bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the Somatostatin Analogue, Octreotide, on Exercise-Induced Hypotension in Human Subjects with Chronic Sympathetic Failure
Authors: Smith G. D. P. , Alam M. , Watson L. P. , Mathias C. J.
Published: August 2015

1. In autonomic failure, supine exercise lowers blood pressure and worsens postural hypotension. The somatostatin analogue, octreotide, reduces postprandial and postural hypotension, but its effects on exercise-induced hypotension and on postural hypotension post-exercise are unknown.

2. Eighteen subjects with chronic sympathetic denervation were studied; 12 had pure autonomic failure and six had additional neurological features of the Shy—Drager syndrome. Haemodynamic, hormonal and biochemical changes were measured before, during and after incremental supine leg exercise on two occasions: on no treatment and after subcutaneous octreotide. Exercise was performed 120 min after octreotide in eight subjects and 60 min after octreotide in ten subjects.

3. Octreotide did not improve exercise-induced hypotension; the blood pressure fall was greater during exercise, but the blood pressure level was no different than without treatment. Heart rate, stroke distance, cardiac index and systemic vascular resistance were similar at rest and changed to the same degree with exercise on and off octreotide. After octreotide, resting levels of serum growth hormone, plasma noradrenaline, adrenaline and renin were unchanged, but glucose was higher and insulin was lower. There was no change in biochemical and hormone levels during exercise either off or on octreotide.

4. After octreotide, although the rate of blood pressure recovery was similar post-exercise, the levels of blood pressure were higher than in the non-treatment phase and postural hypotension was improved before and after exercise.

5. In conclusion, in primary autonomic failure, octreotide did not improve exercise-induced hypotension in the supine position, suggesting that octreotide-sensitive vasodilatory peptides do not contribute to the blood pressure fall. With octreotide, supine blood pressure levels were higher post-exercise and postural hypotension was improved both before and after exercise.
Effect of Breathing, Pressure and Posture on Palatoglossal and Genioglossal Tone
Authors: Mathur Rajat , Mortimore Ian L. , Jan Mohammed A. , Douglas Neil J.
Published: August 2015

1. Patency of the upper airway is critical to respiration. Although about half of patients with the sleep apnoea/hypopnoea syndrome obstruct their upper airway at the retropalatal level, the respiratory actions of the palatal muscles have been little studied. We have therefore tested the hypothesis that the nasopharyngeal dilator muscle palatoglossus is activated during inspiration and by negative pressure.

2. Using intramuscular wire electrodes inserted perorally, we have compared the response of palatoglossus and genioglossus to breathing, posture change and airway negative pressure in 10 normal awake subjects before and after topical anaesthesia. The results are expressed as a percentage of maximal electromyogram. Data were analysed by repeated-measures analysis of variance.

3. Inspiratory activity was exhibited by both genioglossus [inspiratory, 10% ± 2% (SEM); expiratory, 6% ± 1%, P = 0.001] and palatoglossus (inspiratory, 16% ± 5%, expiratory, 10% ± 3%, P = 0.016), but only genioglossus exhibited increased activity on lying (supine 10% ± 2%, erect 6% ± 1% maximum, P = 0.01).

4. One hundred milliseconds after negative pressure application, activity increased in both genioglossus (7% ± 2% and 13% ± 3% respectively, P = 0.02) and palatoglossus (8% ± 2% and 23% ± 6% respectively, P < 0.001). After lignocaine surface anaesthesia to the nose and pharynx both genioglossus and palatoglossus still increased their activity in response to negative upper airway pressure, the extent of the increase being decreased for palatoglossus (P = 0.02) but not for genioglossus.

5. Thus, palatoglossus has respiratory activity and is activated by negative upper airway pressure.
Atrial Natriuretic Factor and Angiotensin Ii Stimulate Nitric Oxide Release from Human Proximal Tubular Cells
Authors: McLay J. S. , Chatterjee P. K. , Mistry S. K. , Weerakody R. P. , Jardine A. G. , McKay N. G. , Hawksworth G. M.
Published: August 2015

1. It has been recently reported that angiotensin II can enhance atrial natriuretic factor-stimulated cyclic GMP release from brain capillary endothelial cells and stimulate directly the release of cyclic GMP by Neuro 2a cells. A possible mechanism mediating such cyclic GMP release could be via the production of nitric oxide and the resultant stimulation of soluble guanylate cyclase.

2. The ability of angiotensin II, atrial natriuretic factor and c(4–23) atrial natriuretic factor to stimulate nitric oxide production was investigated in primary cultures of human proximal tubular cells.

3. Freshly prepared human proximal tubular cells were seeded onto 6-well plates and allowed to reach confluence. Cells were then incubated with incremental concentrations of either angiotensin II, atrial natriuretic factor or c(4–23) atrial natriuretic factor alone for 1, 4, 12 or 24 h or in the presence of the nitric oxide synthase inhibitor NG-monomethyl-l-arginine. Angiotensin II was also incubated with human proximal tubular cells in the presence of the AT, and AT2 receptor antagonists DuP 753 and PD 123319.

4. Incubation of human proximal tubular cells with angiotensin II, atrial natriuretic factor or c(4–23) atrial natriuretic factor produced a dose- and time-dependent increase in nitric oxide production, which was inhibited in the presence of NG-monomethyl-l-arginine. A similar increase in nitric oxide production was observed after incubation with atrial natriuretic factor or c(4–23) atrial natriuretic factor.

5. The angiotensin-induced increase in nitric oxide production was not inhibited in the presence of either the angiotensin AT1 or AT2 receptor antagonists DuP 753 or PD 123319.

6. This study demonstrates that primary cultures of human proximal tubular cells can be stimulated to produce nitric oxide by both atrial natriuretic factor and angiotensin II. Furthermore, the atrial natriuretic factor-induced response appears to be mediated via the atrial natriuretic factor-C receptor, while the angiotensin II-induced response appears to be mediated by a novel, as yet unidentified, angiotensin II receptor.
Acute Effects of Central Neuropeptide Y Injection on Glucose Metabolism in Fasted Rats
Authors: Wilding J. P. H. , Kruszynska Y. T. , Lambert P. D. , Bloom S. R.
Published: August 2015

1. Neuropeptide Y is a potent appetite stimulant and has been found to modulate glucose metabolism when given chronically. The acute effects of neuropeptide on peripheral glucose handling have not been studied in detail. We have studied the acute effects of central nervous system injection of neuropeptide on glucose metabolism in vivo in the rat.

2. Rats implanted with chronic cannulae in the third cerebral ventricle were injected with either neuropeptide Y or saline and peripheral insulin sensitivity was assessed during a hyperinsulinaemic euglycaemic clamp. The effect of centrally injected neuropeptide Y on post-absorptive glucose metabolism was studied using a constant infusion of [6-3H]glucose.

3. Infusion of neuropeptide Y resulted in a 18% increase in glucose requirement during the clamp, suggesting increased peripheral tissue responsiveness to insulin. Neuropeptide Y injection in 10 h fasted rats increased plasma glucose (area under curve 9.9 ± 0.2 versus 9.1 ± 0.1 mmol h−1 I−1, P < 0.01), insulin (103 ± 23 versus 33 ± 8 pmol/l, P < 0.01, at 30 min) and glucagon (5.5 ± 0.5 versus 3.1 ± 0.3 pmol/l, P < 0.05, at 30 min). The increase in plasma glucose was due to an initial increase in the rate of appearance, which peaked between 20 and 30 min after neuropeptide Y infusion; over the entire 90 min 16% more glucose entered the systemic circulation in the neuropeptide Y-treated rats than in control rats, and the total quantity of glucose removed was also greater.

4. Neuropeptide Y in the central nervous system influences glucose metabolism by altering secretion of islet hormones, hepatic glucose production and the peripheral response to insulin.
Relationship between Serum Tryptophan and Tryptophan Metabolite Levels after Tryptophan Ingestion in Normal Subjects and Age-Related Cataract Patients
Authors: Truscott Roger J. W. , Elderfield Anthony J.
Published: August 2015

1. Cataract is the single major cause of blindness worldwide; however, the reasons for the development of this condition remain unknown. It has been suggested that the essential amino acid tryptophan may be implicated in the aetiology but definitive evidence has been lacking.

2. The serum levels of tryptophan and seven of its metabolites have been measured in both cataract patients and control subjects, after administration of tryptophan, in order to determine the typical response profile and to discover whether differences could be found in tryptophan metabolism in the two groups.

3. Tryptophan, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, 5-hydroxyanthranilic acid, 5-hydroxytryptophan and anthranilic acid were measured by HPLC with dual electrochemical and programmable wavelength fluorescence detection. Fasting cataract patients (n = 42) and control subjects (n = 37) were given an oral dose of l-tryptophan and sera were sampled at 0, 1, 2, 4 and 6 h.

4. Statistically significant differences in the distribution of data between the two groups were observed. The responses of kynurenine and 5-hydroxyanthranilic acid were higher in cataract patients, but those of kynurenic acid and total tryptophan were lower than in control subjects. No statistically significant differences in free tryptophan, anthranilic acid, 3-hydroxyanthranilic acid, xanthurenic acid or 5-hydroxytryptophan levels were noted.

5. We conclude that there is a major subgroup of age-related cataract patients with a dysfunction in the metabolism of tryptophan. This may be related to the onset of cataract. The mechanism remains to be established but may operate via the action of tryptophan metabolites, such as 5-hydroxyanthranilic acid, which become reactive towards protein upon oxidation.
The Cost of Breathing in Stable Chronic Obstructive Pulmonary Disease
Authors: Hugli Olivier , Schutz Yves , Fitting Jean-William
Published: August 2015

1. The hypermetabolism frequently observed at rest in patients with chronic obstructive pulmonary disease has been attributed to a high cost of breathing. However, measurement of the cost of breathing by the usual hyperventilation procedure is fraught with methodological problems. The purpose of this study was to measure more directly the cost of breathing in a group of ambulatory patients with stable chronic obstructive pulmonary disease.

2. The cost of breathing was calculated as the difference in oxygen consumption measured by indirect calorimetry between spontaneous breathing and noninvasive mechanical ventilation. Inspiratory muscle rest was achieved by negative or positive pressure ventilation and assessed by the recording of surface electromyograms of the diaphragm and parasternal intercostal muscles.

3. Seven tests were performed in six ambulatory patients with stable chronic obstructive pulmonary disease, four tests using positive pressure ventilation and three with negative pressure ventilation. During mechanical ventilation, the electromyographic activity of the diaphragm decreased by 70 ± 22%, while that of the parasternals was suppressed in four tests, and remained unchanged in three. However, oxygen consumption was only 1.6 ± 6.2% lower during mechanical ventilation.

4. The cost of breathing measured in this study was therefore much lower than previously published values. Stress was not likely to influence the results, as both the heart rate and plasma catecholamines did not change between spontaneous breathing and mechanical ventilation. These results suggest that the cost of breathing in ambulatory patients with stable chronic obstructive pulmonary disease may be lower than previously estimated.
Expression of Endothelin Peptides and Mrna in the Human Heart
Authors: Plumpton C. , Ashby M. J. , Kuc R. E. , O'Reilly G. , Davenport A. P.
Published: August 2015

1. We have examined the expression of endothelin isoforms and their precursors in the human heart using RIA, HPLC, immunocytochemistry and reverse transcriptase—polymerase chain reaction assays.

2. Highly specific RIAs were used to measure the levels of mature endothelin and big endothelin-1 immunoreactivity in extracts of human right ventricle. There was no significant difference between samples from patients with ischaemic heart disease and idiopathic dilated cardiomyopathy.

3. HPLC coupled with RIAs allowed the separation and identification of the three mature isoforms of endothelin, big endothelin-1 and the C-terminal fragment of big endothelin-1. In extracts of human endocardial endothelial cells, peaks of immunoreactivity that co-eluted with authentic endothelin-1, big endothelin-1 and C-terminal fragment were found.

4. Intense immunocytochemical staining of mature endothelin immunoreactivity was detected in the cytoplasm of endothelial cells of all regions of the heart tested. Big endothelin-1 immunoreactivity mirrored that of the mature peptide and, in two of three individuals tested, big endothelin-2 immunoreactivity was also detected. No big endothelin-3 immunoreactivity was detected in any of the tissues examined.

5. Reverse transcriptase—polymerase chain reaction assays demonstrated endothelin-1 and endothelin-2 mRNA in all three samples of human left ventricle tested. In two of the individuals, additional bands were also detected with the endothelin-2 primers which corresponded to splice variants. There was no evidence for the expression of endothelin-3 mRNA.

6. These data suggest that endothelin-1 is the predominant isoform of endothelin in the human heart and is probably largely synthesized by the endothelial cells within the heart. If released from the endothelial cells in vivo, this potent cardiotonic peptide may play an important paracrine role in human cardiovascular function.
Ischaemia—Reperfusion Injury in the Rat is Modulated by Superoxide Generation and Leads to An Augmentation of the Hypoxic Pulmonary Vascular Response
Authors: Messent Mark , Griffiths Mark J. D. , Quinlan Gregory J. , Gutteridge John M. C. , Evans Timothy W.
Published: August 2015

1. The effects of the scavengers of reactive oxygen species superoxide dismutase and catalase, the iron chelator desferrioxamine and the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester and saline (control vehicle) on hypoxic pulmonary vasoconstriction, a measure of albumin flux and an index of lipid peroxidation (palmitic:linoleic acid ratio) were investigated after ischaemia—reperfusion in an isolated, blood-perfused rat lung model.

2. Lungs treated immediately before reperfusion with catalase (5 000 units), desferrioxamine (2 mg/kg), NG-nitro-l-arginine methyl ester (5 mmol/l) or saline showed a significant augmentation in pre-ischaemia—reperfusion hypoxic pulmonary vasoconstriction (57.7 ± 6.0%, 82.7 ± 28.8%, 95.2 ± 36.6% and 45.95 ± 10.53% respectively), an increase in albumin flux (0.35 ± 0.04, 0.31 ± 0.06, 0.29 ± 0.04 and 0.33 ± 0.02) and an increase in pre-ischaemia—reperfusion palmitic:linoleic acid ratio (0.64 ± 0.08, 0.51 ± 0.19, 0.5 ± 0.04 and 0.17 ± 0.07). Superoxide dismutase (2 750 i.u.) administered immediately before reperfusion prevented completely the changes in hypoxic pulmonary vasoconstriction (−0.3 ± 5.4%), albumin flux (0.09 ± 0.11) and palmitic:linoleic acid ratio (–0.06 ± 0.12). In control lungs (2 h of continuous perfusion), superoxide dismutase, catalase, desferrioxamine and saline did not affect hypoxic pulmonary vasoconstriction (5.5 ± 4.9%, 1.0 ± 3.1%, −5.1 ± 1.8% and 3.0 ± 6.6%). However, NG-nitro-l-arginine methyl ester significantly augmented hypoxic pulmonary vasoconstriction (275.1 ± 39.3%). There was no effect of superoxide dismutase, catalase, desferrioxamine, NG-nitro-l-arginine methyl ester or saline in control lungs on albumin flux (0.10 ± 0.04, 0.11 ± 0.01, 0.1 ± 0.01, 0.12 ± 0.01 and 0.11 ± 0.01 respectively) or palmitic:linoleic acid ratio (–0.08 ± 0.08, 0.73 ± 0.76, −0.03 ± 0.12, 0.01 ± 0.17 and 0.00 ± 0.0 respectively).

3. We conclude that superoxide dismutase attenuates ischaemia—reperfusion-induced increases in albumin flux and hypoxic pulmonary vasoconstriction, and prevents consumption of linoleic acid in the isolated, blood-perfused rat lung.
Epoprostenol Increases Plasma Level of Atrial Natriuretic Peptide in humans
Authors: Nielsen C. B. , Bech J. N. , Pedersen E. B.
Published: August 2015

1. In a placebo-controlled, randomized dose—response study the effect of the prostaglandin analogue epoprostenol (FlolanR) on the plasma level of atrial natriuretic peptide has been investigated in 14 healthy control subjects.

2. During epoprostenol infusion, atrial natriuretic peptide increased significantly in a dose-dependent manner, while it remained unchanged during placebo infusion [2 ng min−1 kg−1: epoprostenol 13.2% versus placebo −2.9%; 4 ng min−1 kg−1: epoprostenol 13.4% versus placebo −6.1%; 8 ng min−1 kg−1: epoprostenol 40.7% versus placebo −7.8% (medians), P < 0.01 for all].

3. Mean blood pressure and heart rate increased significantly after epoprostenol, but were unchanged during placebo infusion [8 ng min−1 kg−1; mean blood pressure: epoprostenol −5.6% versus placebo 3.2%; heart rate: epoprostenol 32.7% versus placebo 3.1% (medians), P < 0.01].

4. It is concluded that epoprostenol given intravenously increases the plasma level of atrial natriuretic peptide. The results support the hypothesis of an interaction between the prostaglandin system and atrial natriuretic peptide.
Respiratory Sinus Arrhythmia and Central Respiratory Drive in Humans
Authors: Al-Ani M. , Forkins A. S. , Townend J. N. , Coote J. H.
Published: August 2015

1. The influence of central inspiratory drive on heart rate variability was investigated in young human subjects using power spectral analysis of R—R intervals.

2. The area of the high-frequency component occurring at the respiratory frequency (0.2–0.25 Hz) in the power spectral density curves was used as an index of respiratory sinus arrhythmia.

3. Central inspiratory drive was increased by breathing a CO2-enriched (5%) gas mixture and this condition was compared with a similar degree of ventilation produced voluntarily.

4. Tests were conducted on eight young subjects with and without low-dose scopolamine (scopoderm TTS) in a double-blind cross-over trial.

5. Scopolamine decreased heart rate and increased the high-frequency peak, suggesting that its main action on the cardiac vagal pathway was a peripheral one, possibly increasing the efficacy of vagal impulses on the cardiac pacemaker.

6. With scopolamine, CO2 breathing increased the area of the high-frequency component significantly more than a similar degree of ventilatory movements produced by voluntary hyperventilation.

7. It is concluded that respiratory sinus arrhythmia in humans is at least partly dependent on a central respiratory—cardiac coupling, most probably similar to that shown in animal studies.
Renal Denervation Prevents Sodium Retention and Hypertension in Salt-Sensitive Rabbits with Genetic Baroreflex Impairment
Authors: Weinstock Marta , Gorodetsky Elena , Kalman Ronald
Published: August 2015

1. Rabbits with a genetic impairment in baroreflex control of heart rate become hypertensive on a high salt diet. The present study determined the effect of bilateral renal denervation on blood pressure and sodium balance after salt loading (four times normal intake; 28–36 mEq NaCl/day) in normotensive rabbits with high (Group I) and low (Group II) baroreflex sensitivity, respectively.

2. Eight rabbits in each group were denervated or sham-denervated 1 week before commencement of the high salt diet. Before operation, the two groups differed only in the gain of their cardiac baroreflex (Group I, −6.4 ± 0.4 beats min−1 mmHg−1; Group II, −3.2 ± 0.15 beats min−1 mmHg−1).

3. In Group I sham-denervated rabbits, mean arterial pressure remained unchanged, and plasma renin activity and heart rate fell significantly in response to the high salt. In Group II sham-denervated rabbits, mean arterial pressure increased by 10.6 ± 1.2 mmHg, and heart rate and plasma renin activity remained unchanged. Their cumulative Na+ retention and weight gain was more than twice that of Group I sham-denervated rabbits.

4. Renal denervation decreased plasma renin activity in both groups to <1 pmol Ang I h−1 ml−1, lowered cumulative Na+ retention from 102 ± 4 to 35 ± 5 mEq (P<0.01) and completely prevented the increase in mean arterial pressure in response to high salt in Group II.

5. The results suggest that Group II rabbits retain salt and fluid in response to their diet because of an abnormality in their control of renal nerve activity, possibly via vagal afferents. This results in blood pressure elevation because of an inability to lower peripheral resistance and heart rate in response to the increase in cardiac output.

6. Since they display several of the characteristics of salt-sensitive hypertensive humans, i.e. salt retention, normal plasma renin activity, but abnormal regulation of plasma renin activity and blood flow in response to salt loading, Group II are an appropriate model of human salt-induced hypertension.
Investigation by Polymerase Chain Reaction of Enteroviral Infection in Patients with Chronic Fatigue Syndrome
Authors: McArdle A. , McArdle F. , Jackson M. J. , Page S. F. , Fahal I. , Edwards R. H. T.
Published: August 2015

1. Chronic fatigue syndrome is characterized by muscle fatigue and pain at rest, symptoms which are usually exacerbated with exercise. Although various studies have shown minor, non-specific morphological and biochemical changes in muscle of patients with chronic fatigue syndrome, no consistent defect has been identified. Some have suggested that an enteroviral infection in muscle may cause the chronic muscle fatigue seen in patients with chronic fatigue syndrome, with acute infection directly and irreversibly impairing mitochondrial function, and persistent infection depressing muscle protein synthesis and metabolism.

2. To clarify the involvement of enterovirus infection in chronic fatigue syndrome, muscle biopsies from a group of patients with chronic fatigue syndrome were examined for the presence of enteroviral RNA by reverse transcriptase-polymerase chain reaction techniques in relation to functional studies of muscle mitochondria and the muscle RNA/DNA ratio.

3. Fifty-eight percent of patients reported an uncharacterized ‘viral infection’ before the onset of their illness, but none of the muscle samples from 34 patients contained detectable amounts of enteroviral RNA. Muscle tissue had a general reduction in the RNA/DNA ratio and mitochondrial enzyme activities with no specific abnormality in the activity of enzymes encoded partially on the mitochondrial genome (cytochrome-c oxidase) or nuclear genome (citrate synthase, succinate reductase).

4. These data provide no evidence of an enteroviral infection in muscle of patients with chronic fatigue syndrome, although this does not exclude a role of enterovirus in initiating the disease process. The general reduction in RNA/DNA ratio and mitochondrial enzyme activities is consistent with a general reduction in habitual activity.
β-Oxidation in Human Alcoholic and Non-Alcoholic Hepatic Steatosis
Authors: Eaton S. , Zaitoun A. M. , Record C. O. , Bartlett K.
Published: August 2015

1. The CoA and carnitine ester intermediates of mitochondrial β-oxidation have not previously been quantified in liver disease, although there is some evidence that β-oxidation is inhibited in alcoholic fatty liver. Mitochondria were isolated from needle liver biopsies from normal subjects, from patients with alcoholic fatty liver and patients with fatty liver of other aetiologies, incubated with 60 μmol/l [U-14C]hexadecanoate and the resultant CoA and carnitine esters were measured.

2. Although there was no significant difference in β-oxidation flux between the patient groups, there was a significant rise in the proportion of 3-hydroxyacyl-CoA and 2-enoyl-CoA esters in patients with alcoholic fatty liver compared with normal subjects, and in patients with non-alcoholic fatty liver, suggesting an inhibition at the level of 3-hydroxyacyl-CoA dehydrogenase activity.

3. In alcoholic patients this difference could not be accounted for on the basis of the measured activity of short and long-chain 3-hydroxyacyl-CoA dehydrogenases, and it is suggested that either an inhibition of complex I activity or diminished amounts of ubiquinone are likely to be responsible for the observed accumulation of CoA and carnitine esters, which may contribute to the accumulation of triacylglycerols in alcoholic steatosis. In fatty liver of other aetiologies, short- and long-chain 3-hydroxyacyl-CoA dehydrogenase activities were decreased.
Beneficial Effects of L-Canavanine, a Selective Inhibitor of Inducible Nitric Oxide Synthase, during Rodent Endotoxaemia
Authors: Liaudet Lucas , Feihl François , Rosselet Anne , Markert Michèle , Hurni Jean-Marc , Perret Claude
Published: August 2015

1. The cardiovascular failure in sepsis may result from increased nitric oxide biosynthesis, through the diffuse expression of an inducible nitric oxide synthase. In such conditions, nitric oxide synthase inhibitors might be of therapeutic value, but detrimental side effects have been reported with their use, possibly related to the blockade of constitutive nitric oxide synthase. Therefore, the use of selective inhibitors of inducible nitric oxide synthase might be more suitable. The aim of this study was to evaluate the effects of l-canavanine, a potentially selective inhibitor of inducible nitric oxide synthase, in an animal model of septic shock.

2. Anaesthetized rats were challenged with 10 mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a 5 h infusion of either l-canavanine (20 mg h−1 kg−1, n = 15), nitro-l-arginine methyl ester (5 mgh−1 kg−1, n = 13) or 0.9% NaCl (2 ml h−1 kg−1, n = 21). Lipopolysaccharide induced a progressive fall in blood pressure and cardiac index, accompanied by a significant lactic acidosis and a marked rise in plasma nitrate. All these changes were significantly attenuated by l-canavanine, which also improved the tolerance of endotoxaemic animals to acute episodes of hypovolemia. In addition, l-canavanine significantly increased survival of mice challenged with a lethal dose of lipopolysaccharide. In contrast to l-canavanine, nitro-l-arginine methyl ester increased blood pressure at the expense of a severe fall in cardiac index, while largely enhancing lactic acidosis. This agent did not improve survival of endotoxaemic mice. In additional experiments, we found that the pressor effect of l-canavanine in advanced endotoxaemia (4 h) was reversed by l-arginine, confirming that it was related to nitric oxide synthase inhibition. In contrast, l-canavanine did not exert any influence on blood pressure in the very early stage (first hour) of endotoxaemia or in the absence of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide synthase inhibition by this agent.

3. In conclusion, l-canavanine produced beneficial haemodynamic and metabolic effects and improved survival in rodent endotoxic shock. The actions of l-canavanine were associated with a selective inhibition of inducible nitric oxide synthase and were in marked contrast to the deleterious consequences of nitro-l-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, in similar conditions.
Carbohydrate Metabolism in Insulin Resistance: Glucose Uptake and Lactate Production by Adipose and Forearm Tissues in Vivo before and after a Mixed Meal
Authors: Coppack Simon W. , Fisher Rachel M. , Humphreys Sandy M. , Clark Mo L. , Pointon Jennifer J. , Frayn Keith N.
Published: August 2015

1. To examine whether insulin resistance in vivo is manifest equally in both muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and sex.

2. Compared with non-obese subjects, the forearm of the obese subjects was resistant to insulin stimulation of glucose uptake after a mixed meal. In contrast, adipose tissue showed little evidence of insulin stimulation of glucose uptake, and adipose tissue in subjects in both normal and obese groups behaved very similarly (assessed per 100 g of tissue).

3. For lactate flux, adipose tissue behaved very similarly (per 100 g of tissue) in obese and non-obese subjects, and was a consistent lactate exporter.

4. We conclude that insulin resistance of glucose uptake observed in the forearm of obese subjects is not evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin-resistant subjects is similar to that in lean control subjects, although it occurs at elevated circulating insulin and glucose concentrations.
Luminal Epidermal Growth Factor Preserves Mucosal Mass of Small Bowel in Fasting Rats
Authors: Ulshen Martin H. , Raasch Ralph H.
Published: August 2015

1. Fasting causes atrophy of small bowel mucosa which rapidly resolves with luminal feeding. This effect of enteral nutrient-5-be mediated by stimulation of growth factor secretion. We therefore evaluated whether luminal administration of epidermal growth factor, a peptide hormone found in gastrointestinal contents and trophic for small bowel mucosa, would prevent the mucosal atrophy associated with starvation.¡

2. Adult rats were: (i) fasted for 3 days, (ii) fasted and then refed for 1 day or (iii) fasted and then refed for 2 days. During the 2 days before study, animals in each group received infusions of epidermal growth factor (2.5 μg/day) or diluent alone into distal jejunum.

3. Epidermal growth factor treatment of fasted animals resulted in a tripling of mucosal ornithine decarboxylase activity (P<0.001) and a doubling of mucosal DNA content (P<0.001) in the jejunum, values similar to those of refed animals. Epidermal growth factor infusion in refed rats resulted in a further doubling of mucosal ornithine decarboxylase activity (P<0.001), but no additional increase in DNA content. Effects of epidermal growth factor infusion were generally greater in jejunum than ileum.

4. In conclusion, luminal exposure to epidermal growth factor prevents starvation-induced mucosal atrophy in the small bowel, but does not enhance the mucosal growth associated with refeeding. Effects are greatest at the site of administration. Luminal epidermal growth factor is a potential mediator of the indirect effects of nutrient on mucosal growth in the small bowel. Enteral administration of epidermal growth factor holds promise for preventing atrophy and maintaining mucosal integrity in starved and post-operative patients.
Muscle Protein and Amino Acid Turnover in Rats in Vivo: Effects of Short-Term and Prolonged Starvation
Authors: De Blaauw I. , Deutz N. E. P. , Von Meyenfeldt M. F.
Published: August 2015

1. Protein loss in muscle can be caused by decreased protein synthesis, increased breakdown or both. In small animals the tracer incorporation technique is mostly used to measure protein synthesis, but for degradation measurements in vitro or ex vivo settings are required. In human and large animal studies the arteriovenous dilution technique is used because it enables the measurement of synthesis and breakdown rates simultaneously. The applicability in small animals has not yet been proven. We used a starvation model to compare both techniques.

2. A primed constant infusion of l-[2,6-3H]phenylalanine was given to male Lewis rats after 16, 40, 64 and 112 h starvation. Protein synthesis rates of the gastrocnemius muscle were measured by the incorporation technique and compared with hindquarter protein turnover calculated in a two- and three-compartment arteriovenous dilution model.

3. Whole-body phenylalanine rate of appearance decreased from 456 ± 32 after 16 h to 334 ± 34 (nmol min−1 100 g−1 body weight) after 112 h starvation. Protein synthesis rates of the gastrocnemius muscle measured by the tracer incorporation technique decreased from 3.6 ± 0.4 after 16 h starvation to 2.2 ± 0.3 after 64 h starvation and 1.8 ± 0.4 (%/day) after 112h starvation. Hindquarter protein breakdown, calculated with the tracer dilution model, increased after 112 h starvation from 28 ± 12 to 77 ± 15 nmol min−1 100 g−1 body weight. Using the tracer dilution model, however, the calculated protein synthesis rate across the hindquarter also increased after prolonged starvation (29 ± 7 and 68 ± 16 nmol min−1 100 g−1 body weight after 16 and 112h respectively). In conjunction with this, calculated bidirectional membrane transport rates were also enhanced. Using valine and glutamine as tracers, the enhanced amino acid turnover rates were confirmed.

4. In conclusion, our results show that during short periods of starvation both methods give similar results. After prolonged starvation, however, an opposite change in disappearance rate and protein synthesis rate was observed. Assumptions made to calculate protein turnover using the arteriovenous dilution model may account for the discrepancy and care must be taken with the interpretation when using only one model in anaesthetized small animals.
Angiotensin Receptors in Myometrium and Myometrial Vessels from Uteri of Women during the Follicular and Luteal Phases of the Menstrual Cycle and in Late Pregnancy
Authors: Bing C. , Johnson I. R. , Pipkin F. Broughton
Published: August 2015

1. Receptors for angiotensin II were identified and characterized in membrane fractions from myometrial samples obtained at non-pregnant hysterectomy in women of reproductive age. Specific binding was also measured in paired samples of vascular and ‘vessel-free’ myometrium.

2. A single class of high-affinity receptor sites was identified in the total myometrial preparations (n = 10), with a median equilibrium dissociation constant (Kd) of 0.122 nmol/l (range 0.065–0.465 nmol/l) and concentration of receptor sites (Bmax) of 149 fmol/mg protein (range 105–435 fmol/mg). Receptor characterization studies using losartan (an angiotensin type 1 receptor antagonist) and PD123177 (an angiotensin type 2 receptor antagonist) showed the myometrium to contain almost entirely type 2 receptors.

3. The median Kd and Bmax for specific angiotensin II binding in isolated myometrial vessel homogenates were 0.086 nmol/l (range 0.060–0.433) and 260 fmol/mg protein (range 197–737 fmol/mg) respectively. Vascular specific binding density was always higher in dissected out myometrial vessels than in paired vessel-free myometrium (median 372 compared with 120 fmol/mg protein; n = 20; P < 0.001). The specific binding in the paired samples was strongly correlated (r = 0.8904, P < 0.0001).

4. The specific binding of 125I-labelled angiotensin II in ‘vessel-free’ myometrium was higher in samples from the follicular phase than in samples from the luteal phase (median 144 compared with 37 fmol/mg; P < 0.02). A similar trend was found in the vessels themselves, but this failed to reach statistical significance (459 compared with 225 fmol/mg; P = 0.051).

5. It is suggested that the down-regulation of the angiotensin type 2 receptors in the luteal (secretory) phase is a preparation for pregnancy, removing an inhibitory factor to uterine growth and vascularization and allowing greater prostacyclin synthesis.
Use of Continuous Haemofiltration to Assess the Rate of Lactate Metabolism in Acute Renal Failure
Authors: Wright D. A. , Forni L. G. , Carr P. , Treacher D. F. , Hilton P. J.
Published: August 2015

1. Whole-blood lactate levels were measured at different rates of haemofiltration in 10 patients with acute renal failure undergoing conventional continuous haemofiltration using lactate-buffered replacement fluid.

2. The results enable both basal production rates and the metabolic clearance of lactate to be estimated in man.
Endogenous versus Exogenous Lithium Clearance for Evaluation of Dopamine-Induced Changes in Renal Tubular Function
Authors: Olsen Niels V. , Fogh-Andersen Niels , Strandgaard Svend , Leyssac Paul P.
Published: August 2015

1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 μg min−1 kg−1 of dopamine.

2. Baseline values of endogenous CLi and fractional excretion of lithium (FELi) [27.0 (23.5–30.5) ml/min and 24.2 (203–28.2)% (means with 95% confidence interval)] were lower than exogenous values [lithium, 450 mg: 32.7 (29.9–35.4) ml/min (P < 0.05) and 27.4 (25.2–29.6)% (P < 0.05); lithium, 600 mg: 33.4 (29.2–37.6) ml/min (P < 0.05) and 28.6 (26.3–31.0)% (P < 0.01)]. Both test doses of lithium increased the baseline sodium clearance (CNa), but glomerular filtration rate and urine flow rate remained unchanged.

3. Dopamine increased CNa to similar values on the three study days. CLi increased to 40.9 (35.5–46.5) ml/min (endogenous lithium, P < 0.001), 43.2 (40.8–45.6) ml/min (450 mg of lithium, P < 0.01) and 44.9 (41.3–48.4) ml/min (600 mg of lithium, P < 0.001), respectively. FELi increased to 32.2 (27.5–37.0)% (P < 0.01), 35.4 (33.0–37.7)% (P < 0.01) and 35.9 (32.8–38.9)% (P < 0.01), respectively. Values during dopamine infusion did not differ significantly.

4. The lower baseline values of endogenous CLi and FELi compared with exogenous values suggest that CLi in humans depends on the plasma concentrations of lithium. However, the effect of dopamine on CLi and FELi was expressed to the same extent with endogenous and exogenous lithium, indicating that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function.
Effect of Probucol, An Oral Hypocholesterolaemic Agent, on Acute Tobacco Smoke Inhalation in Rats
Authors: Ishizaki Takeshi , Kishi Youichi , Sasaki Fumihiko , Ameshima Shingo , Nakai Tsuguhiko , Miyabo Susumu
Published: August 2015

1. We hypothesized that probucol, an oral hypocholesterolaemic agent, can suppress the oxidant stress induced by acute tobacco smoke inhalation in rats. We determined lung tissue glutathione (reduced and oxidized), lipid peroxide, tocopherol and plasma elastase inhibitory capacity, ferroxidase activity and lipid peroxide in rats after inhalation of tobacco smoke.

2. Rats treated with the probucol diet for 3 days or 4 weeks equally showed no suppression of plasma elastase inhibitory capacity and ferroxidase activity compared with control rats after acute tobacco smoke inhalation, although both animals treated with probucol for 3 days or 4 weeks had pharmacologically effective concentrations of probucol to lower plasma cholesterol but plasma cholesterol in rats treated with probucol for 3 days was still in the normal range.

3. Probucol treatment for 4 weeks lessened tobacco smoke-induced suppression of lung tissue glutathione, attenuated tobacco smoke-induced increases in lung tissue lipid peroxide and did not alter lung tissue tocopherol compared with control (lungs).

4. These findings demonstrate that probucol, via its antioxidant ability, confers a protective effect on lung exposed to acute tobacco smoke inhalation.
Ambulatory Monitoring of Blood Pressure Disturbs Sleep and Raises Systolic Pressure at Night in Patients Suspected of Suffering from Sleep-Disordered Breathing
Authors: Heude E. , Bourgin P. , Feigel P. , Escourrou P.
Published: August 2015

1. The aim of the study was to assess the effect of ambulatory monitoring of blood pressure on sleep and on blood pressure in middle-aged patients.

2. Nine consecutive patients (seven men, two women; mean age 57 years) complaining of snoring and various degrees of excessive daytime somnolence were studied. Five patients were normotensive and four were being treated for hypertension. During one night standard laboratory polysomnography was performed with monitoring of blood pressure by a silent ambulatory monitor and continuous infrared blood pressure by photoplethysmography.

3. Ambulatory blood pressure significantly disturbs sleep architecture, causing EEG arousals in 64% of measurements, and induces a significant rise in blood pressure during systolic pressure measurement by the ambulatory monitor (rise in systolic pressure, 13.7 ± 15.9 mmHg, P > 0.001; rise in diastolic pressure, 3.7 ± 8.2 mmHg, P > 0.01). At the time of diastolic measurement, blood pressure had returned to the preinflation value. The rise in systolic blood pressure was higher when an arousal was associated with cuff inflation (P > 0.001). This rise in blood pressure is probably the consequence of sympathetic nervous system activation.

4. We conclude that ambulatory blood pressure recordings of systolic blood pressure during sleep should be interpreted with caution as systolic blood pressure may be significantly increased in patients suspected of suffering from sleep-disordered breathing.
High-Performance Capillary Electrophoresis-Pure Creatine Monohydrate Reduces Blood Lipids in Men and Women
Authors: Earnest Conrad P. , Almada Anthony L. , Mitchell Tedd L.
Published: August 2015

1. A randomized, double-blind, placebo-controlled trial utilizing creatine as a potential lipid-lowering agent was conducted to determine plasma lipid, lipoprotein, glucose, urea nitrogen and creatinine profiles in men and women ranging in age from 32 to 70 years.

2. Thirty-four subjects (18 men and 16 women) with total cholesterol concentrations exceeding 200 mg/dl received either a creatine supplement (5 g of creatine plus 1 g of glucose) or a glucose placebo (6 g of glucose) for 56 days. Creatine and placebo were taken orally four times a day for 5 days and then twice a day for 51 days. Plasma analyses were measured at baseline, 4 and 8 weeks of treatment, and at 4 weeks after cessation of treatment (week 12).

3. Significant reductions in plasma total cholesterol, triacylglycerols and very-low-density lipoprotein-C occurred within the creatine monohydrate group. Minor reductions in plasma total cholesterol from baseline (233 ± 9 mg/dl) of 6% and 5% occurred at weeks 4 and 8, respectively, before returning to baseline at week 12. Baseline triacylglycerols (194 ± 21 mg/dl) and very-low-density lipoprotein-C (39 ± 4 mg/dl) were reduced by 23% and 22% at weeks 4 and 8, respectively, and remained attenuated by 26% at week 12. These results remained consistent when data were separated and analysed by gender. Finally, a small, but statistically significant increase in urea nitrogen was observed in women between baseline (11.8 ± 0.7 mg/dl) and week 8 (13.8 ± 0.7 mg/dl, P > 0.05). No significant differences were noted for low-density lipoprotein-C, high-density lipoprotein-C, total cholesterol/high-density lipoprotein ratio, glucose, creatinine, body mass, body mass index or physical activity within or between the experimental and placebo groups. However, a trend towards reduced blood glucose levels was present in males given creatine monohydrate (P = 0.051).

4. These preliminary data suggest that creatine monohydrate may modulate lipid metabolism in certain individuals. These observations may demonstrate practical efficacy to the hyperlipidaemic patient as well as providing possible new mechanistic insights into the cellular regulation of blood lipid concentrations.
Isolation and Characterization of Human Epidermal Stem Cells
Authors: Jones P. H.
Published: August 2015

1. The keratinocytes in human epidermis are constantly turned over and replaced by a population of stem cells located in the basal epidermal layer. Until recently there were no markers allowing the isolation of viable epidermal stem cells. However, it has now been shown that epidermal stem cells can be isolated both in vitro and direct from the epidermis as they express high levels of functional β1 integrin family receptors for extracellular matrix proteins.

2. The evidence for integrins as stem cell markers and the insights that have been gained into stem cell behaviour are reviewed.
Fluid, Ionic and Hormonal Changes Induced by High Salt Intake in Salt-Sensitive and Salt-Resistant Hypertensive Patients
Authors: De La Sierra Alejandro , Lluch María Del Mar , Coca Antonio , Aguilera María Teresa , Giner Vicente , Bragulat Ernesto , Urbano-Márquez Alvaro
Published: August 2015

1. The aim of the study was to detect differences between salt-sensitive and salt-resistant hypertensive patients in the response of the renin—aldosterone axis, plasma noradrenaline and atrial natriuretic peptide to high salt intake.

2. Fifty essential hypertensive patients followed 2 weeks of a standard diet with 20 mmol of NaCl daily, supplemented by placebo tablets for the first 7 days and by NaCl tablets for the last 7 days, in a single-blind fashion. Salt sensitivity was defined as a significant rise (P < 0.05) in 24 h mean blood pressure obtained by ambulatory blood pressure monitoring from the low- to the high-salt period. Biochemical and hormonal measurements were performed on the last day of both periods.

3. Twenty-two (44%) patients fulfilled criteria of salt-sensitive hypertension, whereas the remaining 28 (56%) were considered salt-resistant. High salt intake promoted a significant decrease (P < 0.05) in plasma creatinine, potassium, glucose, cholesterol, low-density lipoprotein-cholesterol, triacylglycerols, uric acid and plasma renin activity, and a significant increase in plasma atrial natriuretic peptide and 24 h urinary calcium excretion. The direction of these changes did not differ between salt-sensitive and salt-resistant patients. Salt-resistant hypertensive patients exhibited a significant decrease in plasma aldosterone induced by high salt intake (from 446 ∓ 35 to 226 ± 35 pmol/l; P < 0.001), whereas this parameter was not significantly modified in salt-sensitive patients (from 485 ± 76 to 364 ± 83 pmol/l; P not significant). Salt-sensitive patients showed an increase in plasma noradrenaline after high salt intake (from 1.15 ± 0.11 to 1.56 ± 0.14 nmol/l; P < 0.05), whereas salt-resistant patients presented a decrease in this parameter (from 1.48 ± 0.08 to 1.12 ± 0.08 nmol/l; P < 0.05). The change in plasma noradrenaline was directly correlated with the change in mean blood pressure induced by high salt intake (r = 0.479; P = 0.003).

4. We conclude that the increase in blood pressure induced by high salt intake in salt-sensitive patients is associated with a stimulation of the sympathetic nervous system and a blunted decrease in plasma aldosterone. Conversely, changes in renal function, electrolyte excretion and plasma concentrations of atrial natriuretic peptide induced by high salt intake seem to be similar in both salt-sensitive and salt-resistant patients.