Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects.

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.

Retention half times in the skeleton of plutonium and Sr-90 from above-ground nuclear tests: A retrospective study of the Swiss population

Plutonium and Sr-90 are considered to be among the most radiotoxic nuclides produced by the nuclear fission process. In spite of numerous studies on mammals and humans there is still no general agreement on the retention half time of both radionuclides in the skeleton in the general population. Here we determined plutonium and Sr-90 in human vertebrae in individuals deceased between 1960 and 2004 in Switzerland. Plutonium was measured by sensitive SF-ICP-MS techniques and Sr-90 by radiometric methods. We compared our results to the ones obtained for other environmental compartments to reveal the retention half time of NBT fallout Pu-239 and Sr-90 in trabecular bones of the Swiss population. Results show that plutonium has a retention half time of 40 +/- 14 years. In contrast Sr-90 has a shorter retention half time of 13.5 +/- 1.0 years. Moreover Sr-90 retention half time in vertebrae is shown to be linked to the retention half time in food and other environmental compartments. These findings demonstrate that the renewal of the vertebrae through calcium homeostatic control is faster for Sr-90 excretion than for plutonium excretion. The precise determination of the retention half time of plutonium in the skeleton will improve the biokinetic model of plutonium metabolism in humans. (C) 2010 Elsevier Ltd. All rights reserved.

Bio-electrical impedance analysis for estimation of fat-free mass and muscle mass in cystic fibrosis patients.

The nutritional status of cystic fibrosis (CF) patients has to be regularly evaluated and alimentary support instituted when indicated. Bio-electrical impedance analysis (BIA) is a recent method for determining body composition. The present study evaluates its use in CF patients without any clinical sign of malnutrition. Thirty-nine patients with CF and 39 healthy subjects aged 6-24 years were studied. Body density and mid-arm muscle circumference were determined by anthropometry and skinfold measurements. Fat-free mass was calculated taking into account the body density. Muscle mass was obtained from the urinary creatinine excretion rate. The resistance index was calculated by dividing the square of the subject's height by the body impedance. We show that fat-free mass, mid-arm muscle circumference and muscle mass are each linearly correlated to the resistance index and that the regression equations are similar for both CF patients and healthy subjects.

SOMATIC MUTATIONS IN THE KREBS CYCLE ENZYME ISOCITRATE DEHYDROGENASE 1 (IDH1) CAUSE METAPHYSEAL ENCHONDROMATOSIS WITH D-2-HYDROXYGLUTARIC ACIDURIA

Metaphyseal chondromatosis with hydroxyglutaric aciduria (MC-HGA) is a generalized skeletal dysplasia, accompanied by urinary excretion of D-2- hydroxyglutarate (HGA), and variable cerebral involvement. By wholeexome sequencing 2 unrelated patients with MC-HGA, we have found mutations in isocitrate dehydrogenase 1 (IDH1) at codon 132, as apparent somatic mosaicism. IDH1 is a key enzyme of the Krebs cycle, which converts isocitrate into alpha-ketoglutarate (a-KG). Mutations at IDH1 Arg132 residue have originally been identified in different tumour types (isolated gliomas, leukemias, and chondrosarcomas). These mutations trans-specify the enzyme activity resulting in HGA accumulation and a-KG depletion. This induces activation of hypoxia-inducible factor 1-alpha (HIF-1a), an important regulator of chondrocyte proliferation at the growth plate. Differently from Arg132 somatic mutations found in isolated tumours, themutation in our patientsmust have occurred very early in embryogenesis to cause a generalized dysplasia with involvement of all long bones metaphyses and mutation detectability in blood. Identical mutations have subsequently been identified in chondromas excised from patients with multiple chondromatosis (Ollier disease). Tissue distribution of themutationmay explain variable cerebral involvement and the susceptibility to develop tumours in other organs. The postulated pathophysiology ofMC-HGA points out the link between Krebs cycle, hypoxia sensing and bone growth.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of atrial natriuretic (3-28) eicosahexapeptide.

The clinical pharmacology of a synthetic rat atrial natriuretic peptide (rANP) was evaluated in normal volunteers. During a dose-ranging study at 1-40 micrograms/min we observed a dose-dependent decrease in mean intra-arterial blood pressure, an acceleration of the heart rate and a transient increase in blood flow to the skin. During a 4-h constant-dose infusion at 0.5 and 5.0 micrograms/min, inulin clearance remained unchanged but there was a dose-related fall in paraaminohippurate (PAH) clearance and an increase in the filtration fraction. Urinary excretion of sodium, chloride and calcium increased in a dose-related fashion, but with the high dose the excretion curve had a bell-shape. No change in plasma renin activity, angiotensin II and aldosterone was observed during the rANP infusion despite the excretion of large amounts of sodium and a blood pressure reduction with the high dose. Indocyanine green clearance, a measure of hepatic blood flow, was significantly decreased by a 2-h rANP infusion at 1.0 microgram/min. In normal volunteers, therefore, rANP induced vasodilation and blood pressure reduction, a decrease in renal and hepatic blood flow and a natriuretic and transient diuretic effect without activation of the renin-angiotensin-aldosterone system.

Effects of SCH 34826, an orally active inhibitor of atrial natriuretic peptide degradation, in healthy volunteers.

Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single-blind, placebo-controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5-hour urinary sodium excretion was 15.7 +/- 7.3 mmol for the placebo and 22.9 +/- 5, 26.7 +/- 6 (p less than 0.05), and 30.9 +/- 6.8 mmol (p less than 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 +/- 0.4 mmol after placebo and by 1.5 +/- 0.3 (p less than 0.01), 1.95 +/- 0.3 (p less than 0.01), and 2.4 +/- 0.4 mmol (p less than 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose-dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipokines as uremic toxins.

The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients.

Changes in sleeping and basal energy expenditure and substrate oxidation induced by short term thyroxin administration in man.

The present study was designed to explore the thermogenic effect of thyroid hormone administration and the resulting changes in nitrogen homeostasis. Normal male volunteers (n = 7) received thyroxin during 6 weeks. The first 3-week period served to suppress endogenous thyroid secretion (180 micrograms T4/day). This dose was doubled for the next 3 weeks. Sleeping energy expenditure (respiratory chamber) and BMR (hood) were measured by indirect calorimetry, under standardized conditions. Sleeping heart rate was continuously recorded and urine was collected during this 12-hour period to assess nitrogen excretion. The changes in energy expenditure, heart rate and nitrogen balance were then related to the excess thyroxin administered. After 3 weeks of treatment, serum TSH level fell to 0.15 mU/L, indicating an almost complete inhibition of the pituitary-thyroid axis. During this phase of treatment there was an increase in sleeping EE and sleeping heart rate, which increased further by doubling the T4 dose (delta EE: +8.5 +/- 2.3%, delta heart rate +16.1 +/- 2.2%). The T4 dose, which is currently used as a substitutive dose, lead to a borderline hyperthyroid state, with an increase in EE and heart rate. Exogenous T4 administration provoked a significant increase in urinary nitrogen excretion averaging 40%. It is concluded that T4 provokes an important stimulation of EE, which is mostly mediated by an excess protein oxidation.

Bolus injections of synthetic atrial natriuretic peptide in patients with chronic renal failure or nephrotic syndrome.

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

Site of the action of a synthetic atrial natriuretic peptide evaluated in humans.

The renal site of the natriuretic effect of human, atrial natriuretic peptide (hANP) was studied using clearance techniques in eight salt-loaded normal volunteers undergoing maximal water diuresis. Lithium was used as a marker of proximal sodium reabsorption. According to a two-way, single blind, crossover design, hANP (Met12-(3-28)-eicosahexapeptide, (2 micrograms/min) or its vehicle (Ve) were infused for two hours, followed by a two-hour recovery period. Blood pressure, heart rate and insulin clearance remained unchanged. During hANP infusion, the filtration fraction increased slightly from 19.6 to 24.3% (P less than 0.001), fractional water excretion rose transiently at the beginning of the infusion. Fractional excretion of sodium increased markedly from 2.2% to 7.4% (P less than 0.001) but remained unchanged with Ve. ANP increased fractional excretion of lithium slightly from 46 to 58% (P less than 0.01), while it remained stable at 47% during Ve. The distal tubular rejection fraction of sodium calculated from sodium and lithium clearances rose markedly from 4.7 to 13% (P less than 0.001) and returned to 6.2% at the end of the recovery period. Thus, under salt loading and water diuresis conditions, hANP infusion did not alter GFR, but reduced proximal reabsorption of sodium, and markedly enhanced the fraction of sodium escaping distal tubular reabsorption, suggesting that hANP-induced natriuresis is due, for an important part, to inhibition of sodium reabsorption in the distal nephron.

Molecular clock is involved in predictive circadian adjustment of renal function.

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.

A general approach to the in situ energy butget of Eudendrium racemosum (Cnidaria, Hydrozoa) in the Western Mediterranean

An in situ energy budget of the hydropolyp Eudendrium racemosum (Cavolini, 1785) is presented. Ingestion and respiration rates and ammonium excretion were studied over two 24 h cycles, with two-hour sample intervals. The species ingested as much as 25.9% of its own biomass per day (minimum rate). Respiration was 1.62 ml O2 g-1 d w h-1 while excretion was 13.6 mM NH4 g-1dw h-1. We estimated that the species increased its biomass at a rate of 9.6% per day (Growth + Reproduction). This value is higher than those previously reported for other cnidarians. We can assume that the capacity of E. racemosum to survive - albeit for a limited period of the year - in the highly-competitive shallow-water communities is based on its high growth rate.

Estrogen receptor-mediated signalling in female mice is locally activated in response to wounding.

Estrogen deprivation is associated with delayed healing, while Hormone Replacement Therapy (HRT) accelerates acute wound healing and protects against development of chronic wounds. Estrogen exerts its effects on healing via numerous cell types by signalling through the receptors ERα and ERβ, which bind to the Estrogen Responsive Element (ERE) and initiate gene transcription. The ERE-luciferase transgenic mouse model has been influential in assessing real-time in vivo estrogen receptor activation across a range of tissues and pathologies. Using this model we demonstrate novel temporally regulated peri-wound activation of estrogen signalling in female mice. Using histological methods we reveal that this signal is specifically localised to keratinocytes of the neoepidermis and wound margin dermal cells. Moreover using pharmacological agonists we reveal that ERβ induces ERE-mediated signal in both epidermal and dermal cells while ERα induces ERE-mediated signal in dermal cells alone. Collectively these novel data demonstrate rapid and regional activation of estrogen signalling in wounded skin. A more complete understanding of local hormonal signalling during repair is essential for the focussed development of new therapies for wound healing.

Energy expenditure and postprandial thermogenesis in obese women before and after weight loss.

In six young obese women (mean weight 85 +/- 3 kg) with a childhood history of obesity, and in six young nonobese women (mean weight 55 +/- 2 kg), the energy expenditure was measured during 24 h in a respiratory chamber with a maintenance energy intake. The next day, the thermogenic response to a mixed meal was investigated by using an open circuit indirect calorimetry hood system. In addition, five of the same obese women were similarly studied after a mean weight loss of 12.1 kg (14% of initial body weight) consecutive to an 11-wk hypocaloric diet (protein-supplemented modified fast). Expressed in absolute terms, the total 24 h and basal energy expenditures were found to be significantly greater in the obese (2208 +/- 105 and 1661 +/- 56 kcal/24 h, respectively) than in the controls (1746 +/- 61 and 1230 +/- 40 kcal/24 h, respectively). After weight loss, both the total 24-h and the basal energy expenditures were significantly reduced (2009 +/- 99 kcal/24 h and 1423 +/- 43 kcal/24 h respectively), but both values were still greater than that of the control subjects. The thermogenic response to the mixed meal (a liquid diet containing 17, 54, and 29% as protein, carbohydrate, and lipid calories, respectively, and an energy level determined to cover 60% of the basal energy expenditure computed for 24 h) was found to be significantly reduced in the obese as compared to controls (ie, 7.6 +/- 0.4% versus 9.5 +/- 0.4% of the energy content of the load, respectively, p less than 0.025). After weight loss, the postprandial thermogenesis of the obese was still markedly reduced (ie, 6.2 +/- 0.8%). Both before and after weight loss, the relative increase in diurnal urinary norepinephrine excretion was found to be lower in the obese than in controls, when compared to the nocturnal values. These results show that the greater 24 h energy expenditure of obese women is entirely due to their higher basal metabolic rate. The lower thermogenic response to the meal in the obese supports the concept of a thermogenic defect which can favor energy gain; furthermore, the unchanged response after weight loss in the obese suggests that the thermogenic defect may be a cause rather than a consequence of obesity.