Reduction In Plasma Volume Research Articles

Role of the Renin Angiotensin System in Blood Pressure Allostasis-induced by Severe Food Restriction in Female Fischer rats

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1–8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1–8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake.

The independent effects of hypovolaemia and pulmonary vasoconstriction on ventricular function and exercise capacity during acclimatisation to 3800m.

We sought to determine the isolated and combined influence of hypovolaemia and hypoxic pulmonary vasoconstriction on the decrease in left ventricular (LV) function and maximal exercise capacity observed under hypobaric hypoxia. We performed echocardiography and maximal exercise tests at sea level (344m), and following 5-10days at the Barcroft Laboratory (3800m; White Mountain, California) with and without (i) plasma volume expansion to sea level values and (ii) administration of the pulmonary vasodilatator sildenafil in a double-blinded and placebo-controlled trial. The high altitude-induced reduction in LV filling and ejection was abolished by plasma volume expansion but to a lesser extent by sildenafil administration; however, neither intervention had a positive effect on maximal exercise capacity. Both hypovolaemia and hypoxic pulmonary vasoconstriction play a role in the reduction of LV filling at 3800m, but the increase in LV filling does not influence exercise capacity at this moderate altitude. We aimed to determine the isolated and combined contribution of hypovolaemia and hypoxic pulmonary vasoconstriction in limiting left ventricular (LV) function and exercise capacity under chronic hypoxaemia at high altitude. In a double-blinded, randomised and placebo-controlled design, 12 healthy participants underwent echocardiography at rest and during submaximal exercise before completing a maximal test to exhaustion at sea level (SL; 344m) and after 5-10days at 3800m. Plasma volume was normalised to SL values, and hypoxic pulmonary vasoconstriction was reversed by administration of sildenafil (50mg) to create four unique experimental conditions that were compared with SL values: high altitude (HA), Plasma Volume Expansion (HA-PVX), Sildenafil (HA-SIL) and Plasma Volume Expansion with Sildenafil (HA-PVX-SIL). High altitude exposure reduced plasma volume by 11% (P<0.01) and increased pulmonary artery systolic pressure (19.6±4.3 vs. 26.0±5.4, P<0.001); these differences were abolished by PVX and SIL respectively. LV end-diastolic volume (EDV) and stroke volume (SV) were decreased upon ascent to high altitude, but were comparable to sea level in the HA-PVX trial. LV EDV and SV were also elevated in the HA-SIL and HA-PVX-SIL trials compared to HA, but to a lesser extent. Neither PVX nor SIL had a significant effect on the LV EDV and SV response to exercise, or the maximal oxygen consumption or peak power output. In summary, at 3800m both hypovolaemia and hypoxic pulmonary vasoconstriction contribute to the decrease in LV filling, but restoring LV filling does not confer an improvement in maximal exercise performance.

Corrected whole blood biomarkers - the equationof Dill and Costill revisited.

An exercise bout or a dehydration often causes a reduction in plasma volume, which should be acknowledged when considering the change in biomarkers before and after the plasma changing event. The classic equation from Dill and Costill (1974, J. Appl. Physiol., 37, 247–248) for plasma volume shift is usually utilized in such a case. Although this works well with plasma and serum biomarkers, we argue in this note that this traditional approach gives misleading results in the context of whole blood biomarkers, such as lactate, white cells, and thrombocytes. In this study, we demonstrate that to calculate the change in the total amount of circulating whole blood biomarker, one should utilize a formula BMpostBMpre×HbpreHbpost−1. Here Hb and BM are, respectively, the concentrations for the hemoglobin and for the inspected whole blood biomarker before (pre) and after (post) the plasma changing incident.

Interval Walking Training and Nutritional Intake to Increase Plasma Volume in Elderly.

Aerobic training-induced plasma volume (PV) expansion improves thermoregulation, and carbohydrate (CHO) + whey protein supplementation enhanced the effects in older people; however, these were suggested by studies on gym-based cycling training but not on home-based interval walking training (IWT). Moreover, long-term walking training effects on PV remain unknown. Seventeen male and 10 female subjects (~69 yr), having performed IWT for ≥24 months before the study, were used. After pre-intervention measurement (PRE) of PV, plasma albumin content (Albcont), fasting glucose concentration ([Glc]f), and HbA1c, the subjects were randomly divided into two groups: CHO and Pro-CHO, either consuming CHO (22.5 g) alone or CHO (15 g) + whey protein (10 g), respectively, during additional 5-month IWT from May to November, 2009. After the additional IWT, we measured the same variables again (postintervention measurement). The baseline PV and Albcont were significantly correlated with the number of IWT days for the 12 months preceding PRE (r = 0.716, P < 0.001 and r = 0.671, P < 0.001, respectively). In postintervention, PV and Albcont marginally decreased in CHO from the baselines (P = 0.081 and P = 0.130, respectively) with increased HbA1c (P < 0.001) after correction for the baseline [Glc]f by ANCOVA, but these values remained unchanged in Pro-CHO (both, P > 0.74), with significant differences in the changes between groups (P = 0.020, P = 0.041, and P = 0.018 respectively). PV was proportional to the number of IWT days for 12 months and a CHO + whey protein supplementation during the 5-month IWT prevented PV reduction for the period of no supplementation, which might be partially linked with blood glucose control mechanisms.

Cardiovascular response to prescribed detraining among recreational athletes.

Exercise-induced cardiac remodeling (EICR) and the attendant myocardial adaptations characteristic of the athlete's heart may regress during periods of exercise reduction or abstinence. The time course and mechanisms underlying this reverse remodeling, specifically the impact of concomitant plasma volume (PV) contraction on cardiac chamber size, remain incompletely understood. We therefore studied recreational runners ( n = 21, age 34 ± 7 yr; 48% male) who completed an 18-wk training program (~7 h/wk) culminating in the 2016 Boston Marathon after which total exercise exposure was confined to <2 h/wk (no single session >1 h) for 8 wk. Cardiac structure and function, exercise capacity, and PV were assessed at peak fitness (10-14 days before) and at 4 wk and 8 wk postmarathon. Mixed linear modeling adjusting for age, sex, V̇o2peak, and marathon finish time was used to compare data across time points. Physiological detraining was evidenced by serial reductions in treadmill performance. Two distinct phases of myocardial remodeling and hematological adaptation were observed. After 4 wk of detraining, there were significant reductions in PV (Δ -6.0%, P < 0.01), left ventricular (LV) wall thickness (Δ -8.1%, <0.05), LV mass (Δ -10.3%, P < 0.001), and right atrial area (Δ -8.2%, P < 0.001). After 8 wk of detraining, there was a significant reduction in right ventricle chamber size (end-diastolic area Δ = -8.0%, P < 0.05) without further concomitant reductions in PV or LV wall thickness. Abrupt reductions in exercise training stimulus result in a structure-specific time course of reverse cardiac remodeling that occurs largely independently of PV contraction. NEW & NOTEWORTHY Significant reverse cardiac remodeling, previously documented among competitive athletes, extends to recreational runners and occurs with a distinct time course. Initial reductions in plasma volume and left ventricular (LV) mass, driven by reductions in wall thickness, are followed by contraction of the right ventricle. Consistent with data from competitive athletes, LV chamber volumes appear less responsive to detraining and may be a more permanent adaptation to sport.

Physiological responses to prolonged saturation diving: a field-based pilot study.

This study aimed to assess the effect of extreme environmental exposure during an operational saturation dive on airway inflammation (exhaled nitric oxide (FeNo)), components of fitness (flexibility and aerobic capacity) and blood hematological variables. Six saturation divers, who undertook a 26±0.5 day operational saturation dive were recruited to take part in this study. Participants completed a field-based repeated measure test battery on three occasions (pre-dive, post-dive and 24 hours after saturation dive). Hemoglobin concentration was significantly (P⟨0.001) reduced from pre- (15.3±0.8 g/dL) to post-saturation (14.25±1.2 g/dL) dive but recovered toward baseline values within 24 hours (15.13±1.03 g/dL; P=0.04). Similarly, a reduction in plasma volume was observed in all participants from pre- to post-saturation dive trials. Airway inflammation response was non-significant, although a large inter-individual response was evident. Hip flexion, assessed by the sit and reach test did not change following the saturation dive. Data on aerobic capacity was collected in one participant only, due to practical difficulties in participant access. In summary, this is the first investigation to conduct a multiple-component field-based study on operational saturation divers. The findings for this exploratory study present interesting groundings for further investigation.

Spot Sample Urine Specific Gravity Does Not Accurately Represent Small Decreases in Plasma Volume in Resting Healthy Males

ABSTRACTBackground: Urine specific gravity (USG) is often used to assess hydration status, particularly around athletic competition, but it is unknown whether high USG is indicative of plasma volume (PV) reduction (i.e., hypohydration). We tested the hypothesis that if high USG is reflective of reduced PV, subsequent fluid ingestion would increase PV.Purpose: The purpose of this study was to examine 24-hour changes in USG and PV in individuals presenting with high and low spot USG.Methods: Nineteen healthy males were provided food and water over 24 hours with a total water volume of 35 ml·kg−1 body mass. Absolute PV and blood volume (BV), measured using the CO-rebreathe technique, along with USG were measured before and after a 24-hour intervention period. Based on a preintervention morning spot USG, subjects were post hoc assigned to groups according to USG (≤1.020 or >1.020; low and high USG, respectively).Results: Despite presenting with an elevated spot USG (1.026 ± 0.004), subsequent fluid ingestion over 24 hours did not lead to changes (∆) in PV (−75 ± 234 ml) or BV (−156 ± 370 ml) in the high USG group (p > 0.05). However, a spot USG after the 24-hour intervention in this group decreased (p = 0.018) to a level indicating improved hydration status (1.017 ± 0.007). In the low USG group, there were no changes in PV (−39 ± 274 ml), BV (−82 ± 396 ml), or USG (0.003 ± 0.007) over the 24-hour fluid intervention (all p > 0.05).Conclusions: Despite a high preintervention USG and subsequent decrease after 24-hour fluid intake, measures of PV and BV were not indicative of this seemingly improved hydration status. This suggests that a highly concentrated spot sample USG and subsequent changes are not accurately representative of PV or BV.

Acute hematological response to a single dose of sprint interval training in competitive cyclists

Summary Objectives The purpose of the study was to evaluate the acute hematological response to a sprint interval testing protocol in cyclists. Methods Sixteen cyclists executed 4 sets of maximal intensity cycling separated by 20–40 min active recovery. Each set involved four 30 s maximal sprints interspersed with 90 s low-intensity recovery. Power output was recorded. Red and white blood cell, hemoglobin, and hematocrit levels were obtained at baseline and 2 min after each set. Percentage change in plasma volume was calculated. Body composition and mass were measured pre- and post-sprint interval testing protocol. Results Power output was maintained at similar level throughout all sets of exercise. Respective increases compared with baseline were observed in each consecutive set for red blood cell (by 8.4%, 6.8%, 5.6%, 3.8%), white blood cell (by 107.8%, 119.6%, 284.3%, 339.2%), hemoglobin (by 7.5%, 6.1%, 4.1%, 2.0%), and hematocrit (by 9.2%, 7.5%, 7.0%, 3.7%). There was a reduction in plasma volume (by −14.5%, −11.7%, −9.2%, −5.4%) compared with baseline. Body mass and water content decreased post- sprint interval testing protocol. Conclusions While sprint interval testing protocol induced acute hypovolemia, the magnitude difference progressively decreased with consecutive sets of exercise, suggesting plasma volume expansion during active recovery between-sets. Significant white blood cell increases in subsequent sets of maximal exercise suggests an inflammatory response and may hinder microcirculation.

Regulation of blood volume in lowlanders exposed to high altitude.

Humans ascending to high altitude (HA) experience a reduction in arterial oxyhemoglobin saturation and, as a result, arterial O2 content ([Formula: see text]). As HA exposure extends, this reduction in [Formula: see text] is counteracted by an increase in arterial hemoglobin concentration. Initially, hemoconcentration is exclusively related to a reduction in plasma volume (PV), whereas after several weeks a progressive expansion in total red blood cell volume (RCV) contributes, although often to a modest extent. Since the decrease in PV is more rapid and usually more pronounced than the expansion in RCV, at least during the first weeks of exposure, a reduction in circulating blood volume is common at HA. Although the regulation of hematological responses to HA has been investigated for decades, it remains incompletely understood. This is not only related to the large number of mechanisms that could be involved and the complexity of their interplay but also to the difficulty of conducting comprehensive experiments in the often secluded HA environment. In this review, we present our understanding of the kinetics, the mechanisms and the physiological relevance of the HA-induced reduction in PV and expansion in RCV.

Postural Induced Changes in Plasma Volume Inversely Influences Plasma Nitrite Concentration in Humans

Moving from a supine to a standing position typically reduces plasma volume (PV) and while this increases the concentration of some molecules in the blood, the effect on plasma nitrate [NO3-] and nitrite [NO2-] has not been reported. PURPOSE: To determine the change (Δ) in PV, [NO3-] and [NO2-] while lying supine, sitting, standing, and following short-duration exercise. METHODS: Fourteen participants (9 male, age 27 ± 4 yr, body mass 71 ± 11 kg) completed two trials. The first was conducted with no dietary intervention (control; CON) and the second was preceded by ingestion of 3 x 70 ml of NO3--rich beetroot juice the day before and 2 x 70 ml two hours before the trial (BR; total of ~31 mmol NO3-). Both trials comprised 30 min lying supine followed by 2 min of standing, 2 min of sitting, and then 5 min of cycling at 60% of the age-predicted maximal heart rate. Repeated blood samples were collected to allow measurements of haemoglobin and haematocrit in whole blood and plasma [NO3-] and [NO2-] by chemiluminescence. The ΔPV was calculated using the Dill and Costill formula. RESULTS: Following the supine phase, PV increased from baseline in both trials (CON Δ12.6 ± 10.3 %; BR Δ12.5 ± 7 %, both P 0.05). CONCLUSIONS: Plasma [NO2-] changes in the opposite direction to PV during changes in posture, both in the presence and absence of prior dietary NO3- supplementation. Given that [NO2-] offers the best approximation of nitric oxide bioavailability, researchers must be cognisant of these outcomes when designing and interpreting dietary NO3- research.

Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients.MethodsTwenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time.ResultsTwo weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = −0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = −0.60, P = 0.0014), but not increased urinary glucose excretion.ConclusionsSGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Relationship between smoking, prognostic factors, and outcomes in patient (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving sipuleucel-T (sip-T): Preliminary analysis of the PROCEED registry.

216 Background: Smoking is associated with poor treatment outcomes after definitive therapy for PC (Steinberger 2015 BJU Int; Joshu 2011 JNCI). However, there is a paucity of data on the effects of active smoking on pts with mCRPC. The PROCEED registry provides an opportunity to evaluate differences in disease characteristics and outcomes by smoking status in men receiving sip-T, an FDA-approved, autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Methods: Enrolled pts with mCRPC who never smoked (NS) or were current smokers (CS) were evaluated.Pt characteristics, time to first anticancer intervention (tACI; measured from last sip-T infusion to first ACI; agents: abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223), PC-specific survival, and OS were assessed. Results: Of 1956 enrolled pts with known smoking status, 904 were NS, 179 were CS; 873 were former smokers and not included in this analysis. Compared with NS, CS were younger, had lower BMI (p &lt; 0.001), higher hemoglobin (Hgb; p &lt; 0.001), lower lactate dehydrogenase (LDH; p = 0.05), and shorter time between PC diagnosis and first sip-T infusion (p = 0.01). Fewer CS pts had Gleason score &lt; 8 (p = 0.2) and prior radical prostatectomy (p = 0.07). CS and NS did not differ in pattern or extent of metastatic disease spread. CS was associated with shorter OS, PC-specific survival, and tACI (Table). Conclusions: CS were younger at enrollment and had shorter OS, PC-specific survival, and tACI. Higher Hgb in CS likely reflects reduced plasma volume and/or increased red cell production. A multivariate analysis of prognostic factors for survival outcomes including smoking status in mCRPC is planned. However, active smoking represents a possible modifiable risk factor in the mCRPC setting. Clinical trial information: NCT01306890. [Table: see text]

Plasma volume reduction and hematological fluctuations in high-level athletes after an increased training load.

The time course of plasma volume (PV) reduction following an increased training load period is unknown and was investigated. The accompanying fluctuations in [Hb] and OFF-hr score were analyzed in the Athlete Biological Passport. Further, whether fluctuations in plasma albumin, soluble transferrin receptors (sTfR), and pro-atrial natriuretic peptide (proANP) concentrations correlate with PV fluctuations was investigated. Eleven high-level competitive cyclists were investigated for 3weeks. After initial measurements in week 1, training load was increased ~250% in week 2 followed by a reversion to baseline training load in week 3. PV and hematological variables were determined frequently during all weeks. The higher training load in week 2 increased (P<.001) PV 10%, while [Hb] and OFF-hr score decreased ~6% (P<.01) and ~16% (P<.001), respectively. PV and [Hb] returned to baseline within 2 and 4days after week 2, respectively, while OFF-hr score remained reduced for 6days. Further, one and three atypical blood profiles of the ABP occurred during weeks 2 and 3, respectively. Individual changes in albumin, sTfR, and proANP only correlated weakly (R2 <.20) with PV fluctuations. In conclusion, PV and [Hb] fluctuations caused by an elevated training load period were reverted within 2 and 4days after returning to baseline training load, respectively, while OFF-hr remained altered for 6days. Furthermore, some atypical blood profiles were induced during and subsequent to the increased training load, demonstrating the importance of knowledge on naturally occurring hematological fluctuations. Finally, concentrations of albumin, sTfR, and proANP could not explain PV fluctuations.

Isolated Brain Trauma in Cats Triggers Rapid Onset of Hypovolemia

BackgroundHemodynamic instability responsive to fluid resuscitation is common after a traumatic brain injury (TBI), also in the absence of systemic hemorrhage. The present study tests if an isolated severe TBI induces a decrease in plasma volume (PV).MethodsThe study was performed in three groups of anesthetized and tracheostomized male cats (n = 21). In one group (n = 8), the cats were prepared with a cranial borehole (10 mm i.d) used to expose the brain to a fluid percussion brain injury (FPI) (1.90–2.20 bar), and two smaller cranial boreholes (4 mm i.d) for insertion of an intracranial pressure (ICP) and a microdialysis catheter. To differentiate the effect of FPI from that of the surgical preparation, a sham group was exposed to the same surgical preparation but no FPI trauma (n = 8). A control group had no brain trauma and no surgical preparation (n = 5). PV was determined by a 125I-albumin dilution technique. PV, electrolytes, pH, BE (base excess), hematocrit (Hct), PaO2, and PaCO2 were measured at baseline and after 3 h. Mean arterial pressure (MAP) was measured continuously. ICP was measured in the FPI and the sham group.ResultsIn the FPI group, PV decreased by 11.2 mL/kg from 31.7 mL/kg (p < 0.01) with a simultaneous increase in Hct and decrease in pH. In the sham group, PV decreased by 5.7 mL/kg from 32.7 mL/kg (p < 0.01). The control group showed no PV reduction.ConclusionsThe results support that an isolated severe head trauma triggers a significant and rapid reduction in PV, most likely due to vascular leak.

Effect of alterations in blood volume with bed rest on glucose tolerance.

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose are also reduced with bed rest, but the potential influence on glucose tolerance has not been investigated. Accordingly, the aim was to investigate whether bed rest-induced impairments in glucose tolerance are related to a concomitant reduction in plasma volume. This hypothesis was tested mechanistically by restoring plasma volume with albumin infusion after bed rest and parallel determination of glucose tolerance. Fifteen healthy volunteers (age 24 ± 3 yr, body mass index 23 ± 2 kg/m2, maximal oxygen uptake 44 ± 8 ml·min-1·kg-1; means ± SD) completed 4 days of strict bed rest. Glucose tolerance [oral glucose tolerance test (OGTT)] and plasma and blood volumes (carbon monoxide rebreathing) were assessed before and after 3 days of bed rest. On the fourth day of bed rest, plasma volume was restored by means of an albumin infusion prior to an OGTT. Plasma volume was reduced by 9.9 ± 3.0% on bed rest day 3 and area under the curve for OGTT was augmented by 55 ± 67%. However, no association (R2 = 0.09, P = 0.33) between these simultaneously occurring responses was found. While normalization of plasma volume by matched albumin administration (408 ± 104 ml) transiently decreased (P < 0.05) resting plasma glucose concentration (5.0 ± 0.4 to 4.8 ± 0.3 mmol/l), this did not restore glucose tolerance. Bed rest-induced alterations in dilution space may influence resting glucose values but do not affect area under the curve for OGTT.

PS 14-45 URIC ACID METABOLISM AND RENAL FUNCTION IN PATIENTS TREATED WITH A FIXED DOSE COMBINATION OF ANTIHYPERTENSIVE MEDICATIONS

Objective: Improvement of serum uric acid (SUA) is thought to have a favorable influence on blood pressure (BP) and renal function in hypertensive patients irrespective of diuretic therapy. The effects of switching therapy to a fixed dose combination (FDC) of losartan (LOS) 50 mg with hydrochlorothiazide (HCTZ) 15 mg (LOS/HCTZ) on BP, UA metabolism, and renal function were assessed in hypertensive patients treated with a FDC of telmisartan (TEL) 40 mg with HCTZ 15 mg (TEL/HCTZ) and compared those of a FDC of TEL with amlodipine (AM) 5 mg (TEL/AM). Design and Method: Sixty-seven hypertensive patients were allocated either LOS/HCTZ (n = 36) or TEL/AM group (n = 31), respectively. Results: Both LOS/HCTZ and TEL/AM were effective in reducing SUA but caused no change in BP after 12 months. LOS/HCTZ increased percent fractional excretion of UA (FEUA) but caused no change in estimated glomerular filtration rate (eGFR). TEL/AM increased eGFR, but trend for increase in FEUA was not significant. Although UA metabolism improved, urinary albumin/creatinine excretion ratio (UACR) increased in two groups. The increase in UACR of TEL/AM was greater than that of LOS/HCTZ. The change in UACR was positively correlated with the changes in eGFR but not with SUA or FEUA. Conclusions: The switching therapy equally controlled BP and improved UA metabolism. Although both LOS-induced inhibitory action of urate transporter 1 and deletion of HCTZ-induced plasma volume reduction were associated with improvement of UA metabolism in the patients, it did not support the beneficial effect of SUA lowering therapy on renal protection.

Salt-losing nephropathy in mice with a null mutation of the Clcnk2 gene.

The basolateral chloride channel ClC-Kb facilitates Cl reabsorption in the distal nephron of the human kidney. Functional mutations in CLCNKB are associated with Bartter's syndrome type 3, a hereditary salt-losing nephropathy. To address the function of ClC-K2 invivo, we generated ClC-K2-deficient mice. ClC-K2-deficient mice were generated using TALEN technology. ClC-K2-deficient mice were viable and born in a Mendelian ratio. ClC-K2-/- mice showed no gross anatomical abnormalities, but they were growth retarded. The 24-h urine volume was increased in ClC-K2-/- mice (4.4±0.6 compared with 0.9±0.2mL per 24h in wild-type littermates; P=0.001). Accordingly, ambient urine osmolarity was markedly reduced (590±39 vs. 2216±132mosmolL-1 in wild types; P<0.0001). During water restriction (24h), urinary osmolarity increased to 1633±153 and 3769±129mosmolL-1 in ClC-K2-/- and wild-type mice (n=12; P<0.0001), accompanied by a loss of body weight of 12±0.4 and 8±0.2% respectively (P<0.0001). ClC-K2-/- mice showed an increased renal sodium excretion and compromised salt conservation during a salt-restricted diet. The salt-losing phenotype of ClC-K2-/- mice was associated with a reduced plasma volume, hypotension, a slightly reduced glomerular filtration rate, an increased renal prostaglandin E2 generation and a massively stimulated renin-angiotensin system. Clckb-/- mice showed a reduced sensitivity to furosemide and were completely resistant to thiazides. Loss of ClC-K2 compromises TAL function and abolishes salt reabsorption in the distal convoluted tubule. Our data suggest that ClC-K2 is crucial for renal salt reabsorption and concentrating ability. ClC-K2-deficient mice in most aspects mimic patients with Bartter's syndrome type 3.

The frequently used intraperitoneal hyponatraemia model induces hypovolaemic hyponatraemia with possible model-dependent brain sodium loss.

What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids (i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs. What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia. Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (i.p. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia.

PlanHab: Hypoxia counteracts the erythropoietin suppression, but seems to exaggerate the plasma volume reduction induced by 3weeks of bed rest.

The study examined the distinct and synergistic effects of hypoxia and bed rest on the erythropoietin (EPO) concentration and relative changes in plasma volume (PV). Eleven healthy male lowlanders underwent three 21‐day confinement periods, in a counterbalanced order: (1) normoxic bed rest (NBR; PIO 2: 133.1 ± 0.3 mmHg); (2) hypoxic bed rest (HBR; PIO 2: 90.0 ± 0.4 mmHg, ambient simulated altitude of ~4000 m); and (3) hypoxic ambulation (HAMB; PIO 2: 90.0 ± 0.4 mmHg). Blood samples were collected before, during (days 2, 5, 14, and 21) and 2 days after each confinement to determine EPO concentration. Qualitative differences in PV changes were also estimated by changes in hematocrit and hemoglobin concentration along with concomitant changes in plasma renin concentration. NBR caused an initial reduction in EPO by ~39% (P = 0.04). By contrast, HBR enhanced EPO (P = 0.001), but the increase was less than that induced by HAMB (P < 0.01). All three confinements caused a significant reduction in PV (P < 0.05), with a substantially greater drop in HBR than in the other conditions (P < 0.001). Thus, present results suggest that hypoxia prevents the EPO suppression, whereas it seems to exaggerate the PV reduction induced by bed rest.

Physiologic and performance effects of sago supplementation before and during cycling in a warm-humid environment

ABSTRACTThe present study determined whether 0.8g/kg bodyweight sago ingested before (Pre-Sago) or during (Dur-Sago) exercise under warm-humid conditions (30 ± 2°C, 78 ± 3 % RH; 20 km·h−1 frontal airflow) conferred a performance and/or physiological benefit compared to a control (Control) condition. Eight trained, male cyclists/triathletes (45 ± 4 y, VO2peak: 65 ± 10 ml·kg−1·min−1, peak aerobic power: 397 ± 71 W) completed 3 15-min time-trials (∼75% VO2peak) pre-loaded with 45 min of steady-state (∼55% VO2peak) cycling following > 24 h standardization of training and diet. Measures of work completed, rectal and mean skin temperatures, heart rate, expiratory gases and venous blood samples were taken. Compared to Control, Pre-Sago resulted in a smaller rise in rectal temperature (0.3 ± 0.5°C) while heart rate increased to a greater extent (6 ± 13 beats·min−1) during exercise (both P < 0.05), however, compared to Control time-trial performance remained unaffected (Pre-Sago: −0.5 ± 4.0%, P > 0.05). During exercise, plasma glucose concentrations were maintained higher for Dur-Sago than Control (P < 0.05), however substrate oxidation rates remained similar (P > 0.05). Dur-Sago also resulted in a higher plasma sodium concentration (2 ± 2 mmol·l1) and lower whole-body sweat loss (544 ± 636 g) and, therefore, reduced plasma volume contraction (all P < 0.05). Heart rate increased to a greater extent (5 ± 13 beats·min−1) during Dur-Sago, yet compared to Control time-trial performance remained unaffected (+0.9 ± 2.3%, P > 0.05). Uniquely, these results indicate that during exercise heat stress feeding sago can result in some ‘beneficial’ physiological responses, however these do not translate to changes in exercise performance when performed in a post-prandial state.