bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of aseptic abscesses in protein-deficient rats on the relationship between interleukin-6 and the acute-phase protein, α2-macroglobulin
Authors: Jennings G. , Cruickshank A. M. , Shenkin A. , Wight D. G. , Elia M.
Published: August 2015

1. Rats established on a normal (20% protein) diet or a protein-deficient (3% protein) diet were given either a subcutaneous injection of turpentine (5 ml/kg), which induces formation of aseptic abscesses, or saline. Plasma samples were obtained at timed intervals (0–14 days) after the injection for determination of albumin, total protein, α2-macroglobulin (a major acute-phase protein in the rat) and interleukin-6 concentrations. The magnitude and pattern of the acute-phase protein response was then compared with the local inflammatory reaction, assessed histologically, and with changes in the circulating concentration of interleukin-6, which is an important mediator of the acute-phase protein response.

2. After turpentine injection there was an early fall in the plasma albumin and total protein concentrations in both normal and protein-deficient rats. After 12 h the total protein concentration increased in both groups of animals reaching a peak at about 48 h, whereas the plasma albumin concentration continued to fall reaching a minimum at 48 h. The main α2-macroglobulin response was delayed and attenuated in the protein-deficient rats (onset 9 versus 24 h, peak concentration 8.95 ± 0.5 versus 5.33 ± 0.75 g/l, P<0.01, and area under the concentration-time curve 18.43 ± 2.13 versus 7.96 ± 1.48 gl−1 days, P<0.01, in the normal group and protein-deficient group, respectively).

3. The circulating interleukin-6 concentration showed a transient early rise at 1 h, and was followed by a larger more sustained peak at 6–48 h. The onset of the secondary rise preceded the onset of the α2-macroglobulin response in both groups of animals, but both the onset and rate of rise were slower in the protein-deficient animals. The peak concentration of interleukin-6 and the area under the concentration-time curve were not significantly different between the groups. There were also no obvious differences in the intensity of the local inflammatory reaction, although the onset of repair was delayed in the protein-deficient animals.

4. This study confirms that the acute-phase protein response is attenuated by protein deficiency, but this does not appear to be due to an attenuated local inflammatory response after turpentine injection. The delayed onset of the interleukin-6 response may explain the delayed onset of the acute-phase response, but the overall magnitude of the interleukin-6 response (total area under the concentration-time curve), which was similar in the two groups, does not explain the overall attenuation of the α2-macroglobulin response.
Biochemical characteristics of human renin expressed in transgenic mice
Authors: Takaori Kazuo , Kim Shokei , Fukamizu Akiyoshi , Sagara Masashi , Hosoi Masayuki , Katsuki Motoya , Murakami Kazuo , Yamamoto Kenjiro
Published: August 2015

1. Biochemical properties of human renin expressed in transgenic mice (hRN8-12 mice) carrying the human renin gene (Fukamizu et al. Biochem Biophys Res Commun 1989; 165: 826–32) were examined. The optimum pH of the enzymic activity against human angiotensinogen was 5.5 for both plasma and renal human renin in the hRN8-12 mice. Plasma concentrations of human active and inactive renin in the plasma of hRN8-12 mice were 16.7 ± 2.8 and 79.9 ± 14.0 pmol of angiotensin 1 h−1 ml−1, respectively, thereby indicating that the predominant form of plasma human renin is the inactive form, as is the case in humans.

2. The molecular masses of plasma human active and inactive renin and renal human active renin in the hRN8-12 mice were estimated to be 46kDa, 48kDa and 44kDa, respectively, as determined by h.p.l.c. on G3,000SW.

3. Human renin in the hRN8-12 mouse kidney was bound to a concanavalin A-Sepharose column, and was eluted with α-methyl-d-mannoside, showing that this renin is glycosylated, as is native human renin.

4. Low sodium treatment of the hRN8-12 mice for 2 weeks increased plasma human active renin, renal human renin and renal human renin mRNA levels by 2.6-, 3.8- and 2.8-fold, respectively. Thus, the biosynthesis and secretion of renal human renin in these transgenic mice are obviously stimulated by sodium depletion.
Renal and systemic sympathetic counterregulation in response to vasodilators in renovascular hypertension
Authors: Herlitz Hans , Hjemdahl Paul , Volkmann Reinhard , Jensen Gert , Aurell Mattias
Published: August 2015

1. Twenty-two patients with renovascular hypertension and significant lateralization of renin secretion were investigated with respect to arterial and renal venous plasma noradrenaline and dopamine concentrations before and 30 min after two different blood pressure-lowering procedures (enalaprilat or dihydralazine intravenously).

2. In one group of patients (n = 10) blood pressure reduction by 7.5 mg of dihydralazine caused stimulation of the renin-angiotensin system and increased heart rate (P < 0.01) as well as arterial and renal venous plasma noradrenaline and dopamine concentrations (P < 0.01 for both). The elevation of the plasma dopamine concentration was more pronounced than that of noradrenaline, yielding increased dopamine/noradrenaline ratios both peripherally (P < 0.05) and in the renal veins (P < 0.05).

3. In the second group of patients (n = 12) a comparable reduction in blood pressure elicited by 1.25 mg of enalaprilat was not accompanied by alterations in heart rate or in noradrenaline or dopamine levels in arterial plasma or renal venous plasma from either kidney.

4. Thus, inhibition of angiotensin-converting enzyme does not elicit the expected sympathetic counter-regulatory response to blood pressure reduction; the mechanism(s) involved remains to be clarified.
Effect of inflammation on peripheral airway reactivity in dogs
Authors: Cormier Y. , Whittom R. , Boulet L. P. , Sériès F.
Published: August 2015

1. Eight mongrel dogs were studied to evaluate the effect of local inflammation on the response of collateral airways to histamine. In each dog we measured the baseline collateral resistance and its response to increasing doses of nebulized histamine. These measurements were obtained at weekly intervals, twice under control conditions and in three subsequent weeks after a local instillation of the bacteria Bordetella bronchiseptica. On each study day, after the measurements of collateral resistance, we lavaged the studied lung segment by instilling and aspirating 100 ml of saline (four 25 ml aliquots). All studies were performed in the same lung segment.

2. Collateral resistance remained stable under control conditions at 19.5 ± 7.2 and 11.7 ± 32 cm H2OI−l mm. With a bacteria-induced, mostly neutrophilic, inflammation, collateral resistance initially increased to 70.2 ± 18.6 cm H2OI−1 min after 1 week and subsequently decreased towards control values (47.3 ± 13 and 30.7 ± 10.1 cm H2OI−1 min at 21 and 29 days, respectively). Collateral pathways reactivity, expressed as the slope of the relationship collateral resistance/log (1 + [histamine]), remained unchanged throughout the study. The values of this slope were (mean ± SEM) 0.021 ± 0.003 and 0.022 ± 0.004 in the two control studies and 0.025 ± 0.004, 0.030 ± 0.006 and 0.023 ± 0.003 in the three subsequent weekly studies. Inflammation, evaluated by the number of bronchoalveolar lavage cells and the percentage of neutrophils in bronchoalveolar cells, closely paralleled baseline collateral resistance with a peak value at the first week after the infection.

3. Local inflammation increases collateral resistance by its mechanical effects, and does not modify the responsiveness of collateral pathways to nebulized histamine.
Intracellular pH regulation in isolated myocytes from adult rat heart in HCO-3-containing and HCO-3-free media
Authors: Ng L. L. , Davies J. E. , Quinn P.
Published: August 2015

1. Using microfluorimetry, intracellular pH, buffering capacity and intracellular pH recovery from intracellular acidosis were determined in isolated adult rat ventricular myocytes, in buffers with and without HCO-3.

2. In nominally HCO-3-free media, the intracellular pH was higher than in HCO-3-containing media. Buffering capacity at resting intracellular pH and at a pH of about 6.3 was also lower in HCO-3-free media.

3. In HCO-3-free media, recovery from an acid load after an NH4C1 prepulse was almost completely inhibited by the Na+/H+ antiport activity specific inhibitor ethylisopropyl amiloride. However, in the presence of HCO-3, H+ efflux rate was enhanced, and ethylisopropyl amiloride led to only partial inhibition of H+ efflux. Complete inhibition was achieved only with further addition of the anion-transport inhibitor 4,4′-di-isothiocyanatostilbene-2,2′-disulphonate.

4. Thus, in adult rat ventricular myocytes, recovery from intracellular acidosis in the absence of HCO-3 was almost wholly due to Na+/H+ antiport activity. In the more physiological situation with HCO-3 present, a third of the recovery from an intracellular acid load was attributed to an additional external Na+-dependent di-isothiocyanatostilbene-disulphonate-sensitive H+ efflux.
A novel thiadiazinone derivative fully reverses acidosis-induced depression of force in cardiac muscle by a calcium-sensitizing effect
Authors: Lee J. A. , Shah N. , White J. , Orchard C. H.
Published: August 2015

1. We examined the effects of the novel thiadiazinone derivative EMD 57033 on developed force and intracellular [Ca2+] in cardiac muscle during control conditions (pH 7.35) and in acidosis (pH 6.8).

2. In the control solution, application of EMD 57033 fully activated the muscle. Acidosis reduced developed force to 18% of maximum, but application of EMD 57033 in acid solution was able to fully reverse this effect and restore force to its previous maximum.

3. During the positive inotropic effect in acidosis, the Ca2+ transients declined to 62% of their initial amplitude, whereas force increased to 557%.

4. These observations suggest that EMD 57033 increases force by a Ca2+-sensitizing action in intact cardiac muscle. Since EMD 57033 is able to fully reverse the effects of acidosis on force without increasing the amplitude of the Ca2+ transients, this compound and others with similar mechanisms of action appear to hold particular promise for heart failure therapy.
Progressive deterioration of muscles in mdx mice induced by overload
Authors: Dick J. , Vrbová G.
Published: August 2015

1. Extensor digitorum longus muscles of C57 BL/10 and mdx mice were overloaded by removing the synergist tibialis anterior muscle of 9–12-day-old animals. The effect of this operation on the weight, contractile properties and force of the extensor digitorum longus muscle was examined at two different ages, i.e. at 2–3 months (young group) and at 5–8 months (old group). The changes with age in both the control and overloaded muscles of normal and mdx mice are also described. The values obtained from the overloaded muscles were always compared with those for the control, unoperated extensor digitorum longus.

2. In the normal strain of mice the weight of the overloaded extensor digitorum longus muscle in the younger group was increased and it remained higher in the older animals. In the mdx mice the overloaded extensor digitorum longus muscles weighed more in the younger animals but not in the older group of mice.

3. The twitch and tetanic tensions of the overloaded muscles were slightly, but not significantly, increased in the younger group of mdx mice, whereas in the older animals there was a significant decrease in both twitch and tetanic tensions.

4. Thus the overloaded muscles from mdx mice progressively deteriorated with age. In both strains of mice the overloaded muscles become less fatiguable with time.
Thyroid hormone stimulates release of calmodulin-enhancing activity from human erythrocyte membranes in vitro
Authors: Lawrence William D. , Deziel Mark R. , Davis Paul J. , Schoenl Marion , Davis Faith B. , Blas Susan D.
Published: August 2015

1. Thyroid hormone (L-thyroxine, 10−10mol/l) incubated in vitro with human erythrocyte membranes induced the release of a soluble calmodulin-like material, the 3′:5′-cyclic nucleotide phosphodiesterase-stimulating activity of which was at least six-fold greater than its concentration measured by a specific calmodulin radioimmunoassay.

2. The material had the characteristics of calmodulin in that it stimulated both phosphodiesterase and erythrocyte Ca2+-ATPase activities, cross-reacted with and was neutralized by anti-calmodulin antibody, was adsorbed by phenothiazine-Sepharose and was heat-stable. Control supernatant from the incubation of membranes in the absence of thyroxine contained calmodulin, the bioactivity of which was not enhanced beyond that predicted from radioimmunoassay. Subsequent addition of thyroxine did not increase calmodulin bioactivity. Calmodulin-agarose removed calmodulin-enhancing activity from the supernatant.

3. Thus, the enhancing factor(s) appears to interact directly with calmodulin. These observations indicate that thyroid hormone promotes the release from human erythrocyte membranes of a soluble factor (or factors) which binds to calmodulin and significantly increases its bioactivity. This enhancing activity is similar to that of a calmodulin activator described in a rat model of hypertension (S.-L. Huang et al., J Clin Invest 1988; 82: 276-81).
Uromodulin levels are decreased in urine during acute tubular necrosis but not during immune rejection after renal transplantation
Authors: McLaughlin P. Jeremy , Alkawa Atsushi , Davies Helen M. , Ward Richard G. , Bakran Ali , Sells Robert A. , Johnson Peter M.
Published: August 2015

1. Uromodulin, an immunosuppressive glycoprotein found in urine, is a high-affinity binding ligand for certain cytokines, including tumour necrosis factor.

2. Its occurrence in urine was monitored after renal transplantation to investigate whether this simple urine test might differentiate common early causes of graft failure: acute immune rejection and acute tubular necrosis.

3. Diluted urine was assayed for uromodulin using a sandwich enzyme-linked immunosorbent assay. When graft function failed due to acute tubular necrosis, urinary uromodulin levels were significantly depressed compared with levels in urine produced during biopsy-proven acute immune rejection episodes (P < 0.01) or during periods of stable graft function (P < 0.02). This suggests that urinary levels of uromodulin may reflect tubular damage rather than other causes of graft functional failure.

4. The cytokine tumour necrosis factor, which binds with high affinity to uromodulin, was found in 30% of urine samples in association with immune rejection episodes, but not during acute tubular necrosis. However, the presence of urinary tumour necrosis factor was not related to levels of uromodulin in the same sample.
Paradoxical forearm vasodilatation and haemodynamic improvement during cardiopulmonary baroreceptor unloading in patients with congestive heart failure
Authors: Nishian Katsuhiko , Kawashima Seinosuke , Iwasaki Tadaaki
Published: August 2015

1. To examine the contribution of paradoxical reflex forearm vasodilatation during unloading of cardiopulmonary baroreceptors to systemic haemodynamics, the responses of central and peripheral haemodynamics during lower-body negative pressure were measured in 24 patients with chronic congestive heart failure (New York Heart Association functional class II-IV) and were compared with those of 10 normal subjects.

2. Lower-body negative pressure of less than −20 mmHg caused a significant forearm vasoconstriction in normal subjects but not in patients with congestive heart failure. In the individual cases, however, eight patients (subgroup A) had a significant forearm vasoconstriction, whereas 10 patients (subgroup B) had a paradoxical forearm vasodilatation. The remaining six patients had a blunted forearm vascular response. Baseline pulmonary capillary wedge pressure (26 ± 3 versus 20 ± 1 mmHg, means ± SEM) and left ventricular wall stress in end-diastole (57 ± 6 versus 37 ± 4 g/cm2) were significantly (P <0.05) higher in subgroup B than in subgroup A.

3. During lower-body negative pressure of −20 mmHg, the plasma level of noradrenaline, systemic vascular resistance and cardiac index did not change significantly in subgroup A. In subgroup B, however, during this orthostatic stimulus systemic vascular resistance fell significantly from a baseline value of 2023 ± 109 to 1740 ± 110 dyns−1 cm−5 (P <0.01) and cardiac index increased significantly from a baseline value of 2.0 ± 0.1 to 2.5 ± 0.21 min−1 m−2 (P <0.01) despite there being no significant change in the plasma level of noradrenaline.

4. After treatment, a second bout of lower-body negative pressure was applied to seven patients in subgroup B. The forearm vascular response to the second bout of lower-body negative pressure was normalized.

5. These data suggest that the patients with more severe heart failure show a paradoxical forearm vasodilatation during mild lower-body negative pressure and that this altered cardiopulmonary baroreflex control of the circulation serves to improve the depressed cardiac performance.
Chronic insulin treatment in rats: Evidence against a role for insulin as a pressor agent
Authors: Vargas Félix , Sabio José Mario , Castillo Miguel Angel , De Dios Luna Juan , Haro José Manuel , García Del Río Cipriano
Published: August 2015

1. The present study was undertaken to test whether insulin acts as a pressor agent and causes hypertension in rats.

2. Insulin at doses of 10 or 100 units day−1 kg−1 was administered daily by subcutaneous injection to normal rats for 6 weeks. As it has been suggested that sodium retention plays a major role in the putative hypertensive activity of this hormone, insulin was also administered to saline- (1% NaCl) drinking rats according to the same protocol. Water- and saline-drinking rats served as controls.

3. After 6 weeks of insulin treatment, the mean arterial blood pressure did not increase in any of the insulin-treated or the insulin-salt-treated groups. However, in both insulin-salt-treated groups, absolute and relative ventricular and renal hypertrophy with increased ventricular water content as well as increased urine output with reduced osmolality were observed.

4. All insulin-treated groups showed increased plasma levels of glucose, insulin and antidiuretic hormone when compared with their respective controls.

5. These results demonstrate that chronic insulin treatment did not increase blood pressure in rats, even when drinking water was supplemented with NaCl, and suggest that a polyuria-polydipsia syndrome was present in both insulin-salt-treated groups. Moreover, increased plasma levels of antidiuretic hormone were observed in all insulin-treated groups.
Cerebrospinal fluid levels of substance P and calcitonin-gene-related peptide: Correlation with sural nerve levels and neuropathic signs in sensory diabetic polyneuropathy
Authors: Tsigos C. , Diemel L. T. , White A. , Tomlinson D. R. , Young R. J.
Published: August 2015

1. Lumbar spinal substance P and calcitonin-gene-related peptide derive from spillage out of the dorsal horns associated with activity of small primary sensory afferents (C- and Aδ-fibres). Cerebrospinal fluid and sural nerve levels of substance P and calcitonin-gene-related peptide have been measured in patients with diabetic polyneuropathy to determine whether differences in small primary sensory afferent activity are related to the presence or absence of painful symptoms.

2. Calcitonin-gene-related peptide was undetectable in the cerebrospinal fluid of the majority of diabetic patients (14 out of 22); it was lower overall in diabetic patients as compared with control subjects (P <0.01), it was lower in those diabetic patients with painless neuropathy (100% undetectable) as compared with those with painful neuropathy (50% undetectable; P <0.05) and it correlated conversely with warming threshold (r = 0.50; P <0.01).

3. Substance P showed no overall numerical inter-group differences or correlation with other measured variables, but six diabetic patients as compared with one control subject had undetectable cerebrospinal fluid levels and the proportion of patients with undetectable levels was higher in the group with painless neuropathy than in the group with painful neuropathy (P <0.05).

4. The levels of each peptide in cerebrospinal fluid correlated with its equivalent in sural nerve (P <0.01 for calcitonin-gene-related peptide and P <0.03 for substance P). Calcitonin-gene-related peptide correlated with substance P in the sural nerve (r = 0.84; P <0.002) and in the cerebrospinal fluid (r = 0.30; P <0.03).

5. We conclude that in sensory diabetic polyneuropathy the lumbar cerebrospinal fluid levels of substance P and calcitonin-gene-related peptide relate directly to their levels in sural nerve and appear to be reduced in the painless compared with the painful syndrome, suggesting a relatively spared and/or more active primary sensory afferent fibre population in the latter.
Normal values for handgrip strength in 920 men and women aged over 65 years, and longitudinal changes over 4 years in 620 survivors
Authors: Bassey E. J. , Harries U. J.
Published: August 2015

1. The maximal grip strength of the hand has been measured in a random sample of 359 men and 561 women aged over 65 years living in their own homes. The response rate was 80% from a representative demographic area of the U.K. Measurements were made of body mass, skeletal size (demispan) and grip strength. Grip strength was measured using a custom-built strain-gauged dynamometer. The best of three attempts was taken as definitive. A structured questionnaire was used to obtain information about customary activity, use of handgrip muscles, health and psychological well-being. This was repeated with 620 survivors 4 years later.

2. The results for strength were normally distributed. The right hand was 10% stronger than the left and men had twice the strength of women. Strength was significantly related to skeletal size and in men to body mass. The gender difference was only partly accounted for by skeletal size and women were substantially disadvantaged in terms of their strength/body mass ratio.

3. There was a significant decline in strength with age of 2%/year for men and women. Strength was also significantly related to customary activity, reported use of the hands and psychological and physical health.

4. After 4 years 620 survivors were re-measured. Grip strength had declined by 12% in men and 19% in women and these losses were significantly related to age. A significant decline was also found in reported use, customary activity and health scores, and in women in body mass and psychological health. The loss of strength was significantly related to the decline in reported use of the hands but not to the other losses.

5. It is concluded that loss of strength over time in old age may be seriously underestimated by cross-sectional studies, especially in women; and that the loss is consistently and predominantly related to lack of use, rather than loss of health.
Antibodies to Human Recombinant Lipocortin-L in Inflammatory Bowel Disease
Authors: Stevens T. R. J. , Smith S. F. , Rampton D. S.
Published: August 2015

1. Corticosteroid drugs are widely employed for the treatment of active inflammatory bowel disease. Not all patients receiving corticosteroid treatment, however, respond satisfactorily, their disease either remaining active in spite of continued treatment, or relapsing upon corticosteroid withdrawal. Raised levels of autoantibodies to lipocortin-I, a corticosteroid-inducible protein with anti-inflammatory activity in vitro, in patients receiving chronic oral corticosteroid therapy have been associated with poor clinical response in rheumatoid arthritis.

2. To determine whether a similar mechanism is responsible for the variable clinical response to corticosteroids in inflammatory bowel disease, we have measured circulating lipocortin-I antibody levels in sera from affected patients and related them to disease activity, treatment and subsequent outcome.

3. IgM, but not IgG, lipocortin-I antibody levels were elevated in patients with ulcerative colitis and Crohn's disease compared with healthy control subjects. In patients with Crohn's disease not taking corticosteroids, IgM lipocortin-I antibody levels were directly related to disease activity scored clinically.

4. IgM lipocortin-I antibody levels were higher in patients receiving sulphasalazine or no treatment and in patients receiving corticosteroids who responded to treatment within 2 months (steroid responders) than in those patients undergoing long-term corticosteroid therapy because of continued disease activity or repeated relapse on corticosteroid withdrawal (steroid non-responders).

5. The high levels of IgM lipocortin-I antibodies in patients with inflammatory bowel disease not taking corticosteroids provides further evidence of disturbed immunity in inflammatory bowel disease. The low levels of IgM lipocortin-I antibody in patients undergoing long-term corticosteroid therapy (steroid nonresponders) contrasts with previous findings in patients with rheumatoid arthritis and might reflect corticosteroid-induced antibody suppression and/or depressed production of endogenous lipocortin-I antigen.
Changes in Sodium Transport during the Human Menstrual Cycle and Pregnancy
Authors: Webb G. D. , Ashmead G. G. , Al-Mahdi S. , Auletta F. J. , McLaughlin M. K.
Published: August 2015

1. We have studied the transport of Na+ and K+ by erythrocytes during the follicular and luteal phases of the human menstrual cycle, and in pregnant compared with non-pregnant women. Venous blood was drawn from 10 healthy young women (not taking any medication or hormones) 1-2 days after menstruation and from the same women 7-9 days after ovulation. For the pregnancy part of the study, blood was drawn from eight other normotensive non-pregnant women and from eight age-matched normotensive pregnant women (36-43 weeks gestation).

2. Intracellular erythrocyte and plasma Na+ and K+ concentrations were measured by flame photometry. The increase in the intracellular Na+ concentration during a 1 h 37°C incubation of fresh whole blood with 0.2 mmol/l ouabain (compared with no ouabain) was measured to determine the rate of active Na+ efflux. The Na+-K+ pump rate constant was calculated by dividing the active Na+ efflux rate by the intracellular Na+ concentration.

3. In fresh blood, the intracellular erythrocyte Na+ concentration (P < 0.002) and the plasma K+ concentration (P < 0.01) were both lower in pregnant than in non-pregnant women. The Na+-K+ pump rate constant was higher (P < 0.02) during the luteal phase than during the follicular phase, and in pregnant compared with non-pregnant women.

4. We conclude that short-acting hormones in the plasma most probably account for the changes in the Na+-K+ pump rate constant during the menstrual cycle.
In the Groove: The Fine Detail of Antigen Presentation to Cytotoxic T Lymphocytes
Authors: Moots Robert J.
Published: August 2015

1. A panel of cells designed to express normal or mutated human HLA-A0201 was constructed and used to investigate the interactions between the peptide antigen, class I major histocompatibility complex, CD8 and cytotoxic T lymphocyte antigen receptor.

2. Analysis of the extensive data generated has revealed that the optimum peptide presented to cytotoxic T lymphocytes by HLA-A0201 contains nine amino acids. It lies in the peptide-binding groove of the class I molecule, orientated from N- to C-termini, and its detailed position within the groove has been deduced. The roles of individual residues in the class I molecule in antigen presentation are described, and the site of the ligand on target cells for interaction with CD8 on cytotoxic T lymphocytes is located.
Repeatability of Transcranial Doppler Measurements of Arterial Blood Flow Velocities in Healthy Subjects
Authors: Demolis Pierre , Chalon Stephan , Giudicelli Jean-François
Published: August 2015

1. Transcranial Doppler measurements of the mean blood flow velocity and the resistance index in the middle cerebral artery are used to assess cerebral haemodynamics. The prerequisite for the use of these parameters in clinical pharmacology studies is an evaluation of their repeatability and spontaneous variation with time.

2. Repeatability of transcranial Doppler measurements of mean blood flow velocity and resistance index was investigated in healthy subjects by calculation of the repeatability coefficient as defined by the British Standards Institution. Intra-observer repeatability (comparison of two successive determinations by one observer, n = 30 subjects), between-observer repeatability (comparison of two successive measurements each performed by a different observer, n = 30) and long-term repeatability (comparison of two determinations performed at the same hour with a 1 week interval by one observer, n = 14) were assessed. In addition, the spontaneous evolution with time of mean blood flow velocity and resistance index was determined over an 8 h period (n = 14).

3. Repeatability coefficients for intra-observer repeatability, between-observer repeatability and long-term repeatability were 4.83, 4.59 and 3.32 cm/s for mean blood flow velocity (normal value = 61.2 ± 10.2 cm/s) and 2.62, 3.12 and 3.49% for resistance index, respectively (normal value = 53.6 ± 5.9%), indicating that transcranial Doppler measurements are repeatable enough to be used over periods of time of up to 1 week in clinical pharmacology studies.

4. Finally, a time effect was detected for mean blood flow velocity, indicating that this parameter undergoes diurnal variation.
Iso-Oncotic Volume Expansion in the Nephrotic Syndrome
Authors: Rabelink Ton J. , Bijlsma Joost A. , Koomans Hein A.
Published: August 2015

1. In previous studies we found that albumin infusions caused only a modest natriuresis in the nephrotic syndrome, suggesting that hypovolaemia played no part in the sodium retention of these patients. However, this finding was inconclusive, since the hyperoncocity of the infused albumin probably opposed sodium excretion.

2. In the present study, we examined the effect of sustained (68 h) plasma volume expansion (+18%), by means of iso-oncotic albumin infusions, on renal function, blood pressure, humoral factors and sodium balance.

3. Plasma atrial natriuretic peptide levels increased almost threefold and renin-angiotensin system activity was suppressed. Glomerular filtration rate remained unchanged, whereas estimated renal plasma flow increased, resulting in a further decrease in filtration fraction.

4. The increase in plasma volume expansion was accompanied by a modest increase in sodium excretion, which, however, was less than the amount of sodium daily infused with the albumin solutions and consumed with the diet, so that net sodium was retained.

5. This observation supports the concept that an intrinsic renal defect causes the sodium retention in the nephrotic syndrome, and argues against the therapeutic use of albumin infusions.
A Method for the Continuous Measurement and Display of Pulmonary Resistance in Man
Authors: Lane R. , Freedman S. , Guz A.
Published: August 2015

1. We have validated a method for the continuous display and ‘on-line’ measurement of total pulmonary resistance in man, using a hybrid digital/analog computer.

2. The basic variables, which are measured by standard techniques, are flow rate of the mouth (V̇) and oesophageal pressure (Poes), and these are the only analog inputs necessary to the computer.

3. Resistance (RL, cont) is calculated continuously as: RL, cont = (Poes - V/C)/V̇ where V is tidal volume and C is the dynamic compliance. RL, cont is continuously displayed as an analog signal on an oscilloscope.

4. Changes in resistance, measured by this method over a wide range of values in three subjects, showed an almost exact correlation with those measured by a standard method (Mead-Whittenberger).
Effect of Chronic Smoking on Endothelium-Dependent Vascular Relaxation in Humans
Authors: Jacobs Marie-Cécile , Lenders Jacques W. M. , Kapma Jan A. , Smits Paul , Thien Theo
Published: August 2015

1. Cigarette smoking is one of the major risk factors for the development of atherosclerosis. It is not clear, however, whether chronic cigarette smoking impairs the normal physiological function of the endothelium before the development of morphological vascular lesions. To test this, we investigated endothelium-dependent vascular relaxation in young habitual smoking subjects.

2. In 11 non-smokers and 10 habitual smokers we measured the changes in bilateral forearm blood flow, arterial blood pressure and forearm vascular resistance (ratio between mean arterial blood pressure and forearm blood flow) during three interventions: postocclusive forearm hyperaemia, intrabrachial infusion of methacholine which causes vasodilatation by stimulating the release of endothelium-dependent relaxing factor, and intrabrachial infusion of sodium nitroprusside which causes vasodilatation independently from the endothelium by a direct effect on the vascular smooth muscle wall.

3. During infusion of the highest dose of methacholine, forearm vascular resistance decreased by 91.7 ± 1.4% in the smokers and by 89.9 ± 1.8% in the non-smokers. During infusion of sodium nitroprusside, forearm vascular resistance decreased by 80.0 ± 3.8% in the smokers as compared with 80.7 ± 6.1% in the non-smokers. There was no difference in basal forearm vascular resistance or in post-ischaemic reactive hyperaemia between smokers and non-smokers. Thus, vasodilatation induced by both methacholine and sodium nitroprusside was not significantly different between smokers and non-smokers.

4. We conclude that in young habitual cigarette smokers the endothelium-dependent vasodilatation in the forearm seems to be preserved, suggesting that habitual smoking does not result in permanent endothelial dysfunction in the human forearm.
Reduced Renal Papillary Plasma Flow in Non-Ascitic Cirrhotic Rats
Authors: Atuchá Noemí M. , Quesada Tomás , Garcia-Estañ Joaquín
Published: August 2015

1. The purpose of the present investigation was to determine whether an abnormality of the renal papillary circulation is present in a well-established model of cirrhosis without ascites (carbon tetrachloride/phenobarbital).

2. Compared with the control animals, cirrhotic rats showed a reduced diuretic (61.0 ±5.1 versus 18.0 ±2.5%) and natriuretic (67.8 ±8.3 versus 29.6 ±3.6%) response to a volume expansion (3% body weight infusion of 0.9% NaCl). The volume expansion-induced increase in renal interstitial hydrostatic pressure was also blunted in the cirrhotic rats (control 9.3 ±0.9 versus cirrhotic 6.1±1.0 mmHg) and there were no differences in mean arterial blood pressure, renal blood flow or glomerular filtration rate between control and cirrhotic animals.

3. Papillary plasma flow was determined by the 125I-albumin accumulation technique and expressed as mlmin−1100 g−1. In the basal state, papillary plasma flow was significantly lower in cirrhotic rats (59.1 ±4.4, n = 9) than in the control animals (81.8 ±6.9, n = 9). An isotonic saline expansion similar to the one described above significantly increased papillary plasma flow in control rats (108.4±9.1, n = 7) but did not change it in cirrhotic rats (60.2 ±4.9, n = 6).

4. Our results indicate the existence of a selective alteration in the renal papillary circulation in cirrhotic rats, both in the basal state and after a well-established vasodilatory stimulus. The reduced papillary plasma flow of the cirrhotic animals, probably mediated through changes in renal interstitial hydrostatic pressure, may participate in the sodium and water retention that precedes the development of ascites and may be an important mechanism mediating the blunted renal response to extracellular volume expansion.
Haemodynamic and Hormonal Responses to Losartan (DuP753/MK954) Infusion during Cardiac Catheterization in Conscious Salt-Deplete Dogs
Authors: MacFadyen R. J. , Tree M. , Lever A. F. , Reid J. L.
Published: August 2015

1. Haemodynamic and hormonal responses to infused angiotensin II were studied in conscious salt-deplete dogs during infusion of D-glucose or losartan (DuP753/MK954).

2. Mean arterial pressure (118±13mmHg) fell rapidly after losartan (60 min 106±18 mmHg) with a rise in heart rate (107±16 beats/min) from baseline (98±17 beats/min). Pressor responses to angiotensin II during D-glucose infusion (6 ng min−1 kg−1, 99±10 mmHg; 18 ng min−1 kg−1, 140±15 mmHg; 54 ng min−1 kg−1, 157±12 mmHg; 162 ng min−1 kg−1, 178±14 mmHg) showed a parallel shift during losartan infusion with very similar pressures in response to higher rates of angiotensin II infusion (54 ng min−1 kg−1,108 ± 17 mmHg;162 ng min−1 kg−1 138±14 mmHg; 486 ng min−1 kg−1, 155±14 mmHg; 1458 ng min−1 kg−1, 177 ± 12 mmHg). Losartan caused a fall in baseline systemic vascular resistance. Despite the similar mean arterial pressure, the rise in systemic vascular resistance after angiotensin II during D-glucose infusion (162 ng min−1 kg−1, 8065± 1967 dyn s cm−5) was reduced during losartan infusion (1458 ng min−1 kg−1, 6645 ±1720 dyn s cm−5. Losartan caused a small rise in cardiac output related to a rise in heart rate and increased stroke volume. Pressure infusions of angiotensin II caused a fall in cardiac output during D-glucose infusion, which was blocked during losartan infusion. The rise in heart rate in response to angiotensin II was similar during both D-glucose and losartan infusion, but with higher absolute values during losartan alone. There was a linear relationship between heart rate and the plasma concentration of angiotensin II, which was unaffected by losartan. Pulmonary pressure was marginally elevated by losartan, related to the rise in cardiac output, and was much less sensitive to angiotensin II infusion, rising only at the highest rate of infusion during both D-glucose and losartan infusion.

3. Losartan infusion alone caused a rise in plasma angiotensin II concentration with a fall in aldosterone concentration. During pressor infusions the measured angiotensin II concentrations suggested that losartan increased the clearance of angiotensin II. 4. Losartan has complex effects on cardiovascular function. The pressor response of mean arterial pressure to angiotensin II shows competitive inhibition, but this marks subtle effects on cardiac output and heart rate, in addition to systemic vascular resistance. In addition to elevating endogenous angiotensin II and suppressing aldosterone, losartan may enhance clearance of infused angiotensin II.
Magnesium Sulphate Reverses the Carotid Vasoconstriction Caused by Endothelin-1, Angiotensin II and Neuropeptide-Y, but Not That Caused by NG-nitro-l-Arginine Methyl Ester, in Conscious Rats
Authors: Kemp P. A. , Gardiner S. M. , Bennett T. , Rubin P. C.
Published: August 2015

1. Magnesium sulphate (MgSO4) has been used for many years in the prevention of eclamptic seizures, but its mechanism of action has never been elucidated. Recent studies suggest that cerebral vasospasm is an important feature of eclampsia and we have developed and tested the hypothesis that MgSO4 can reverse cerebral vasoconstriction.

2. Studies were performed in conscious, male Long Evans rats with pulsed Doppler probes sutured around both common carotid arteries after the external carotid artery had been ligated on the left, thus allowing simultaneous measurement of changes in common and internal carotid blood flow. Intravascular catheters were placed in the abdominal aorta for measurement of systemic blood pressure and in the right jugular vein for administration of drugs. Mean arterial blood pressure and mean Doppler shift signals were used to calculate percentage changes in common and internal carotid vascular conductance.

3. After a period of recovery the animals were infused with endothelin-1, angiotensin II, neuropeptide-Y or NG-nitro-l-arginine methyl ester alone or in combination, and MgSO4 in low or high dose was infused when the effects of the vasoconstrictors had become established.

4. MgSO4 itself, at the low dose, had no effect on carotid vascular conductance. Endothelin-1, angiotensin II and neuropeptide-Y all reduced common and internal carotid vascular conductance and this effect was significantly attenuated by low dose MgSO4. The carotid vasoconstrictor action of endothelin-1 was completely abolished by high dose MgSO4. Combinations of the peptides (endothelin-1/angiotensin II; endothelin-1/neuropeptide-Y; angiotensin II/neuropeptide-Y) also reduced common and internal carotid vascular conductance and these effects were substantially reversed, or completely abolished, by high dose MgSO4. The effect of NG-nitro-l-arginine methyl ester on common and internal carotid vascular conductance was significantly inhibited by human α-calcitonin gene-related peptide, but, in contrast, MgSO4 had no influence.

5. We have tested and confirmed our hypothesis that MgSO4 can reverse cerebral vasoconstriction. The failure of MgSO4 to influence the effects of NG-nitro-l-arginine methyl ester suggest that its vasodilator effect may involve the production of nitric oxide. These findings provide a basis for the action of MgSO4 in eclampsia, and suggest that it may be of value in other circumstances where cerebral vasoconstriction occurs.
Effect of Glucocorticosteroid Treatment on β-Adrenoceptor Subtype Function in Adipocytes from Patients with Asthma
Authors: Reynisdottir Signy , Wahrenberg Hans , Bylin Gunnar , Arner Peter
Published: August 2015

1. Adrenoceptor subtype function was studied in isolated adipocytes obtained by subcutaneous fat biopsies from nine patients with mild asthma. The biopsies were taken before and after 7 days treatment with 25 mg of prednisolone given orally. Lipolytic activity after stimulation with various adrenergic agents was measured, using glycerol release as an index of lipolysis. The number of β1- and β2-adrenoceptor binding sites was determined in radioligand binding experiments and β1- and β2-adrenoceptor mRNA levels were measured with a solution hybridization assay.

2. Lipolytic sensitivity (ED50) to isoprenaline, a nonselective β-adrenoceptor agonist, increased 50-fold after treatment (P = 0.04). Sensitivity to terbutaline, a selective β2-adrenoceptor agonist, increased 25-fold (P =0.01), whereas the ED50 values for dobutamine, a selective β1-adrenoceptor agonist, did not change significantly. Likewise, the sensitivity to the α2-adrenoceptor agonist, clonidine, and to the drugs acting at post-receptor levels did not change significantly. Basal and maximum lipolytic rates on stimulation were not altered by the treatment.

3. The number of β2-adrenoceptor binding sites increased by 60% after treatment (P <0.05), whereas the β1-adrenoceptor binding sites were not affected. The affinity of each receptor subtype for the displacing ligand, ICI 118.551, was not significantly altered by steroids. No significant changes were demonstrated in either β1- or β2-adrenoceptor mRNA levels.

4. Thus, glucocorticoids selectively increase β2-adrenoceptor density and function in patients with asthma, studied by using subcutaneous fat cells as an experimental model.
Bombesin Reduces Food Intake after a Preload in Man by a Cholecystokinin-Independent Mechanism
Authors: Lieverse R. J. , Jansen J. B. M. J. , Masclee A. A. M. , Lamers C. B. H. W.
Published: August 2015

1. A double-blind study was undertaken to determine whether the infusion of bombesin inhibits the intake of a carbohydrate-rich meal, consumed 15 min after a 300 ml banana shake, in nine lean healthy subjects and whether the possible inhibition of food intake by bombesin is mediated by cholecystokinin.

2. The amount of food eaten during infusion of bombesin (267 ±60 g) and bombesin combined with the cholecystokinin-receptor antagonist loxiglumide (269±39g) was slightly (P = 0.09) less than during saline infusion (384 ± 40 g). In addition, preprandial feelings of hunger were significantly less during infusion of both bombesin and bombesin combined with loxiglumide.

3. In conclusion, infusion of bombesin tends to inhibit the intake of a carbohydrate-rich meal after a preload by a cholecystokinin-independent mechanism.
Gene Expression of Metalloproteinases and Their Inhibitor in Renal Tissue of New Zealand Black/White F1 Mice
Authors: Nakamura Tsukasa , Ebihara Isao , Osada Shiori , Takahashi Toshimasa , Yamamoto Masatoshi , Tomino Yasuhiko , Koide Hikaru
Published: August 2015

1. The present study was carried out to determine how levels of the mRNA of metalloproteinases (metalloproteinase-1, 72 kDa type IV collagenase, metalloproteinase-3 and 92 kDa type IV collagenase) and tissue inhibitor of metalloproteinases are regulated in the renal tissues of New Zealand Black/White F1 mice.

2. mRNA levels for metalloproteinase-1, 72 kDa type IV collagenase, metalloproteinase-3 and tissue inhibitor of metalloproteinases increased significantly with the progression of nephritis in New Zealand Black/White F1 mice.

3. At 48 weeks of age, the levels of mRNA for metalloproteinase-1, 72 kDa type IV collagenase, metalloproteinase-3 and tissue inhibitor of metalloproteinases increased by 8-, 4-, 8- and 15-fold, respectively, in the renal tissues of New Zealand Black/White F1 mice compared with New Zealand White mice.

4. In the kidneys of New Zealand White mice, however, the mRNA levels for these proteins changed little throughout the experimental period.

5. We could not detect expression of mRNA for 9 2 kDa type IV collagenase in the renal tissue of New Zealand Black/White F1 mice at 8 weeks of age or in New Zealand White mice at 8, 24 or 48 weeks of age, whereas we could detect expression of mRNA for this protein in New Zealand Black/White F1 mice at 24 and 48 weeks of age when mononuclear cells had infiltrated the interstitium and surrounding blood vessels.

6. At 24 weeks of age, New Zealand Black/White F1 mice were divided into two groups and received either methylprednisolone or saline injection for 24 weeks.

7. The development of histopathological lesions and increases in mRNA for metalloproteinases and tissue inhibitor of metalloproteinases were suppressed by treatment with methylprednisolone.

8. These data suggest that abnormal regulation of the genes for metalloproteinases and tissue inhibitor of metalloproteinases contribute to the accumulation of extracellular matrix components in lupus nephritis and that the beneficial effect of methylprednisolone is associated with its ability to suppress the expression of mRNA for metalloproteinases and tissue inhibitor of metalloproteinases.