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Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet.
Gueneau de Mussy, P, Sidharta, PN, Wuerzner, G, Maillard, MP, Guérard, N, Iglarz, M, Flamion, B, Dingemanse, J, Burnier, M
Clinical pharmacology and therapeutics. 2021;(3):746-753
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Abstract
Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.
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Towards Addressing the Body Electrolyte Environment via Sweat Analysis:Pilocarpine Iontophoresis Supports Assessment of Plasma Potassium Concentration.
Vairo, D, Bruzzese, L, Marlinge, M, Fuster, L, Adjriou, N, Kipson, N, Brunet, P, Cautela, J, Jammes, Y, Mottola, G, et al
Scientific reports. 2017;(1):11801
Abstract
Electrolyte concentration in sweat depends on environmental context and physical condition but also on the pathophysiological status. Sweat analyzers may be therefore the future way for biological survey although how sweat electrolyte composition can reflect plasma composition remains unclear. We recruited 10 healthy subjects and 6 patients to have a broad range of plasma electrolyte concentrations (chloride, potassium and sodium) and pH. These variables were compared to those found in sweat produced following cycling exercise or pilocarpine iontophoresis, a condition compatible with operating a wearable device. We found no correlation between plasma and sweat parameters when exercise-induced sweat was analyzed, and we could identify a correlation only between plasma and sweat potassium concentration (R = 0.78, p < 0.01) when sweat was induced using pilocarpine iontophoresis. We tested measurement repeatability in sweat at 24hr-interval for 3 days in 4 subjects and found a great intra-individual variability regarding all parameters in exercise-induced sweat whereas similar electrolyte levels were measured in pilocarpine-induced sweat. Thus, electrolyte concentration in sweat sampled following physical activity does not reflect concentration in plasma while pilocarpine iontophoresis appears to be promising to reproducibly address sweat electrolytes, and to make an indirect evaluation of plasma potassium concentration in chronic kidney disease and arrhythmia.
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Increased salt consumption induces body water conservation and decreases fluid intake.
Rakova, N, Kitada, K, Lerchl, K, Dahlmann, A, Birukov, A, Daub, S, Kopp, C, Pedchenko, T, Zhang, Y, Beck, L, et al
The Journal of clinical investigation. 2017;(5):1932-1943
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Abstract
BACKGROUND The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
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Plasma vasopressin, oxytocin, estradiol, and progesterone related to water and sodium excretion in normal pregnancy and gestational hypertension.
Risberg, A, Olsson, K, Lyrenas, S, Sjöquist, M
Acta obstetricia et gynecologica Scandinavica. 2009;(6):639-46
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Abstract
OBJECTIVE To investigate associations between plasma oxytocin and vasopressin concentrations and renal water and sodium excretion during normal pregnancy in comparison with gestational hypertension. DESIGN A prospective open trial conducted in the 12th, 24th, and 36th weeks of gestation. SETTINGS Seven antenatal clinics in Sweden. PARTICIPANTS Thirty-seven normotensive women, 15 women with gestational hypertension, and five women with mild preeclampsia. MAIN OUTCOME MEASURES Hormones were analyzed with radioimmunoassay. Albumin, osmolality, sodium, and urea were analyzed by routine methods. RESULTS Blood pressure was elevated in the hypertensive women and body mass index in mild preeclampsia from week 12. Renal sodium excretion did not differ between groups or weeks and mean renal free water clearance was negative. In normotensive women, the vasopressin concentration was 1.1+/-0.2 (week 12) and 0.7+/-0.1 pmol/L (week 36: p = 0.053). In hypertensive women, vasopressin concentration was 1.7+/-1.0 pmol/L, week 12, and 0.7+/-0.1 pmol/L in week 36 (ns). In normotensive women, oxytocin concentration increased from 23+/-1 pmol/L in week 12 to 48+/-3 pmol/L in week 36 (p<0.001). Corresponding values in hypertensive women were 36+/-11 (week 12) and 55+/-5 pmol/L (week 36: ns). In all groups, plasma estradiol concentration increased. Plasma progesterone increased until week 24 in normotensive and hypertensive women with further increase in normotensive women. CONCLUSIONS The low plasma vasopressin and increasing plasma oxytocin concentrations with unchanged water and sodium excretion indicate that oxytocin assists vasopressin in concentrating urine during pregnancy.
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Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise.
Hew-Butler, T, Jordaan, E, Stuempfle, KJ, Speedy, DB, Siegel, AJ, Noakes, TD, Soldin, SJ, Verbalis, JG
The Journal of clinical endocrinology and metabolism. 2008;(6):2072-8
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CONTEXT Although the primary cause of exercise-associated hyponatremia (EAH) is relative overconsumption of fluids beyond the kidneys' ability to excrete excess fluid, the mechanisms limiting maximum renal excretory ability during exercise remain to be elucidated. OBJECTIVE The objective of the study was to: 1) perform a comprehensive evaluation of the endocrine secretion of pituitary, natriuretic and adrenal steroid hormones, and cytokines immediately before and after running an ultramarathon; and 2) evaluate the relationship between osmotic and nonosmotic stimuli to arginine vasopressin (AVP) secretion within the overall context of assessing the hormonal regulation of fluid balance during prolonged endurance exercise. DESIGN This was an observational study. SETTING The study setting was a 56-km ultramarathon. PARTICIPANTS Eighty-two runners participated in the study. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES Plasma sodium concentration [Na(+)] and plasma volume [(AVP)(p)] were measured. RESULTS Fluid homeostasis during exercise (356 +/- 4 min) was maintained with ad libitum fluid intakes. [Na(+)] was maintained from before the race (139.3 +/- 0.3 mmol/liter) to after the race (138.1 +/- 0.4 mmol/liter) with a significant decrease in plasma volume (-8.5 +/- 0.1%, P < 0.01). Increases in the plasma (AVP)(p) (3.9-fold), oxytocin (1.9-fold), brain natriuretic peptide (4.5-fold), and IL-6 (12.5-fold) were highly significant (P < 0.0001). Changes in brain natriuretic peptide, oxytocin, and corticosterone were associated with 47% of the variance noted in (AVP)(p) and 13% of the variance in plasma [Na(+)] in pathway analyses. CONCLUSIONS (AVP)(p) was markedly elevated after the ultramarathon despite unchanged plasma [Na(+)](.) Therefore, an inability to maximally suppress (AVP)(P) during exercise as a result of nonosmotic stimulation of AVP secretion may contribute to the pathogenesis of exercise-associated hyponatremia if voluntary fluid intake were to exceed fluid output.
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Dehydration rates and rehydration efficacy of water and sports drink during one hour of moderate intensity exercise in well-trained flatwater kayakers.
Sun, JM, Chia, JK, Aziz, AR, Tan, B
Annals of the Academy of Medicine, Singapore. 2008;(4):261-5
Abstract
INTRODUCTION The aim of this study is to investigate the amount of water loss and percentage dehydration experienced during 1 hour of paddling on the kayak ergometer so as to help coaches and athletes tailor a suitable and adequate rehydration regime. Also, rehydration efficacy between water and a well established, commercially available sports drink (Gatorade, Quaker Oats company, USA) was investigated in this cross-over study. MATERIALS AND METHODS Ten national flatwater kayakers were monitored in a controlled setting while paddling the kayak ergometer for 1 hour at an intensity sustainable for long distance marathon. They rehydrated themselves ad libitum with provided beverage. Post-void towel-dried body mass was measured before and after the exercise with percentage dehydration calculated. Body core temperature (tympanic temperatures), ratings of perceived exertion and thirst index were monitored every 15 minutes. The amount of fluid consumed, urine output and urine specific gravity were obtained after exercise. RESULTS The results [mean +/- standard deviation (SD)] showed that kayakers underwent 1.10 +/- 0.52% dehydration while rehydrating with water as compared to 0.72 +/- 0.38% while rehydrating with Gatorade. Also, athletes on water rehydration had higher rating of perceived exertion (RPE) at the 30th and 60th minute mark of the exercise. Overall, athletes undergoing water rehydration lost significantly more body mass (0.70 +/- 0.39 kg) as compared to rehydrating with Gatorade (0.46 +/- 0.27). CONCLUSION Although the hydration efficacy of Gatorade proved superior to that of water, the athletes' hydration habits with either fluids did not provide adequate hydration. It is recommended that specific strategies be developed to address dehydration and rehydration issues of kayakers in Singapore.
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Apparent bicarbonate space in children.
Repetto, HA, Penna, R
TheScientificWorldJournal. 2006;:148-53
Abstract
The amount needed to change the concentration of a solute requires the knowledge of its volume of distribution in the solution. Electrolytes that do not participate in active metabolic reactions have a fixed volume of distribution that corresponds to the volume of water in which they solubilize. Bicarbonate infusion is used to correct hyperchloremic metabolic acidosis. Its volume of distribution (bicarbonate space) changes with its participation in the blood buffer systems. In other words, it is not a fixed physical volume, like that of other solutes. In this paper, we shall review experimental studies that supported evidence for this knowledge and analyze the basic hypothesis to explain the phenomena. Since we have not found clinical studies in children, we shall report our experience in a group of patients with metabolic acidosis treated with bicarbonate infusion in whom apparent bicarbonate space was measured and compared with data in adults from the literature. Guidelines for amount of bicarbonate needed to increase its concentration according to baseline bicarbonate concentration will be suggested.
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Ten-day endurance training attenuates the hyperosmotic suppression of cutaneous vasodilation during exercise but not sweating.
Ichinose, T, Okazaki, K, Masuki, S, Mitono, H, Chen, M, Endoh, H, Nose, H
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(1):237-43
Abstract
It is well known that hyperosmolality suppresses thermoregulatory responses and that plasma osmolality (P(osmol)) increases with exercise intensity. We examined whether the decreased esophageal temperature thresholds for cutaneous vasodilation (TH(FVC)) and sweating (TH(SR)) after 10-day endurance training (ET) are caused by either attenuated increase in P(osmol) at a given exercise intensity or blunted sensitivity of hyperosmotic suppression. Nine young male volunteers exercised on a cycle ergometer at 60% peak oxygen consumption rate (V(O2 peak)) for 1 h/day for 10 days at 30 degrees C. Before and after ET, thermoregulatory responses were measured during 20-min exercise at pretraining 70% V(O2 peak) in the same environment as during ET under isoosmotic or hyperosmotic conditions. Hyperosmolality by approximately 10 mosmol/kgH2O was attained by acute hypertonic saline infusion. After ET, V(O2 peak) and blood volume (BV) both increased by approximately 4% (P < 0.05), followed by a decrease in TH(FVC) (P < 0.05) but not by that in TH(SR). Although there was no significant decrease in P(osmol) at the thresholds after ET, the sensitivity of increase in TH(FVC) at a given increase in P(osmol) [deltaTH(FVC)/deltaP(osmol), degrees C x (mosmol/kgH2O)(-1)], determined by hypertonic infusion, was reduced to 0.021 +/- 0.005 from 0.039 +/- 0.004 before ET (P < 0.05). The individual reductions in deltaTH(FVC)/deltaP(osmol) after ET were highly correlated with their increases in BV around TH(FVC) (r = -0.89, P < 0.005). In contrast, there was no alteration in the sensitivity of the hyperosmotic suppression of sweating after ET. Thus the downward shift of TH(FVC) after ET was partially explained by the blunted sensitivity to hyperosmolality, which occurred in proportion to the increase in BV.
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Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial.
Albers, MJ, Steyerberg, EW, Hazebroek, FW, Mourik, M, Borsboom, GJ, Rietveld, T, Huijmans, JG, Tibboel, D
Annals of surgery. 2005;(4):599-606
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OBJECTIVE To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery. SUMMARY BACKGROUND DATA Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability, attenuate nitrogen loss, improve survival, and lower the incidence of nosocomial infections. Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results. METHODS Eighty newborns and infants were included in a double-blind, randomized trial comparing standard parenteral nutrition (sPN; n = 39) to glutamine-supplemented parenteral nutrition (GlnPN; glutamine target intake, 0.4 g kg day; n = 41), starting on day 2 after major digestive-tract surgery. Primary endpoints were intestinal permeability, as assessed by the urinary excretion ratio of lactulose and rhamnose (weeks 1 through 4); nitrogen balance (days 4 through 6), and urinary 3-methylhistidine excretion (day 5). Secondary endpoints were mortality, length of stay in the ICU and the hospital, number of septic episodes, and usage of antibiotics and ICU resources. RESULTS Glutamine intake plateaued at 90% of the target on day 4. No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints. Glutamine supplementation was not associated with adverse effects. CONCLUSIONS In newborns and infants after major digestive-tract surgery, we did not identify beneficial effects of isonitrogenous, isocaloric glutamine supplementation of parenteral nutrition. Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise.
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Water balance, hydration status, and fat-free mass hydration in younger and older adults.
Bossingham, MJ, Carnell, NS, Campbell, WW
The American journal of clinical nutrition. 2005;(6):1342-50
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BACKGROUND Older adults are at increased risk of dehydration, yet water balance is understudied in this population. OBJECTIVE This controlled diet study assessed the effect of age on water input, output, and balance in healthy adults. Hydration status (plasma osmolality and urine specific gravity) and body composition were also measured. DESIGN Eleven men and 14 women aged 23-46 y and 10 men and 11 women aged 63-81 y were subjects. Water balance was assessed during days 7-10 of three 18-d controlled feeding trials with protein intakes of 0.50, 0.75, and 1.00 g . kg(-1) . d(-1). Total water input included water from the provided foods and beverages, ad libitum intake, and metabolic production. Water output included the losses in urine and stool and the insensible losses from respiration and nonsweating perspiration. RESULTS Ad libitum water consumption, total water intake, water output through urine, total water output, and net water balance were not different in the older subjects than in the younger subjects. Markers of hydration status were within the range of clinical normalcy for all groups. Total body water (TBW) was not significantly different, fat-free mass (FFM) was significantly lower (P < 0.05), and FFM hydration (TBW:FFM) was significantly higher (P < 0.05) in the older subjects than in the younger subjects. Dietary protein intake did not influence any of these results. CONCLUSIONS These results show that healthy older adults maintain water input, output, and balance comparable to those of younger adults and have no apparent changes in hydration status. The results support that the hydration of FFM is increased in older men and women.