bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypotension induced by intravascular administration of nerve growth factor in the rat
Authors: Yan Q. , Settle S. L. , Wilkins M. R.
Published: August 2015

1. The observation that the area postrema expresses a high level of nerve-growth-factor-receptor immunoreactivity prompted an investigation of the effects of nerve growth factor on autonomic function in the rat.

2. Bolus injection of pharmacological doses of the peptide via the femoral vein led to reproducible, dose-dependent falls in blood pressure.

3. Administration via the vertebral artery, a more direct route to the brainstem, did not appear to lower the threshold dose required to induce hypotension. Furthermore, pretreatment with hexamethonium did not inhibit the hypotensive response to nerve growth factor.

4. Administration of a second dose of nerve growth factor after recovery from the first injection produced little or no fall in blood pressure. Similarly, pretreatment with the mast cell degranulating agent, compound 48/80, rendered the animal refractory to nerve growth factor.

5. The fall in blood pressure induced by nerve growth factor was markedly attenuated by pretreatment with chlorpheniramine.

6. It is concluded that the fall in blood pressure induced by intravenous administration of pharmacological doses of nerve growth factor is mediated by vasoactive substances, particularly histamine, released from mast cells.
Enhancement of ischaemic rabbit skin flap survival with the antioxidant and free-radical scavenger N-acetylcysteine
Authors: Knight Kenneth R. , MacPhadyen Karen , Lepore Diana A. , Kuwata Noriyuki , Eadie Patricia A. , O'Brien Bernard McC.
Published: August 2015

1. The burst of damaging oxygen free-radicals at the time of reperfusion is one of the crucial factors affecting skin flap survival after an ischaemic interval. In these experiments the efficacy of the antioxidant and free-radical scavenger N-acetylcysteine in improving the survival of ischaemic rabbit epigastric skin flaps was tested.

2. At the time of reperfusion flaps were given: (1) balanced salt solution by intravenous whole-body administration, (2) N-acetylcysteine (200 mg/kg) by intravenous whole-body administration, (3) balanced salt solution by intra-arterial infusion into the flap, (4) N-acetylcysteine (20 mg/kg) by intra-arterial infusion into the flap, or (5) N-acetylcysteine (200 mg/kg) by intra-arterial infusion into the flap. Flap survival at 1 week, and tissue levels of parameters related to free-radical production, blood levels of thromboxane B2 and peripheral resistance during reperfusion were determined.

3. Compared with controls (groups 1 and 3) which had flap survival rates (expressed as percentage surface area surviving) of 27.1% and 31.6%, respectively, N-acetylcysteine treatment in group 2 (55.2%) and group 4 (51.9%) resulted in significant (P < 0.05) improvements in flap survival. The survival rate in group 5 (37.7%) was not significantly better than that of the controls.

4. N-Acetylcysteine significantly reduced parameters related to free-radical production in the skin flap after 30 min of reperfusion, determined as tissue levels of malonyldialdehyde and protein oxidation products. There was also a significant decrease in peripheral resistance when low-dose N-acetylcysteine (group 4) was infused intra-arterially into the flap. The systemic levels of thromboxane B2, a prostanoid promoting thrombosis, were not significantly altered by administration of N-acetylcysteine.

5. N-Acetylcysteine proved to be a successful therapeutic agent for the salvage of experimental ischaemic rabbit skin flaps, when used as a low-dose intra-arterial or high-dose intravenous treatment. The possible clinical benefits in humans have yet to be demonstrated.
Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man
Authors: Shirley D. G. , Singer D. R. J. , Sagnella G. A. , Buckley M. G. , Miller M. A. , Markandu N. D. , MacGregor G. A.
Published: August 2015

1. The possible natriuretic and kaliuretic effects of a single dose of lithium, as used in lithium clearance studies, were investigated in 15 healthy subjects on fixed sodium (100 mmol/24 h) and potassium (70 mmol/24 h) intakes. Lithium carbonate (300 mg or 600 mg) or placebo tablets were administered, double-blind and in random order, midway through a 48 h urine collection (divided into six 8 h periods), at 23.00 hours.

2. During the three 24 h periods which preceded the administration of lithium or placebo (control days), rates of sodium and potassium excretion followed normal circadian patterns, but no differences in excretion rates between the 3 control days were observed. Placebo tablets did not affect excretion rates.

3. After the 300 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 17 mmol (P < 0.05); almost all of the natriuretic effect occurred during the first two 8 h periods. No effect on potassium excretion was observed.

4. After the 600 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 48 mmol (P < 0.001) and 24 h potassium excretion increased by approximately 19 mmol (P < 0.01). These effects were confined to the first two 8 h periods and thus occurred before and during the usual lithium clearance period.

5. Plasma renin activity, measured in 10 subjects, increased after the 600 mg dose of lithium carbonate (P < 0.005), but plasma concentrations of aldosterone and atrial natriuretic peptide were not significantly affected. Neither the 300 mg dose of lithium carbonate nor the placebo tablets affected hormone levels.

6. It is recommended that the test dose of lithium carbonate for use in lithium clearance studies should not exceed 300 mg.
Responses of glucose and glucoregulatory hormones to exercise in thyrotoxic and myxoedematous patients before and after 3 months of treatment
Authors: Sestoft Leif , Christensen Niels Juel , Saltin Bengt
Published: August 2015

1. The effect of moderate endurance exercise on blood glucose concentration and on glucoregulatory hormones was studied in nine thyrotoxic and five myxoedematous humans before and 3 months after anti-thyroid and substitution therapy, respectively.

2. At rest, the fasting concentrations of insulin and pro-insulin correlated positively with the prevailing total tri-iodothyronine concentration, whereas the concentrations of noradrenaline and cortisol correlated inversely with the tri-iodothyronine concentration.

3. During exercise the plasma insulin, pro-insulin and C-peptide concentrations decreased. The plasma glucagon concentration increased slightly in thyrotoxic patients before and after treatment and was largely unchanged in myxoedematous patients in either state.

4. The plasma noradrenaline concentration increased before and after treatment in both groups, with concentrations two times higher in the myxoedematous than in the thyrotoxic patients. Treatment for 3 months did not change this pattern. The plasma adrenaline concentration increased in both groups, but in the untreated thyrotoxic patients the increase was two to three times greater than that after treatment or that in the myxoedematous group.

5. The blood glucose concentration decreased in eight of nine untreated thyrotoxic patients, but was largely unchanged after treatment or in the myxoedematous patients. A strong negative correlation was found between the decline in blood glucose concentration and the increase in plasma adrenaline concentration in the thyrotoxic group.

6. Thus, during exercise untreated thyrotoxic patients are prone to hypoglycaemia, show an inadequate glucagon response, and exhibit a large counter-regulatory increase in plasma adrenaline concentration.
Albumin metabolism in fasted subjects during late pregnancy
Authors: Olufemi O. Samson , Whittaker Paul G. , Halliday Dave , Lind Tom
Published: August 2015

1. Albumin fractional synthetic rate was determined in five non-pregnant subjects and five normal pregnant subjects in late gestation after an overnight fast by simultaneous prime and intravenous infusion of two precursor amino acids, [15N]glycine and l-[1-13C]leucine, with additional priming of the large but, slowly turning over, urea pool with [15N2]urea.

2. The two tracers yielded similar values of albumin fractional synthetic rate: 6.1 and 6.0%/day in nonpregnant subjects and 7.3 and 7.6%/day in pregnant subjects, for glycine and leucine, respectively. While plasma volume was greater and serum albumin concentration was significantly reduced during pregnancy, the calculated intravascular albumin mass was significantly increased in pregnant subjects.

3. The amount of albumin synthesized in the intravascular compartment was significantly greater at 8.8 and 9.5 g/day in pregnant subjects compared with 6.4 and 6.3 g/day in non-pregnant control subjects (glycine and leucine methods, respectively). Calculated whole-body protein turnover using glycine was not different between the two subject groups, but leucine flux was higher in pregnant subjects. Partitioning of nitrogenous products in urine revealed that pregnant subjects excreted less urea, less ammonia and less creatinine than the non-pregnant control subjects.

4. These findings suggest that whereas the serum albumin concentration decreases during pregnancy secondary to the large increase in plasma volume, there is an increase in albumin synthesis such that total intravascular albumin mass is increased in late pregnancy.
Evidence for two distinct and functionally important sites of enhanced thromboxane production after bilateral ureteral obstruction in the rat
Authors: Harris K. P. G. , Yanagisawa H. , Schreiner G. F. , Klahr S.
Published: August 2015

1. After bilateral ureteral obstruction there is an enhanced production of thromboxane A2 by the kidney which contributes to a decline in renal function. An acute interstitial macrophage infiltrate also occurs.

2. The relative contribution of infiltrating cells and intrinsic renal cells to the enhanced production of thromboxane A2 by the hydronephrotic kidney were determined. The effects of both irradiation and subsequent administration of the thromboxane synthesis inhibitor OKY-046 on both thromboxane B2 excretion and renal function were examined in rats with 24 h bilateral ureteral obstruction.

3. Irradiation effectively prevented the leucocyte infiltrate after bilateral ureteral obstruction (1.2 ± 0.8 × 105 versus 27.1 ± 0.1 × 105 cells/g of cortex, n = A in each group), resulted in a significantly higher inulin clearance (2.78 ± 0.27 versus 1.49 ± 0.17 ml min−1 kg−1 body weight, n = 7 and n = 8, respectively, P < 0.001) and reduced thromboxane B2 excretion to 39% of non-irradiated values. Subsequent administration of OKY-046 to previously irradiated animals further reduced thromboxane B2 excretion to 20% of the value in non-irradiated rats with bilateral obstruction and further increased inulin clearance to 3.34 ± 0.26 ml min−1 kg−1 body weight.

4. Glomerular macrophage numbers were decreased after bilateral ureteral obstruction (in contrast to the interstitium). However, glomeruli isolated from rats with 24 h bilateral ureteral obstruction exhibited enhanced production of thromboxane B2 compared with sham-operated control rats (855.6 ± 31.1 versus 392.2 ± 25.5 pg 60 min−1 mg−1 of protein, P < 0.001).

5. These data suggest that the increased renal production of thromboxane A2 after bilateral ureteral obstruction results from both renal infiltration by metabolically active macrophages and enhanced prostanoid production by the glomeruli. Both sources of thromboxane A2 contribute to altered renal function after bilateral ureteral obstruction.
Haemostatic responses and vasopressin release during colonoscopy in man
Authors: Hampton K. K. , Grant P. J. , Primrose J. , Dean H. G. , Davies J. A. , Prentice C. R. M.
Published: August 2015

1. During major abdominal surgery there are increases in Factor VIII and plasminogen activator activity, associated with elevated plasma concentrations of vasopressin, of a magnitude shown to affect haemostasis.

2. To investigate the mechanisms involved in the haemostatic response to surgery, 12 patients undergoing fibre-optic colonoscopy were studied, of which six had a complete and six had an incomplete examination.

3. Venous blood samples were taken before, during and after the procedure for assay of plasma vasopressin, adrenaline and noradrenaline concentrations, Factor VIII coagulant activity, von Willebrand factor antigen level, euglobulin clot lysis time, tissue-type plasminogen activator activity and tissue-type plasminogen activator inhibition.

4. In the six patients who underwent a complete procedure the median plasma vasopressin concentration rose from 0.6 pg/ml to 153 pg/ml during colonoscopy. Factor VIII coagulant activity rose from 0.9 to 2.4 i.u./ml and von Willebrand factor antigen level rose from 139 to 224%. Plasminogen activator activity increased from 20 to 144 units and tissue-type plasminogen activator activity rose from 107 to 1338 m-i.u./ml, whereas tissue-type plasminogen activator inhibition fell from 4.8 to 1.0 i.u./ml.

5. In the six patients in whom a limited procedure was performed, there were no changes in haemostatic function or in plasma vasopressin concentration. Plasma concentrations of adrenaline and noradrenaline did not change in either group.

6. The results indicate that vasopressin regulates the intrinsic coagulation pathway and fibrinolytic system in the absence of adrenaline release.
Angiotensin II augments sympathetically mediated arteriolar constriction in man
Authors: Seidelin Peter H. , Collier Joseph G. , Struthers Allan D. , Webb David J.
Published: August 2015

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and postsynaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man.

2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5–150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography.

3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure.

4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P < 0.01). Blood flow was reduced by 21 ± 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 ± 7% in the infused arm, but only by 21 ± 4% in the control arm (P < 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline.

5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow. The absence of an effect of angiotensin II on the response to noradrenaline suggests that augmentation of sympathetic vasoconstriction occurs pre-synaptically through facilitation of noradrenaline release.
Effect of age on hypothalamic prostaglandin E2 production and fever in response to tumour necrosis factor (cachectin) and endotoxin in rats
Authors: Bibby D. C. , Grimble R. F.
Published: August 2015

1. Decreased febrile responses to interleukin-1 and endotoxin have been noted in a number of species with ageing.

2. The present study extends these observations by examining the pyrogenic response to intravenous recombinant human tumour necrosis factor-α (50 μg/kg) using conscious rats aged 7,20 and 80 weeks.

3. The febrile response decreased in magnitude and duration with age. Fevers of 0.9 °C and of 5 h duration were observed in the youngest rats, whereas those aged 80 weeks were afebrile. The depression in serum zinc level and the elevation in liver zinc level, which occurred 7 h after injection, were unaffected by age.

4. The mechanism of the reduced pyrogenic response was examined by assessing prostaglandin E2 production in vitro from hypothalami of rats, aged 10 and 24 weeks, in response to Escherichia coli endotoxin and tumour necrosis factor.

5. Whereas the production of prostaglandin E2 increased by 47% and 52%, respectively, in hypothalami from 10-week-old rats, no response to either pyrogen was obtained in tissue from rats aged 24 weeks.

6. Maturity brings about a decreased responsiveness of hypothalamic prostaglandin E2 production to pyrogens, which may explain the decreased febrile responses observed.
Role of plasma non-esterified fatty acids during and after exercise
Authors: Walker M. , Cooper B. G. , Elliott C. , Reed J. W. , Orskov H. , Alberti K. G. M. M.
Published: August 2015

1. The importance of circulating non-esterified fatty acids as a substrate during and after low-grade exercise has been examined by using a nicotinic acid analogue to inhibit lipolysis. Seven healthy men received acipimox or placebo on separate occasions. After 90 min, bicycle exercise was performed for 45 min (40% of pre-determined maximum oxygen uptake), followed by a 60 min recovery period.

2. The plasma concentration of non-esterified fatty acids increased during exercise after placebo (320 ± 80 to 630 ± 110 μmol/l) and remained elevated in the post-exercise period. Basal concentrations were lower after acipimox (100 ± 10 μmol/l; P < 0.05); they declined to 60 ± 10 μmol/l during exercise and remained at this level for the rest of the study.

3. Lipid oxidation increased from 0.8 ± 0.1 to 4.2 ± 0.5 mg min−1 kg−1 during exercise after placebo (P< 0.001) and remained elevated in the post-exercise period (1.2 ± 0.1 mg min−1 kg−1). It was lower after acipimox, but still increased from 0.3 ± 0.1 to 2.3 ± 0.2 mg min−1 kg−1 with exercise. Carbohydrate oxidation was increased after acipimox compared with after placebo, but only reached significance during the post-exercise period (P < 0.05).

4. Although acipimox abolished the rise in the plasma concentration of non-esterified fatty acids during exercise, there was only a 50% decrease in the rate of lipid oxidation. This suggests that an alternative source of non-esterified fatty acids makes an important contribution to the supply of lipid for oxidation during exercise. The elevated plasma concentration of non-esterified fatty acids and lipid oxidation after exercise serve to limit the further oxidation of carbohydrate.
Kidney renin gene expression after renin inhibition in the marmoset
Authors: Kitami Yutaka , Hiwada Kunio , Murakami Eiki , Iwata Takeru , Muneta Shinjiro , Kokubu Tatsuo
Published: August 2015

1. The effects of renin inhibitor ES-8891 on renin synthesis and its secretion by the kidney were investigated in normotensive sodium-depleted marmosets. We measured plasma renin activity, plasma immunoreactive renin concentration, plasma angiotensin II concentration and kidney renin mRNA content after oral administration of ES-8891 (60 mg day−1 kg−1) for 1 week.

2. The mean blood pressure was significantly decreased (P< 0.01) on day 7 after oral administration of ES-8891. There was no significant change in heart rate during the administration.

3. Oral administration of ES-8891 for 1 week markedly decreased the plasma renin activity, the plasma immunoreactive renin concentration and the plasma angiotensin II concentration (to 18%, 41% and 24% of the corresponding control values; P < 0.05 for each, n = 5).

4. The kidney renin mRNA content in ES-8891-treated marmosets was significantly lower than that in normal controls (4.2 ± 3.5 versus 12.8 ± 5.5 pg/μg of total RNA, means ± sd, P < 0.05, n = 5).

5. Oral administration of the renin inhibitor ES-8891 for 1 week not only inhibited plasma renin activity but also decreased renin synthesis and its secretion by the kidney.
Stimulating effects of atenolol on vasodepressor prostaglandin generation in spontaneously hypertensive rats
Authors: Hirawa Nobuhito , Uehara Yoshio , Numabe Atsushi , Takada Satoru , Matsuoka Hiroaki , Ikeda Toshio , Sugimoto Tsuneaki , Yagi Shigeru , Ishii Masao
Published: August 2015

1. To assess the role of the vasodepressor prostaglandin system in the antihypertensive properties of β-adrenoceptor antagonist, we investigated the alterations of prostaglandin generation in the kidney and in the aorta when spontaneously hypertensive rats were treated with atenolol for 2 weeks.

2. The blood pressure reduction was associated with an increase in urinary sodium excretion and urinary prostaglandin E2 excretion. The sodium excretion was positively related to the prostaglandin E2 excretion.

3. Basal release of prostaglandin E2 from the sliced renal cortex was enhanced by the atenolol treatment. Prostacyclin-generating capacity in the aortic wall was also significantly increased.

4. Atenolol treatment stimulated prostaglandin synthesis in the kidney and vascular wall in a dose-dependent manner. However, atenolol per se did not directly stimulate prostaglandin synthesis in the vascular wall.

5. Inhibition of prostaglandin generation by a cyclo-oxygenase inhibitor, indomethacin, was associated with attenuation of the antihypertensive effects of atenolol.

6. Thus these data indicate that sub-chronic atenolol treatment stimulates vasodepressor prostaglandin generation in the kidney and in the aortic vessels, and this shares the antihypertensive effects of this drug with the mechanism of β-adrenergic antagonism probably mediated through vasorelaxation and natriuresis.
Splanchnic haemodynamic changes during acute hypoglycaemia in man
Authors: Braatvedt G. D. , Newrick P. G. , Halliwell M. , Wells P. N. T. , Read A. E. , Corrall R. J. M.
Published: August 2015

1. Splanchnic haemodynamic changes were studied in seven healthy subjects during hypoglycaemia induced by the intravenous infusion of insulin. Superior mesenteric artery blood flow and cardiac output were examined non-invasively by a Doppler ultrasound technique.

2. Blood glucose concentration fell from 4.5 (0.14) mmol/l basally to 1.5 (0.09) mmol/l [mean (sem), P < 0.003] at the hypoglycaemic reaction (‘R’) and recovered to baseline by ‘R’ + 60 min. There was an associated rise in plasma glucagon, adrenaline and noradrenaline levels.

3. Superior mesenteric artery blood flow rose at ‘R’ from a basal value of 532 (38) ml/min to a peak of 803 (73) ml/min at ‘R’+10 min [mean (sem), P < 0.005] and remained significantly elevated until ‘R’ + 40 min. Resistance in this vessel fell by 33% at ‘R’+ 10 min (P < 0.005) and remained significantly low until ‘R’ + 40 min.

4. Cardiac output rose by 33% at ‘R’ (P < 0.004) and returned to normal by ‘R’ + 20 min. This was associated with a 24% rise in pulse rate (P 0.03), but no change in stroke volume or mean arterial pressure. Total peripheral resistance fell by 21% at ‘R’ (P 0.005) and had returned to normal by ‘R’ + 20 min.

5. The sustained rise in splanchnic blood flow during hypoglycaemic recovery may be of homoeostatic importance by providing metabolic fuel to the liver for gluconeogenesis.
Betaine-homocysteine methyltransferase: organ distribution in man, pig and rat and subcellular distribution in the rat
Authors: McKeever M. P. , Weir D. G. , Molloy A. , Scott J. M.
Published: August 2015

1. Conflicting reports exist as to the organ distribution of betaine-homocysteine methyltransferase (EC 2.1.1.5). It is important to establish its presence or absence in brain, since its substrate, betaine, has recently become established in the treatment of certain diseases involving this organ.

2. It remains unclear whether the reported success of this treatment results from the use of betaine to methylate homocysteine and produce methionine in situ in neural tissue, or whether the effect is secondary to these same reductions happening in other organs, such as the liver. The former would require the presence of betaine-homocysteine methyltransferase in neural tissue.

3. This study demonstrates the complete absence of any activity for this enzyme in the brain of the three species examined. The enzyme was found to be present in both the liver and kidney of man and pig, but only in the liver of the rat.

4. The only source of betaine in cells is via the oxidation of choline. Since the enzymes involved in this conversion have never been shown to exist anywhere other than the mitochondria, it has been assumed that the methyltransferase is also mitochondrial. In this study, it is demonstrated that the enzyme exists only in the cytoplasm of rat liver cells.
Separation of the impairment of haemostasis by aspirin from mucosal injury in the human stomach
Authors: Hawkey C. J. , Hawthorne A. B. , Hudson N. , Cole A. T. , Mahida Y. R. , Daneshmend T. K.
Published: August 2015

1. An increasing body of data suggests that the anti-haemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena.

2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied.

3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7–10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2–16.5, P < 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration.

4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin.

5. We conclude that aspirin can be shown to have both erosive and anti-haemostatic effects in the human stomach. Each can be evaluated separately in our model system. Both are potential therapeutic targets for the prevention of major upper-gastrointestinal bleeding caused by aspirin and probably other non-steroidal antiinflammatory drugs.
Short-term reproducibility of a mental arithmetic stress test
Authors: Jern Sverker , Pilhall Martin , Jern Christina , Carlsson Sven G.
Published: August 2015

1. To evaluate the short-term reproducibility of heart rate, oscillometrically determined blood pressure, ante-cubital venous plasma catecholamine concentrations and subjective responses to strictly standardized mental arithmetic, we performed two identical tests 1 h apart in 14 young, healthy and normotensive male subjects (age 22–35 years)

2. Heart rate and blood pressure responses to the two stress tests were highly correlated, when expressed both as correlations between levels attained during stress (rs >0.80 throughout) and as absolute reactivity measures (all rs >0.75). Also, subjective stress responses were highly correlated, when considering both levels during stress and reactivity (r = 0.97 and r = 0.85, respectively). Stress levels of catecholamines were correlated, but the change scores (reactivity) were unrelated.

3. The measurement error sd for heart rate was 2.6 and 3.0 beats/min for reactivity and stress levels, respectively. The corresponding sd for blood pressure ranged between 2.7 and 4.4 mmHg. Subjective stress experience showed an sd of a similar magnitude. The responses of plasma catecholamine concentrations were subject to considerable variability.

4. It is concluded that haemodynamic and subjective stress responses and stress levels during the mental arithmetic stress test show acceptable reproducibility and high test-retest correlations. However, stress-induced changes in venous plasma catecholamine concentrations show low reproducibility.
Abnormal expression of growth regulatory factors in Barrett's oesophagus
Authors: Jankowski J. , McMenemin R. , Hopwood D. , Penston J. , Wormsley K. G.
Published: August 2015

1. In order to assess potential abnormalities in the control of mucosal proliferation, 30 patients with Barrett's oesophagus were studied in order to evaluate the presence and distribution of epidermal growth factor, transforming growth factor-α and epidermal growth factor receptor to determine the Ki-67 labelling index in the affected oesophageal mucosa. Serial sections were analysed immunohistochemically. Ten of the patients had adenocarcinoma in the Barrett's mucosa and the other 20 had differing histological types of Barrett's mucosa (10, intestinal-type; 10, fundic-or cardiac-type).

2. The expression of transforming growth factor-α, epidermal growth factor and epidermal growth factor receptor was increased and the Ki-67 labelling index was higher in Barrett's mucosa compared with normal gastric mucosa. The ‘intestinal-type’ of Barrett's mucosa had the greatest expression of transforming growth factor-α, epidermal growth factor receptor and the highest Ki-67 labelling index compared with the other types of Barrett's metaplasia. Five cases of ‘intestinal-type’ Barrett's metaplasia had especially high Ki-67 labelling indices and these patients over-expressed both transforming growth factor-α and epidermal growth factor receptor. The patients with adenocarcinomas in the Barrett's mucosa also over-expressed transforming growth factor-α and epidermal growth factor receptor, but not epidermal growth factor, compared with normal gastric mucosa.

3. In conclusion, both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett's mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.
Strenuous exercise: analogous to the acute-phase response?
Authors: Weight Lindsay M. , Alexander Donald , Jacobs Peter
Published: August 2015

1. It has been suggested that the physiological consequences of strenuous exercise are analogous to those of the acute-phase response.

2. In 70 male and 20 female competitive distance runners, a marked, but transient, neutrophil leucocytosis occurred immediately after these athletes completed a standard (42 km) marathon race. Concomitant significant increases were noted in the plasma cortisol levels, creatine kinase activity, C-reactive protein level, total protein level and albumin level (P <0.01).

3. The plasma fibrinogen, C-reactive protein and total protein concentrations were markedly increased both 24 h and 48 h after exercise (P <0.01). The serum haptoglobin level was significantly decreased after exercise (P <0.01), and increased 48 h later (P <0.05). There was no change in the serum iron level, total iron-binding capacity, per cent saturation of transferrin and serum ferritin level.

4. A significant increase in interleukin-1-type activity was demonstrated immediately and 24 h after exercise (P <0.01).

5. It is concluded that the metabolic sequelae of sustained exercise are similar, but not analogous, to the acute-phase response, and interleukin-1 probably plays a significant role in linking the haematological and immunological changes observed after sustained strenuous exercise.
Na+/H+ and HCO3−/Cl− exchange in the control of intracellular pH in vivo in the spontaneously hypertensive rat
Authors: Syme P. D. , Aronson J. K. , Thompson C. H. , Williams E. M. , Green Y. , Radda G. K.
Published: August 2015

1. We have previously shown that the cytosolic acid concentration changes in skeletal muscle during contraction in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats in vivo. We have now found that this change was unaffected by 20% inhaled CO2 or by 4,4′-di-isothiocyanostilbene-2,2′-disulphonate. This is evidence that HCO3− exchange in vivo is not important in the control of cytosolic acid concentration during skeletal muscle contraction in either spontaneously hypertensive or Wistar-Kyoto rats.

2. We have also previously shown that the difference in cytosolic acid response during contraction between spontaneously hypertensive and Wistar-Kyoto rats is due to increased Na+/H+ antiporter activity in the spontaneously hypertensive rats. Our current findings suggest that this increase in Na+/H+ antiporter activity is more likely to be due to a change in the Km of the antiporter than to a change in the Vmax. We estimate that the Km of the antiporter changes in hypertension from pH 7.16 to 7.33.

3. We did not find any differences between adult spontaneously hypertensive and Wistar-Kyoto rats with regard to resting intracellular and extracellular pH and resting intracellular and extracellular HCO3− concentrations. In addition, we did not find any evidence of a difference in skeletal muscle HCO3−/Cl− exchange between adult spontaneously hypertensive and Wistar-Kyoto rats.

4. At rest, skeletal muscles of the spontaneously hypertensive and Wistar-Kyoto rats have the same lactate production, HCO3−/Cl− exchange and arterial partial pressure of CO2. In addition, we can also calculate that at a resting intracellular pH of 7.05 in the spontaneously hypertensive rats, the antiporter is 66% saturated. The corresponding value in the Wistar-Kyoto rats (resting intracellular pH 7.04) is 57%. This explains the lack of difference in resting intracellular pH between the two strains of rat and suggests that at rest differences in Na+/H+ antiporter activity due to a shift in Km of the antiporter are too small to result in a difference in resting pH.

5. Furthermore, Na+/H+ antiporter activity around pH 7.0 was unable to prevent the acidosis caused by CO2 loading. Thus resting pH in skeletal muscle in vivo is determined largely by the HCO3− system and in this regard skeletal muscle is similar to vascular smooth muscle.
Nocturnal variations in lower-leg subcutaneous blood flow in paraplegic men
Authors: Sindrup J. H. , Wroblewski H. , Kastrup J. , Biering-Sørensen F.
Published: August 2015

1. Lower-leg subcutaneous adipose tissue blood flow rates were measured over 12-20 h under ambulatory conditions by means of the 133Xe-washout technique in nine paraplegic men, all with complete spinal cord lesions at or below the Th 6 level, and in nine age-matched healthy men. Portable CdTe(Cl) detectors and datastorage units were used.

2. The central and local sympathetic vasoconstrictive activity at the lower leg was measured under laboratory conditions by means of the l33Xe-washout technique and a stationary NaI(TI) detector system.

3. The paraplegic men were found to have intact central and local sympathetic vasoconstrictive activity in their lower legs. Moreover, they all had a nocturnal hyperaemic blood flow phase of the same magnitude and duration as the control subjects.

4. The possibility that the somaesthetic nerves play a role in the hyperaemic response could be excluded, as all the paraplegic men suffered from complete lower-leg somaesthetic denervation.

5. A significant correlation was found between the time of going to bed and the nightly hyperaemic response in the right and left lower legs (P < 0.01).

6. It is concluded that the present data are in accordance with the concept of a central nervous or humoral elicitation of nocturnal hyperaemia, although local metabolic and other factors might participate as well. Paraplegic men have an intact regulation of the postural and nocturnal changes in peripheral blood flow whether of central sympathetic or humoral origin.
Increased energy expenditure in cystic fibrosis is associated with specific mutations
Authors: O'Rawe A. , McIntosh I. , Dodge J. A. , Brock D. J. H. , Redmond A. O. B. , Ward R. , MacPherson A.J. S.
Published: August 2015

1. Measurements of resting metabolic rate were made by open-circuit indirect calorimetry in 78 unrelated cystic fibrosis patients and 30 healthy control subjects. The aims of this study were: (i) to determine the range of variability in resting metabolic rate in cystic fibrosis, (ii) to relate this to pulmonary function and body size, and (iii) to investigate the hypothesis that, in cystic fibrosis, genotype exerts a significant influence on energy requirements.

2. There was no significant difference in age or body weight between patients with cystic fibrosis and control subjects. Resting metabolic rates for control subjects fell within ± 10% of predicted values. Fifty-nine per cent of patients with cystic fibrosis had elevated resting metabolic rates (i.e. > 111% of predicted). Genotype analysis divided the patients with cystic fibrosis into three groups: AF508 homozygotes, AF508 heterozygotes and others. Patients homozygous for the AF508 allele had a significantly higher resting metabolic rate (121% of predicted, 95% confidence interval 116-126%), compared with other genotypes (P> 0.005).

3. There were significant differences in pulmonary function between the groups (P> 0.005). However, after adjustment of individual resting metabolic rates for differences in pulmonary function by using analysis of co-variance, resting metabolic rates remained significantly higher for ΔF508 homozygotes than for other genotypes (P<0.05).

4. We conclude that there is a significant contribution to resting metabolic rate in cystic fibrosis associated with specific mutations that is not explained by declining pulmonary function. The increase in resting metabolic rate in patients homozygous for mutations involving a nucleotide-binding fold, which may result from a disruptive effect on ATP binding, indicates a practical implication of genotype identification with the need for effective nutritional intervention and support in this patient subgroup.
Metabolic effects of dobutamine in normal man
Authors: Green Ceri J. , Frazer R. S. , Underhill S. , Maycock Paula , Fairhurst Judith A. , Campbell I. T.
Published: August 2015

1. Dobutamine in 5% (w/v) d-glucose was infused at sequential doses of 2, 5 and 10 μg min−1 kg−1, 45 min at each dose, into eight healthy male subjects, and the effects were compared with those produced by infusion of the corresponding volumes of 5% (w/v) d-glucose alone.

2. The energy expenditure increased and was 33% higher than control (P<0.001) at 10 μg of dobutamine min−1 kg−1. The respiratory exchange ratio decreased from 0.85 (sem 0.02) before infusion to 0.80 (sem 0.01) at 10 μg of dobutamine min−1 kg−1, but did not alter during the placebo infusion (P> 0.001).

3. Plasma noradrenaline concentrations were lower during the dobutamine infusion compared with during the infusion of d-glucose alone (P < 0.025). Plasma dopamine concentrations remained below 0.1 nmol/l throughout both infusions.

4. Compared with during the placebo infusion, the blood glucose concentration decreased (P < 0.001), the plasma glycerol and free fatty acid concentrations increased by 150 and 225%, respectively (both P < 0.001), and the plasma potassium concentration decreased from 3.8 (sem 0.07) to 3.6 (sem 0.04) mmol/l (P<0.01) during dobutamine infusion. The plasma insulin concentration increased at 2 and 5 μg of dobutamine min−1 kg−1 (P<0.001) with no further rise at 10 μg of dobutamine min−1 kg−1.

5. Compared with during the placebo infusion, the systolic and diastolic blood pressures and the heart rate increased during dobutamine infusion (P<0.01). At 10 μg of dobutamine min−1 kg−1, the systolic blood pressure was around 160 mmHg (P < 0.001) and the heart rate was around 92 (sem 8) beats/min compared with 59 (sem 4) beats/min during the placebo infusion (P < 0.001).

6. Dobutamine has metabolic effects. It is markedly thermogenic and lipolytic. It depresses the respiratory exchange ratio and endogenous noradrenaline secretion, stimulates insulin secretion and depresses the blood glucose concentration.
Insulin resistance and Na+/K+-ATPase in hypertensive women: a difference in mechanism depending on the level of glucose tolerance
Authors: Mattiasson Ingrid , Berntorp Kerstin , Lindgärde Folke
Published: August 2015

1. The peripheral glucose disposal rate (assessed with the euglycaemic-hyperinsulinaemic clamp technique), the serum sex hormone-binding globulin concentration and total and ouabain-sensitive 22Na-efflux rate constants in leucocytes were determined in 41 women with impaired glucose tolerance and in 40 women with normal glucose tolerance. The groups were matched for body mass index and diastolic blood pressure (range 55-112 mmHg).

2. Stepwise regression analysis showed that diastolic blood pressure in the group with impaired glucose tolerance was inversely correlated with the glucose disposal rate (model r2 = 21%) and was correlated with the plasma glucose concentration at 120 min after an oral glucose load (model r2 = 31%). In the group with normal glucose tolerance, however, neither of these two variables was correlated with blood pressure, although the ouabain-sensitive 22Na efflux rate constant was (model r2=11%).

3. Among insulin-resistant subjects, those with hypertension had significantly lower serum sex hormone-binding globulin concentrations than the normotensive subjects.

4. We conclude that insulin resistance is correlated with high blood pressure in women with glucose intolerance and increased androgenic activity. In women with normal insulin sensitivity, a low level of the Na+/K+-ATPase-mediated sodium efflux is associated with high blood pressure.
Changes in erythrocyte sodium-lithium countertransport kinetics in diabetic nephropathy
Authors: Rutherford Peter A. , Thomas Trevor H. , Carr Susan J. , Taylor Roy , Wilkinson Robert
Published: August 2015

1. It has been proposed that raised erythrocyte sodium-lithium countertransport activity in type 1 diabetic patients is associated with an increased risk of developing diabetic nephropathy. Diabetic patients with established nephropathy would therefore be expected to have high activity.

2. Standard sodium-lithium countertransport activity, sodium affinity (Km) and maximum velocity (Vmax.) were measured in type 1 diabetic patients at different stages of diabetic nephropathy and in appropriately matched uncomplicated diabetic patients and normal control subjects.

3. A small proportion (15%) of patients with nephropathy had standard sodium-lithium countertransport activity higher than the control range. However, mean standard sodium-lithium countertransport activity in the diabetic patients with nephropathy [mean ± sem, 0.26 + 0.12 mmol of Li+ h−1 (l of cells)−1] was not significantly higher than in the uncomplicated diabetic patients [0.27 ± 0.03 mmol of Li+ h−1 (1 of cells)−1] or in the normal control subjects [0.25 ± 0.02 mmol of Li+ h−1 (l of cells)−1].

4. There were marked changes in the kinetic characteristics of the sodium-lithium countertransport in the diabetic patients with nephropathy so that there were decreases in both Km and Vmax.

5. These kinetic changes could not be attributed to an effect of either renal failure per se or the duration of diabetes.

6. The characteristic kinetic changes in sodium-lithium countertransport may indicate underlying alterations in membrane function with the onset of nephropathy in type 1 diabetes.
Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes
Authors: Rogers Mark E. , Williams Dean T. , Niththyananthan Ratnam , Rampling Michael W. , Heslop Kirsten E. , Johnston Desmond G.
Published: August 2015

1. Sialic acid moieties of erythrocyte membrane glycoproteins are the principal determinants of the negative charge on the cell surface. The resultant electrostatic repulsion between the cells reduces erythrocyte aggregation and hence the low shear rate viscosity and yield stress of blood.

2. Using g.c.–m.s., a decrease in sialic acid content has been observed in the major erythrocyte membrane glycoprotein, glycophorin A, obtained from nine diabetic patients compared with that from seven normal control subjects [median (range): 3.30 (0.01–11.90) versus 18.60 (3.20–32.60) μg/100 μg of protein, P<0.02].

3. Erythrocyte aggregation, measured by viscometry as the ratio of suspension viscosity to supernatant viscosity (Ls/S) in fibrinogen solution, was increased in ten diabetic patients compared with ten normal control subjects (mean ± sem, 37.6 ± 1.3 versus 33.8 ± 0.6, P<0.02).

4. In the patients in whom both viscometry and carbohydrate analysis were performed, the decrease in erythrocyte glycophorin sialylation and the increase in erythrocyte aggregation in fibrinogen solution were related statistically(LS/S correlated negatively with glycophorin sialic acid content, r = 0.73, P <0.05).

5. Decreased glycophorin sialylation provides an explanation at the molecular level for increased erythrocyte aggregation and it may be important in the pathogenesis of vascular disease in diabetes.
Endothelium-derived prostacyclin: effect of serum from women with normal and hypertensive pregnancy
Authors: Zammit Vivienne C. , Whitworth Judith A. , Brown Mark A.
Published: August 2015

1. Pregnancy-induced hypertension (or pre-eclampsia) is characterized by vasoconstriction, platelet aggregation and altered capillary permeability, implying disordered endothelial function and/or structure. Serum from women with pregnancy-induced hypertension has been reported by others to be cytotoxic to endothelial cells in vitro. We hypothesized that such serum contains a factor that limits the ability of endothelial cells to produce and/ or release prostacyclin.

2. Prostacyclin production by intact and damaged cultured human umbilical vein endothelial cells was measured after incubating these cells with serum from non-pregnant and normal pregnant women and women with pregnancy-induced hypertension. Confluent human umbilical vein endothelial cell monolayers (intact and damaged) were incubated with sera for 24 h at 37°C followed by 1 h of incubation with added thrombin (stimulated production) or media (basal production). Supernatants were then collected for measurement of 6-keto-prostaglandin F1α by radioimmunoassay.

3. Basal production of 6-keto-prostaglandin F1α was greater in response to serum from non-pregnant women than to that from pregnant women. Within each group, sub-lethally damaged cells had a similar basal production of 6-keto-prostaglandin F1α to that of intact cells.

4. Basal production of 6-keto-prostaglandin F1α by intact or damaged cells incubated with sera from normal pregnant women and from women with pregnancy-induced hypertension was similar.

5. In all groups the addition of thrombin to intact endothelial cells increased 6-keto-prostaglandin F1α production approximately 15–30-fold over basal levels, but only three- to five-fold in damaged endothelial cells. Stimulated production of 6-keto-prostaglandin F1α by intact or damaged cells was similar with sera from normal pregnant women and women with pregnancy-induced hypertension.

6. These results indicate that any cytotoxic factor present in the sera of women with pregnancy-induced hypertension is unlikely to act by reducing basal endothelial production of prostacyclin. Secondly, if endothelial cell injury occurs in these women they may have a reduced capacity to increase endothelial production of prostacyclin in response to thrombin and possibly other important physiological stimuli.