/l), coronary arteries from SHR and WKY generated significantly greater myogenic tone. This increase in tone was similar in both strains.

3. In endothelium-denuded arteries, indomethacin and l-NNA did not influence tone.

4. Therefore, these results demonstrate that endothelium-derived nitric oxide is basally released to attenuate SHR and WKY coronary artery myogenic tone, whereas endothelium-derived cyclo-oxygenase products have no net vasoactive influence. Additionally, these data suggest that basal nitric oxide-mediated relaxation is normal in SHR coronary arteries and is therefore unlikely to be a pathogenic mechanism in this animal model of hypertension.
Non-Invasive Investigation of Endothelium-Dependent Dilatation of the Brachial Artery in Women with Primary Raynaud's Phenomenon
Authors: Ringqvist Åsa , Jonason Tommy , Leppert Jerzy , Ringqvist Ivar
Published: August 2015

1. Primary Raynaud's phenomenon is characterized by white fingers and toes with impaired perfusion in response to cold or emotional stress. The aetiology has not been clarified. In previous studies we have demonstrated a season-linked inability in women with primary Raynaud's phenomenon to raise their plasma cGMP levels in response to whole-body cooling, suggesting a dysfunction of the l-arginine—NO—cGMP pathway. To further elucidate the possibility of such a defect in patients with primary Raynaud's phenomenon, we determined flow-mediated dilatation of the brachial artery.

2. Twenty-two premenopausal, non-smoking women with primary Raynaud's phenomenon (mean age 39 ± 8 years) and 23 healthy controls (mean age 41 ± 7 years) were studied during two winter weeks. The diameter of the right arm brachial artery was measured by high resolution ultrasonography, at rest and during reactive hyperaemia. The investigation was conducted both with the participants at rest at room temperature and after 40 min of whole-body cooling.

3. Both study groups showed a marked attenuation of flow-mediated dilatation during whole-body cooling, which could partly but not solely be explained by a decreased shear rate. There was, however, no significant difference in flow-mediated diameter (D) increase (% flow-mediated dilatation; ΔD/D × 100) between primary Raynaud's phenomenon and controls, either at room temperature (7.8 ± 0.8 and 9.0 ± 0.8) or in response to whole-body cooling (3.8 ± 1.2 and 4.4 ± 0.7).

4. Thus, whole-body cooling markedly impairs flow-mediated dilatation in women. Flow-mediated dilatation is, however, not decreased in women with primary Raynaud's phenomenon at room temperature or during whole-body cooling, indicating that this particular aspect of endothelial function is not impaired in this setting.
Mild Metabolic Alkalosis Impairs the Natriuretic Response to Bumetanide in Normal Human Subjects
Authors: Loon Nicholas R. , Wilcox Christopher S.
Published: August 2015

1. This study was designed to test the hypothesis that acid—base status affects the response to a loop diuretic in human subjects. The renal responses to bumetanide (1 mg intravenously) were studied in eight normal subjects consuming a constant diet supplemented for 3 days on three separate occasions with equivalent quantities of NaCl, NaHCO3 (metabolic alkalosis) or NH4Cl (metabolic acidosis).

2. A significant (P < 0.025) reduction in bumetanide-induced diuresis (−40%), natriuresis (−21%), and chloruresis (−25%) was observed during NaHCO3 compared with NaCl. The renal response was unaltered during NH4Cl.

3. The creatinine and para-aminohippurate clearances were unchanged during NaHCO3, as were the blood pressure and plasma levels of renin activity, aldosterone and noradrenaline, and the plasma volume.

4. Bumetanide excretion was increased during NaHCO3 compared with NaCl (2.13 ± 0.18 versus 1.76 ± 0.17 μg/min, P < 0.025) but was not changed during NH4Cl (1.68 ± 0.26 μg/min; not significant).

5. Plasma aldosterone concentration was increased 3-fold during acidosis and the kaliuretic response to bumetanide was enhanced significantly.

6. In conclusion, compared with NaCl, NaHCO3 reduces the diuretic, natriuretic and chloruretic response to bumetanide without significant changes in renal haemodynamics, plasma volume, the renin—angiotensin—aldosterone axis or the sympathetic nervous system, and despite increasing renal bumetanide excretion. NH4Cl enhances aldosterone secretion and diuretic-induced kaliuresis.
Sustained Modifications of Protein Metabolism in Various Tissues in a Rat Model of Long-Lasting Sepsis
Authors: Breuillé Denis , Arnal Maurice , Rambourdin Fabienne , Bayle Gérard , Levieux Didier , Obled Christiane
Published: August 2015

1. Sepsis was induced in rats by an intravenous injection of live bacteria. Infected and pair-fed animals were studied before the infection, in an acute septic phase (day 2 post-infection), in a chronic septic phase (day 6) and in a late septic phase (day 10). Protein synthesis rates were measured in vivo after administration of a flooding dose of l[1-13C]valine.

2. During the acute phase, muscle protein loss associated with infection resulted from both a decrease in protein synthesis and an increase in proteolysis. During the chronic phase and the late phase, the increase of proteolysis in infected rats as compared with pair-fed animals persisted, worsening muscle atrophy. Skin protein synthesis rates were not significantly modified by infection. However, skin protein content decreased 6 and 10 days after infection, suggesting an increased proteolysis in response to sepsis.

3. Protein synthesis in liver of infected rats was twice that of pair-fed animals. Liver protein synthesis remained elevated in infected rats compared with pair-fed animals until day 10. Hypoalbuminaemia and high plasma concentrations of fibrinogen were evident at all periods studied. α2-Macroglobulin and α1-acid glycoprotein reached peak concentrations during the acute phase (concentrations increased 50 times in infected rats). On day 10, the levels of these proteins were still about 12-fold higher.

4. Protein synthesis rates were significantly increased in the digestive tract and lung of infected rats compared with pair-fed groups on days 2 and 6, but were similar in the two groups on day 10 postinfection. The fractional protein synthesis rate was increased 3-fold over the entire experimental period in the spleen.

5. The results show that sepsis stimulates protein synthesis in various tissues over a long time, and that skin, like muscle, can provide amino acids to the rest of the body.
Effect of Oxidative Stress on Lymphocytes from Elderly Subjects
Authors: García-Arumí E. , Andreu A. L. , López-Hellín J. , Schwartz S.
Published: August 2015

1. Oxidative damage has been associated with ageing, but there is no agreement as to whether or not it is produced by a decrease in antioxidant defences with the ageing process. In purified lymphocytes from 47 healthy elderly (75.27 ± 0.91 years) and 47 healthy young (29.87 ± 0.53 years) volunteers, we studied the levels of antioxidant enzyme activity (superoxide dismutase, catalase and glutathione peroxidase), protein oxidative damage (as protein carbonyl content) and lysosomal proteolytic activity (cathepsins B, H and L), with and without exposure to oxidative stress produced by 25 μmol/l H2O2.

2. There were no differences in antioxidant enzyme activities in the stressed and non-stressed samples between the young and elderly subjects, indicating that there was no relationship between age and antioxidant enzyme activity even in oxidative stress. However, a dissimilar response to oxidative stress was observed in protein oxidative damage and cathepsin B and L activities, depending on the age of the donor.

3. With these results we conclude that oxidative stress produces greater protein oxidative damage and increased protein degradation in elderly subjects than in young ones; this effect cannot be attributed to dissimilar antioxidant enzyme responses to oxidative stress, since these did not differ between the two age groups.
Neutrophil Priming: Pathophysiological Consequences and Underlying Mechanisms
Authors: Condliffe A. M. , Kitchen E. , Chilvers E. R.
Published: August 2015

1. Neutrophil priming by agents such as tumour necrosis factor-α, granulocyte/macrophage colony-stimulating factor and lipopolysaccharide causes a dramatic increase in the response of these cells to an activating agent; this process has been shown to be critical for neutrophil-mediated tissue injury both in vitro and in vivo.

2. The principle consequence of priming, aside from a direct effect on cell polarization, deformability and integrin/selectin expression, is to permit secretagogue-induced superoxide anion generation, degranulation and lipid mediator (e.g. leukotriene B4 and arachidonic acid) release. It is now recognized that most priming agents also serve an additional function of delaying apoptosis and hence increasing the functional longevity of these cells at the inflamed site.

3. The potential mechanisms underlying priming are discussed; current data suggest a dissociation between priming and changes in receptor number and/or affinity, G-protein expression, phospholipase C and phospholipase A2 activation and changes in intracellular Ca2+ concentration. However, more recent studies support a key role for protein tyrosine phosphorylation and enhanced phospholipase D and phosphoinositide 3-kinase activity in neutrophil priming.

4. Recent work has also revealed the potential for neutrophils to spontaneously and fully ‘de-prime’ after an initial challenge with platelet-activating factor. This ability of neutrophils to undergo a complete cycle of priming—de-priming (and re-priming) reveals a previously unrecognized flexibility in the control of neutrophil behaviour at an inflamed site.
CYFRA 21-1, a Cytokeratin Subunit 19 Fragment, in Bronchoalveolar Lavage Fluid from Patients with Interstitial Lung Disease
Authors: Kanazawa Hiroshi , Yoshikawa Takahiro , Yamada Masashi , Shoji Seiichi , Fujii Tatsuo , Kudoh Shinzoh , Hirata Kazuto , Yoshikawa Junichi
Published: August 2015

1. It has been suggested that CYFRA21-1, a cytokeratin subunit 19 fragment, is potentially useful for diagnosis and monitoring of lung carcinoma. However, serum levels of CYFRA21-1 are also increased in a high proportion of patients with interstitial lung disease. In this study we measured CYFRA21-1 levels in bronchoalveolar lavage fluid from 10 normal subjects, 18 patients with idiopathic pulmonary fibrosis and 14 patients with sarcoidosis, and determined whether any relationship exists between CYFRA21-1 levels in bronchoalveolar lavage fluid and clinical parameters.

2. CYFRA21-1 levels in bronchoalveolar lavage fluid were significantly higher in patients with sarcoidosis (mean value 8.3 ng/ml, P < 0.01) and idiopathic pulmonary fibrosis (42.5 ng/ml, P < 0.005) than in normal controls (1.0 ng/ml). Moreover, higher CYFRA21-1 levels in bronchoalveolar lavage fluid were found in sarcoidosis patients in radiological stage 2 or 3 than in those in stage 1. In patients with idiopathic pulmonary fibrosis, there was a significant correlation between CYFRA21-1 levels, and percentage of inflammatory cells in bronchoalveolar lavage fluid (r = 0.56, P < 0.05) and the magnitude of the alveolar — arterial oxygen pressure difference [P(a — a)o2] gradient (r = 0.66, P < 0.01).

3. Serial bronchoalveolar lavage samples were obtained from six patients with clinically active pneumonitis after they had undergone systemic corticosteroid therapy. CYFRA21-1 levels were significantly lower after these patients exhibited clinical improvement (P < 0.05).

4. These findings suggest that the level of CYFRA21-1 in bronchoalveolar lavage fluid is a useful marker for the clinical diagnosis of pneumonitis, and is also adequate for the evaluation of disease activity, especially over the course of treatment.
Effects of β-blockers on the Concentration and Oxidizability of Plasma Lipids
Authors: Dimmitt Simon B. , Williams Peta D. , Croft Kevin D. , Beilin Lawrence J.
Published: August 2015

1. β-blockers improve morbidity and mortality after myocardial infarction, probably by several mechanisms. We investigated potentially relevant effects of β-blockers in vivo and in vitro on plasma lipid oxidizability. Forty-two healthy men were randomized to receive placebo (13), metoprolol (14) or propranolol (15).

2. At 4 weeks, the effects on heart rate, blood pressure and lipids appeared similar and subjects taking a β-blocker were combined. Compared with placebo, those on a β-blocker gained 0.5 kg in weight (P = 0.04), heart rate fell from 63 to 52 beats/min (P < 0.0001) and blood pressure fell from 116/74 to 113/69 mmHg (P < 0.005); high-density lipoprotein (HDL)-cholesterol fell from 1.26 to 1.11 mmol/l (P = 0.005), there being no change in the ratio of free to esterified cholesterol in HDL, and there was an apparent rise in serum triacylglycerols from 1.18 to 1.43 mmol/l (P = 0.15 when adjusted for weight gain). Low-density lipoprotein (LDL)-cholesterol and lipoprotein (a) did not change. In this study, the oxidizability of LDL was unaffected by β-blocker therapy. β-blockade was not associated with any change in LDL fatty acid profile, or β-carotene or α-tocopherol content which might account for the reduced LDL oxidizability previously reported in patients treated with β-blockers. Furthermore, neither atenolol nor propranolol, at concentrations up to 100 μmol/l, had any effect on in vitro oxidizability of LDL obtained from healthy volunteers.

3. In contrast to the favourable haemodynamic effects conferred by β-blockers, the effects on weight and serum triacylglycerols and HDL-cholesterol appear to be adverse and we did not demonstrate any changes in lipid oxidizability which might be relevant to the protective effects of β-blockers in patients with coronary disease.
Increased Nitric Oxide Synthesis and Inducible Nitric Oxide Synthase Expression in Patients with Alcoholic and Non-Alcoholic Liver Cirrhosis
Authors: Sánchez-Rodríguez A. , Criado M. , Rodríguez-López A. M. , Esteller A. , De Arriba A. Martín , López-Novoa J. M.
Published: August 2015

1. The synthesis and release of nitric oxide may play a role in the pathogenesis of peripheral vasodilatation and hyperdynamic circulation observed in liver cirrhosis. In this work, we analysed the synthesis of nitric oxide by the lympho-mononuclear cells of peripheral blood from patients with chronic alcoholic and non-alcoholic liver disease and we identified the isoform of nitric oxide synthase involved in the increased nitric oxide synthesis.

2. Patients were classified following clinical and histological criteria in non-alcoholic cirrhotic, alcoholic cirrhotic and non-cirrhotic chronic liver disease. We studied clinical and analytical characteristics, haemodynamic parameters and endotoxin levels in these patients.

3. Cirrhotic patients showed an increase of cardiac output and a decrease of peripheral vascular resistance. These patients had higher levels of plasma endotoxin than those observed in the control group. Nω-Nitro-l-arginine methyl ester (l-NAME)-inhibitable nitrite production from mononuclear lymphocyte cells was higher in patients than in the control group, the highest levels being in non-alcoholic cirrhotic patients, and the lowest levels in patients with non-cirrhotic alcoholic liver disease.

4. Immunocytochemistry studies revealed a positive immunoreactivity for the inducible isoform of nitric oxide synthase in lympho-mononuclear cells that was more evident in non-alcoholic than in alcoholic cirrhotic patients. By Northern blot, inducible nitric oxide synthase mRNA expression was observed only in lympho-mononuclear cells from non-alcoholic cirrhotic patients.

5. Our patients show a correlation between nitric oxide synthesis, endotoxin levels and haemodynamic parameters.

6. These findings indicate that lympho-mononuclear cell stimulation may play a role in elevated nitric oxide production in hepatic cirrhosis. Thus, this increased nitric oxide synthesis could be implicated in the pathogenesis of the haemodynamic disturbances frequently found in cirrhotic patients. This increase seems to be induced, at least in part, by activation of an inducible isoform of nitric oxide synthase.
Cardiovascular control and plasma catecholamines during rest and mental stress: effects of posture
Authors: TULEN J. H. M. , BOOMSMA F. , MAN IN ′TVELD A. J.
Published: August 2015

In order to understand the complex autonomic adjustments that occur during the psychological challenges of normal daily life, autonomic responses to psychological stress were studied by evaluating the effects of body posture on various indices of sympathetic and parasympathetic regulation during performance of a psychological task. Twelve male subjects were studied in various postures (supine, sitting and standing), and during performance of the Colour Word Test (CWT) when sitting and then when standing. This procedure was subsequently repeated in reverse order (first standing and then sitting) after 15 min of supine rest. Blood samples for assay of plasma catecholamines were obtained before and during each CWT. Spectral analysis of beat-to-beat variations of heart rate (HR) and blood pressure (BP) was applied in order to obtain non-invasive indices of sympathetic and parasympathetic regulation. HR, diastolic BP, mid-frequency band power (0.07-0.14 Hz) of HR and systolic BP, and plasma adrenaline and noradrenaline concentrations showed significant increases when changing from supine to sitting to standing posture, whereas high-frequency band power (0.15-0.50 Hz) of HR decreased in a posture-dependent fashion. In the sitting position, the CWT caused significant increases in HR, BP and plasma adrenaline levels, and decreased HR and BP variability indices. In the standing posture, the CWT responses differed significantly from those during sitting for HR (a mild decrease during standing), high-frequency band power of HR (decreased more while sitting), high-frequency band power of BP (decreased more while standing), and plasma adrenaline responses (larger during sitting). Posture-related differential effects were observed on indices of sympatho-adrenomedullary activation during performance of a psychological challenge, whereas indices of parasympathetic activity indicated primarily less vagolytic effects when the task was performed in the standing posture. Our findings therefore underline the complexity of the adjustments that occur in neurohumoral and haemodynamic parameters during the psychological challenges of daily life.
Discrepancies between echocardiographic measurements of left ventricular mass in a healthy adult population
Authors: DEAGUE Jenny A. , WILSON Catherine M. , GRIGG Leeanne E. , HARRAP Stephen B.
Published: August 2015

Increased left ventricular (LV) mass is associated with increased cardiovascular morbidity and mortality. LV mass is commonly estimated from echocardiography according to the Penn or ASE (American Society of Echocardiography) conventions. No formal statistical test of agreement between these methods has been published. Therefore we compared M-mode echocardiographic LV mass estimates by the Penn and ASE methods in a normal adult population. M-mode echocardiographic tracings were obtained in 169 healthy volunteers and used to calculate LV mass using the Penn and ASE methods. Median values of the estimates were similar [Penn, 126 g (interquartile range 96–170 g); ASE, 129 g (105–164 g); P = 0.08] and were highly intercorrelated (r = 0.98, P < 0.0001). However, the Bland–Altman analysis of agreement revealed significant inconsistencies between Penn and ASE LV mass values. The difference between Penn and ASE values was correlated significantly with heart size (P < 0.0001), such that, for small hearts, the Penn LV mass was lower than the ASE LV mass; in contrast, for large hearts, Penn estimates were greater than ASE values. In the upper 5% of the LV mass distribution, the median value for the Penn LV mass index was 132.4 g/m2, compared with 116.5 g/m2 for ASE values (2P = 0.017). Thus the two most common methods of echocardiographic estimation of LV mass differ significantly at the upper and lower ends of the heart size distribution. These results have important implications for both cardiac research and clinical evaluation.
Comparison between spectral analysis and the phenylephrine method for the assessment of baroreflex sensitivity in chronic heart failure
Authors: COLOMBO Roberto , MAZZUERO Giorgio , SPINATONDA Gianluca , LANFRANCHI Paola , GIANNUZZI Pantaleo , PONIKOWSKI Piotr , COATS Andrew J. S. , MINUCO Giuseppe
Published: August 2015

Baroreflex sensitivity assessed by means of the phenylephrine test plays a prognostic role in patients with previous myocardial infarction, but the need for drug injection limits the use of this technique. Recently, several non-invasive methods based on spectral analysis of systolic arterial pressure and heart period have been proposed, but their agreement with the phenylephrine test has not been investigated in patients with heart failure. The two methods (phenylephrine test and spectral analysis) were compared in a group of 49 patients with chronic congestive heart failure both at rest and during controlled breathing. The linear correlation and the limits of agreement between the phenylephrine test slope and the α-index [αc; corrected by the coherence function between the interbeat interval (RR interval) and systolic arterial pressure] were evaluated. Only 16 patients had a measurable α-index at rest in both the low-frequency (LF) and high-frequency (HF) bands; the αc-index allowed measurements in all patients. It correlated moderately with the phenylephrine test slope at rest (r = 0.71 and P< 0.001 in LF; r = 0.57 and P< 0.001 in HF) and during controlled breathing (r = 0.51 and P< 0.001 in LF; r = 0.63 and P< 0.001 in HF). Multivariate regression analysis showed that only αcLF during rest and αcHF during controlled breathing contributed significantly to baroreflex gain estimation. However, the agreement between methods was weak; the normalized limits of agreement and bias were -162 to 243% (0.46 ms/mmHg) for αcLF and -185 to 151% (-0.99 ms/mmHg) for αcHF. Thus the comparison between baroreflex sensitivity measurements obtained by the phenylephrine test and spectral analysis showed a moderate correlation between the two methods; however, despite the linear association, a consistent lack of agreement between the two techniques was found. Because both systematic and random factors contribute to the difference, these two techniques cannot be considered as alternatives for the assessment of heart failure.