Reduction In Plasma Volume Research Articles

Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia

Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia

Abstract 55: Spatiotemporal Heterogeneity of Platelet Activation and Thrombus Architecture Regulates Plasma Protein Accessibility During Thrombus Formation in Vivo

While often described as a linear process in which platelets react in a uniform manner, recent in vivo studies demonstrate that the platelet response to vascular injury is quite heterogeneous. Here, we utilized confocal fluorescence intravital microscopy to provide a detailed description of the heterogeneous nature of thrombi formed in vivo while asking the following questions: 1) does platelet accumulation and activation during thrombus formation follow specific spatio-temporal patterns that result in subpopulations of platelets with different activation states; 2) does the architecture of the hemostatic mass depend on the mechanism of injury; and 3) does heterogeneity within the platelet mass result in discrete regions of a thrombus that are more or less accessible to plasma and its constituents? We found that regardless of the mode of injury, stable thrombi were composed of two distinct and contiguous populations of platelets defined both by their activation state and their packing density. Closest to the site of injury was a population of fully activated, stably adherent, degranulated platelets, which was covered by multiple layers of loosely adherent platelets that had not undergone granule release. Increased packing density of platelets within the thrombus core was associated with reduced plasma volume in this region as well as limited accessibility of large plasma borne tracer molecules and proteins. Taken together, these findings clearly demonstrate the heterogeneous nature of thrombus formation at the molecular and structural levels. Further, the finding of reduced plasma volume and protein accessibility to the thrombus core has implications for delivery of pro- and anti-thrombotic blood factors and therapeutic agents to this region of a thrombus.

Effects of dehydration on cerebrovascular control during standing after heavy resistance exercise

We tested the hypothesis that dehydration exacerbates reductions of middle cerebral artery blood velocity (MCAv) and alters cerebrovascular control during standing after heavy resistance exercise. Ten males participated in two trials under 1) euhydration (EUH) and 2) dehydration (DEH; fluid restriction + 40 mg furosemide). We recorded finger photoplethysmographic arterial pressure and MCAv (transcranial Doppler) during 10 min of standing immediately after high-intensity leg press exercise. Symptoms (e.g., lightheadedness) were ranked by subjects during standing (1-5 scale). Low-frequency (LF) oscillations of mean arterial pressure (MAP) and mean MCAv were calculated as indicators of cerebrovascular control. DEH reduced plasma volume by 11% (P = 0.002; calculated from hemoglobin and hematocrit). During the first 30 s of standing after exercise, subjects reported greater symptoms during DEH vs. EUH (P = 0.05), but these were mild and resolved at 60 s. While MAP decreased similarly between conditions immediately after standing, MCAv decreased more with DEH than EUH (P = 0.02). With prolonged standing under DEH, mean MCAv remained below baseline (P ≤ 0.01), and below EUH values (P ≤ 0.05). LF oscillations of MAP were higher for DEH at baseline and during the entire 10 min of stand after exercise (P ≤ 0.057), while LF oscillations in mean MCAv were distinguishable only at baseline and 5 min following stand (P = 0.05). Our results suggest that mean MCAv falls below a "symptomatic threshold" in the acute phase of standing after exercise during DEH, although symptoms were mild and transient. During the prolonged phase of standing, increases in LF MAP and mean MCAv oscillations with DEH may help to maintain cerebral perfusion despite absolute MCAv remaining below the symptomatic threshold.

Ineffective normobaric LHTL: room confinement or inappropriate training intensity?

to the editor: To explain an ineffective live high-train low (LHTL) in normobaric hypoxia (e.g., where the athletes slept in hypoxic chamber), Siebenman et al. ([4][1]) suggested that the recommended 16 h/day of room confinement may lead to a reduction in plasma volume: 13.8% and 20.1% in the

Vasopressin V1 receptor‐mediated aldosterone production as a result of selective V2 receptor antagonism: a potential explanation for the failure of tolvaptan to reduce cardiovascular outcomes in the EVEREST trial

Plasma volume expansion in patients with heart failure (HF) is associated with neurohumeral activation; symptom and signs of pulmonary congestion and peripheral oedema; an increase in hospitalizations for HF; and cardiovascular mortality. A reduction in plasma volume, as evidenced by haemoconcentration, has recently been suggested to be associated with an improvement in cardiovascular mortality. However, while loop diuretics reduce plasma volume and relieve the symptoms and signs of pulmonary congestion, they activate the renin–angiotensin–aldosterone system (RAAS) and, in experimental studies and some, although not all, retrospective clinical studies have been associated with an increase in cardiovascular mortality. Due to the controversy associated with the use of high-dose loop diuretics and their effect on cardiovascular mortality in patients with HF and a reduced left ventricular ejection fraction (REF) there has been increasing interest in alternative and or supplemental diuretic strategies to reduce plasma volume and to improve cardiovascular outcomes in patients with HFREF. Tolvaptan, a selective V2 vasopressin antagonist, has been shown in pre-clinical and short-term studies in patients with HF to be a potent aquaretic with a resultant increase in urine output; a decrease in body weight; a decrease in pulmonary capillary wedge pressure; an increase in serum sodium concentration; without activation of the RAAS. However when studied over the longer term in patients with HFREF, it has not been shown to reduce natriuretic peptide levels or left ventricular remodelling, and did not improve cardiovascular outcomes despite an early improvement in symptoms of dyspnoea, a prolonged reduction in body weight, and normalization of serum sodium in hyponatraemic patients. The finding that tolvaptan failed to reduce natriuretic peptide levels and cardiovascular outcomes despite a reduction in body weight is especially notable since an increase in body weight post-discharge is the single most important predictor for readmission in patients with heart failure and a major predictor of mortality. The explanation for the failure of tolvaptan to improve ventricular remodelling, natriuretic peptide levels, and cardiovascular outcomes despite a reduction in body weight remains uncertain. Several explanations have, however, been proposed, including the suggestion that the dose of tolvaptan (30 mg/day) may have been inadequate; that patients selected for study did not have hyponatraemia; and the possibility that a reactive increase in vasopressin levels might over the long term stimulate the V1a receptor with a resultant increase in vasoconstriction, which might negate the beneficial effects associated with aquareses. Without further prospective mechanistic studies it is difficult to confirm or refute these explanations. Recently, however, it has been shown that a deficiency of the V1a receptor causes hyporeninaemic hypoaldsteronism, and stimulation of the V1a receptor causes the adrenal production of aldosterone. The V1a receptor also affects the renal tubular effects of aldosterone. We postulate that these findings may explain the paradox of a persistent reduction in body weight despite the lack of an improvement in natriuretic peptide levels and cardiovascular outcomes associated with the use of tolvaptan in EVEREST. This hypotheses and its implications for the therapy of patients with HF will be briefly discussed below. As noted above, V2 receptor antagonism results in a sustained reduction in body weight along with an early transient decrease in pulmonary capillary wedge pressure without activation of the RAAS. However, over the long term there is a reactive increase in vasopressin levels, with a resultant increased activation of the unprotected V1a receptor in the myocardium and vascular wall. This increase in vasopressin levels in patients receiving tolvaptan has recently been associated with an increase in aldosterone levels.

Unilateral Fluid Absorption and Effects on Peak Power After Ingestion of Commercially Available Hypotonic, Isotonic, and Hypertonic Sports Drinks

Isotonic sports drinks are often consumed to offset the effects of dehydration and improve endurance performance, but hypotonic drinks may be more advantageous. The purpose of the study was to compare absorption and effects on performance of a commercially available hypotonic sports drink (Mizone Rapid: 3.9% carbohydrate [CHO], 218 mOsmol/kg) with those of an isotonic drink (PowerAde: 7.6% CHO, 281 mOsmol/ kg), a hypertonic drink (Gatorade: 6% CHO, 327 mOsmol/kg), and a noncaloric placebo (8 mOsmol/kg). In a crossover, 11 cyclists consumed each drink on separate days at 250 ml/15 min during a 2-hr preload ride at 55% peak power followed by an incremental test to exhaustion. Small to moderate increases in deuterium oxide enrichment in the preload were observed with Mizone Rapid relative to PowerAde, Gatorade, and placebo (differences of 88, 45, and 42 parts per million, respectively; 90% confidence limits ±28). Serum osmolality was moderately lower with Mizone Rapid than with PowerAde and Gatorade (-1.9, -2.4; mOsmol/L; ±1.2 mOsmol/L) but not clearly different vs. placebo. Plasma volume reduction was small to moderate with Mizone Rapid, PowerAde, and Gatorade relative to placebo (-1.9%, -2.5%, -2.9%; ± 2.5%). Gut comfort was highest with Mizone Rapid but clearly different (8.4% ± 4.8%) only vs PowerAde. Peak power was highest with Mizone Rapid (380 W) vs. placebo and other drinks (1.2-3.0%; 99% confidence limits ±4.7%), but differences were inconclusive with reference to the smallest important effect (~1.2%). The outcomes are consistent with fastest fluid absorption with the hypotonic sports drink. Further research should determine whether the effect has a meaningful impact on performance.

Hypovolemia-induced Cardiac Tamponade in a Patient with Hypothyroidism

BackgroundPericardial effusion occurs frequently in patients with hypothyroidism and is typically mild. Although extremely uncommon, massive pericardial effusion can compromise hemodynamics and cause cardiac tamponade. Reduced plasma volume has been reported to induce cardiac tamponade in massive pericardial effusion, but to our knowledge, hypovolemia-induced cardiac tamponade has not been reported in cases of hypothyroidism with pericardial effusion. ObjectivesWe describe a case of hypothyroidism with cardiac tamponade due to an uncommon cause that, to our knowledge, has never been reported. Case ReportA 64-year-old woman with untreated hypothyroidism presented with acute abdominal pain and watery diarrhea. The patient experienced shock and cardiac arrest during the examination. Massive pericardial effusion was detected and cardiac tamponade was diagnosed. We suspected that the pericardial effusion was pre-existing due to an 11-year history of untreated hypothyroidism. On presentation, there was no hemodynamic compromise. Watery diarrhea persisted and intravenous fluid supplementation may have been inadequate. Hypovolemia developed and induced cardiac tamponade in the presence of the massive pericardial effusion. Successful resuscitation was achieved after cardiopulmonary resuscitation, aggressive intravenous fluid supplementation, and immediate pericardiocentesis. ConclusionPericardiocentesis is indicated for hypothyroid patients with cardiac tamponade. We recommend the use of small, multi-hole catheters and daily measurement of drainage fluid. If the pericardial effusion does not resolve, a pericardial window with chest tube drainage should be performed.

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

The purpose of this study was to determine whether a diuretic effect may be detectable in patients treated with eplerenone, a mineralocorticoid receptor antagonist, as compared with placebo during the first month of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study) (n = 6,080) and whether this was associated with eplerenone's beneficial effects on cardiovascular outcomes. The mechanism of the survival benefit of eplerenone in patients with heart failure post-myocardial infarction remains uncertain. A diuretic effect was indirectly estimated by changes at 1 month that was superior to the median changes in the placebo group in body weight (-0.05 kg) and in the estimated plasma volume reduction (+1.4%). A potassium-sparing effect was defined as a serum potassium increase greater than the median change in the placebo group: +0.11 mmol/l. In the eplerenone group, body weight (p < 0.0001) and plasma volume (p = 0.047) decreased, whereas blood protein and serum potassium increased (both, p < 0.0001), as compared with the placebo group, suggesting a diuretic effect induced by eplerenone, associated with a potassium-sparing effect. A diuretic effect, as defined by an estimated plasma volume reduction, was independently associated with 11% to 19% better outcomes (lower all-cause death, cardiovascular death or cardiovascular hospitalization, all-cause death or hospitalization, hospitalization for heart failure). Potassium sparing was also independently associated with 12% to 34% better outcomes. There was no statistically significant interaction between the observed beneficial effects of eplerenone (9% to 17%) on cardiovascular outcomes and potassium-sparing or diuretic effects. Eplerenone's beneficial effects on long-term survival and cardiovascular outcomes are independent from early potassium-sparing or diuretic effects, suggesting that mineralocorticoid receptor antagonism provides cardiovascular protection beyond its diuretic and potassium-sparing properties.

Beneficial Effect of Switching from a Combination of Angiotensin II Receptor Blockers other than Losartan and Thiazides to a Fixed Dose of Losartan/Hydrochlorothiazide on Uric Acid Metabolism in Hypertensive Patients

Among the angiotensin II receptor blockers (ARBs), losartan (LOS) has uricosuric action. The clinical benefits of LOS compared with those of other ARBs may be apparent when it is combined with diuretics, which have an unfavorable influence on serum uric acid (SUA). The effects of switching from combinations of ARBs other than LOS and thiazides to a fixed-dose combination comprising 50 mg LOS and 12.5 mg hydrochlorothiazide on blood pressure (BP), SUA, percent fractional excretion of UA (FEUA), and urine pH were assessed in 57 hypertensive outpatients. A significant reduction in BP was observed after 6 months (P < .01). The switching therapy significantly decreased SUA level (6.0 ± 1.3 vs. 5.7 ± 1.3 mg/dL, P < .01), which was accompanied by increases in FEUA (P < .01) and urine pH (P < .01). The change in SUA was negatively correlated with the changes in FEUA (P < .004) and estimated glomerular filtration rate (P < .05). The change in FEUA was positively correlated with the changes in urine pH (P < .05) but not with BP or estimated glomerular filtration rate. In a separate group of patients treated with ARBs other than LOS (n = 82), a significant BP reduction was observed, but no change in SUA or FEUA was observed. In conclusion, switching therapy decreased SUA level, which was accompanied by an increase in FEUA. This result may depend on the balance between LOS-induced inhibitory action of urate transporter 1 and hydrochlorothiazide-induced plasma volume reduction. The increase in urine pH plays a role in UA urinary excretion.

Atrial natriuretic peptide increases the albumin permeability of mouse skeletal muscle microcirculation by the caveolae-mediated transcellular pathway

Background Cardiac atrial natriuretic peptide (ANP) is an essential physiological regulator of arterial blood pressure and intravascular volume. Unlike other “natriuretics”, which reduce interstitial fluid volume with little change in plasma volume, ANP has important extrarenal, endothelial actions that enable it to reduce plasma volume preferentially. Thus ANP, via its guanylyl cyclase-A (GC-A) receptor and cyclic GMP formation, enhances microvascular endothelial permeability to albumin, ultimately moving plasma fluid into interstitial pools. However, the cellular pathways mediating this effect are unknown.v Here we investigated the role of caveolae-mediated endothelial albumin transcytosis in the mechanism of increased permeability induced by ANP.

Effect of short‐term water restriction in hot season on some blood parameters and immune response to Newcastle disease vaccine of local and commercial layers in the late phase of production

Forty-five Hisex commercial layers and forty-five local Saudi breed layers were used to compare and assess the effect of water restriction under hot conditions on blood constituents and immune response to Newcastle disease (ND) vaccine. The trial was divided into three periods: control (7 day), water restriction (14 day) and rehydration (7 day). During water restriction, layers from each breed were divided into three groups that received 0%, 20% and 40% restriction of drinking water relative to the control period. The immune response against ND was affected by breed; it also declined significantly with 40% water restriction 10 days post-restriction. Water restriction did not affect haematocrit value, plasma total protein, albumin, glucose or osmolality, which may not suggest a reduction in plasma volume. However, plasma creatinine increased in both breeds because of water restriction that remained elevated during rehydration. Water restriction increased plasma urea in the local group, while it decreased in the commercial group. Irrespective of rate of water restriction, it can be concluded that the two breeds can withstand up to 40% water restriction during high environmental temperature. However, the local breed may be superior in water conservation in relation to the commercial layers.

Dehydration during whole‐body heat stress contributes to subsequent reductions in lower‐body negative pressure (LBNP) tolerance

This study tested the hypothesis that dehydration, which accompanies heat stress, further compromises the maintenance of blood pressure during a simulated hemorrhagic challenge via LBNP. Seven individuals (34±9 y; 77±4 kg) underwent heat stress on two separate days (randomized), one with and one without intravenous (IV) infusion of Lactated Ringers solution sufficient to replace sweat loss. Hemorrhage was simulated via progressive LBNP to pre-syncope after core body (intestinal) temperature was raised ~1.4°C using a water perfused suit. LBNP tolerance was quantified with a cumulative stress index (CSI). Blood samples were obtained at normothermia and just prior to LBNP to estimate changes in plasma volume during heat stress. Body core temperature increases and sweat losses (~1.7% body mass deficit) were similar (P>0.05) between trials. IV infusion (1.3±0.5 L) prevented the reduction in plasma volume that occurred during the dehydration trial (IV infusion trial: +3.1±7.1%; dehydration trial: −6.5±5.5%, P=0.01). LBNP tolerance during the dehydration trial (407±126 CSI units) was lower compared to the IV trial (641±64 CSI units, P<0.01). These data indicate that dehydration during heat stress reduces an individual's tolerance to a subsequent hemorrhagic challenge, therefore, increasing the likelihood of syncope. Supported by NIH Grant HL061388

Endocrine Aspects of High Altitude Acclimatization and Acute Mountain Sickness

The acute acclimatization to high altitude is underpinned by a diuresis (and to a lesser extent a natriuresis) that facilitates a reduction in plasma volume. This allows a haemoconcentration to...

Control of cerebral blood velocity with furosemide-induced hypovolemia and upright tilt

The purpose of this study was to test the hypothesis that exacerbated reductions of cerebral blood velocity (CBV) during upright tilt with dehydration are associated with impaired cerebrovascular control. Nine healthy men were tilted head-up (HUT) to 70° for 10 min on two occasions separated by 7 days under euhydration (EUH) and dehydration (DEH; 40 mg of furosemide and water restriction) conditions. Beat-by-beat arterial pressures and CBV were measured during a 5-min supine baseline and during the first (T1) and last (T2) 5 min of HUT. Cerebral autoregulation and arterial baroreflex sensitivity were assessed in the frequency domain with cross-spectral techniques. DEH reduced plasma volume by 10% (P = 0.008) and supine mean CBV (CBV(mean)) by 11% (P = 0.002). Mean arterial pressure (MAP), stroke volume, and baroreflex sensitivity decreased during HUT (P ≤ 0.002), but absolute reductions were similar between hydration conditions, with the exception of stroke volume, which was lower at T1 during DEH than EUH (P = 0.04). CBV(mean) during DEH was lower (7 cm/s) over the course of the entire 10 min of HUT (P ≤ 0.004) than during EUH. Low-frequency oscillations (0.07-0.2 Hz) of MAP and CBV(mean) and MAP-CBV(mean) coherence were higher during DEH than EUH at T1 (P ≤ 0.02), but not at T2. Our results suggest that increased coherence between arterial pressure and CBV with the combination of DEH and HUT are indicative of altered cerebrovascular control. Increased CBV oscillations with DEH may reflect acute protective mechanisms to ensure adequate cerebral perfusion under conditions of reduced central blood volume.

Age related decreases in thermoregulation and cardiovascular function in horses

Older horses have an increased risk of hyperthermia due to impaired cardiovascular function. While many studies have investigated thermoregulation in horses during exercise, none have investigated the effects of ageing. To test the hypothesis that there is a difference in thermoregulation during exercise and plasma volume (PV) in young and old horses. Study 1: 6 young (Y, 7.7 ± 0.5 years) and 5 old (O, 26.0 ± 0.8 years) unfit Standardbred mares (507 ± 11 kg, mean ± s.e.) ran on a treadmill (6% grade, velocity calculated to generate a work rate of 1625 watts) until core temperature reached 40 °C. Core (CT), skin (ST), rectal temperature (RT) and heart rate (HR) were measured every min until 10 min post exertion. Packed cell volume (HCT), lactate (LA) and plasma protein (TP) were measured in blood samples collected before, at 40 °C and every 5 min until 10 min post exercise. Sweat loss was estimated using bodyweight. Study 2: Plasma volume was measured in 26 young (8.2 ± 0.7 years) and 8 old (26.6 ± 0.7 years) Standardbred mares (515 ± 12 kg) using Evans Blue dye. Pre-exercise blood (rBV) and red cell (rRCV) volumes were calculated using PV and HCT. Data analysis utilised repeated measures ANOVA and t tests and data are expressed as mean ± s.e. Old horses reached 40 °C faster (998 ± 113 vs. 1925 ± 259 s; P < 0.05) with a greater HR at 40 °C (184 ± 6 vs. 140 ± 5 beats/min; P < 0.05) and greater sweat losses (P < 0.05). Heart rate did not differ (P > 0.05) post exercise. Age did not alter (P > 0.05) CT, ST, RT, LA, HCT or TP. Plasma volume was greater in Y vs. O horses (P < 0.05, 28.5 ± 1.4 vs. 24.1 ± 1.6 l) as was rBV (41.3 ± 2.0 vs. 35.3 ± 2.3 l) and rRCV (13.3 ± 0.6 vs. 11.1 ± 0.8 l). Ageing compromises the ability to handle the combined demand of exercise and thermoregulation in part due to decreased absolute pre-exercise PV.

A gel-based method for purification of apolipoprotein A-I from small volumes of plasma

We present here a gel-based method for rapid purification of apolipoprotein A-I (apoA-I) from small volumes of human plasma. After isolation of high density lipoprotein from plasma, the apoA-I protein was separated by electrophoresis and the apoA-I band excised from the gel. The apoA-I was then eluted from the gel strip, concentrated, and delipidated ready for use. The structure and function of the gel-purified apoA-I protein was compared against apoA-I purified by the traditional size-exclusion chromatography method. The α-helical content of the gel-purified apoA-I as determined by circular dichroism was similar to chromatography-purified apoA-I. The functional activity of gel-purified apoA-I, as determined by cholesterol efflux assays in primary human fibroblasts and RAW264.7 macrophages, was also comparable with chromatography-purified apoA-I. This method is a valid alternative for apoA-I purification with some advantages over traditional chromatography purification including a much reduced plasma volume requirement, less time and cost, and a higher percentage protein recovery. The method is particularly suitable for applications requiring the purification of apoA-I from multiple human or animal samples of interest.

Hypoproteinemia does not alter plasma volume expansion in response to a 0.9% saline bolus in awake sheep

To test the hypothesis that hypoproteinemia reduces plasma volume expansion produced by a bolus of crystalloid solution given to awake sheep. Prospective and observational. Laboratory. Five female merino sheep (n = 5) weighing 37 ± 3 kg were anesthetized. Each animal was subjected to a 5-day test period: day 1: 50 mL/min 0.9% saline infusion over 20 mins. Days 2-4: daily plasmapheresis and replacement of the shed plasma with 6 L of 0.9% saline were performed in increments. Fractional plasma volume expansion after rapid infusion of saline on days 1 and 5 was calculated from changes in hemoglobin concentration. There was a significant reduction in total plasma protein concentration after plasmapheresis (p < .05). Colloid osmotic pressures were also significantly lowered (p < .05). A crystalloid infusion of 0.9% saline did not alter any of these values compared with baseline. The hemodynamic measurements did not show significant differences between the experiments. The plasma volume expansion reached approximately 20% at the end of infusion and stayed at 10-15% during the experiments. No difference was found in plasma volume expansion produced by a bolus of 50 mL/min of 0.9% in the hypoproteinemic state when compared with the euproteinemic state (p = .61). No difference in cumulative urinary output was found between the two states. In contrast to our hypothesis, severe acute hypoproteinemia does not reduce plasma volume expansion in response to 50 mL/min 0.9% saline infusion in nonspleenectomized sheep when compared with the resultant plasma volume expansion after a 50 mL/min of 0.9% infusion in the euproteinemic state.

Therapy refractory hypertension in haemodialysis patients has become a rare indication for bilateral nephrectomy.

In haemodialysis patients, blood pressure (BP) is usually plasma volume-dependent. Ultrafiltration during haemodialysis typically leads to reductions in plasma volume and body weight with a consequent lowering of elevated BP. However, in few cases, hypertension is refractory to reductions in plasma volume and to therapy with multiple antihypertensive drugs. In some patients, BP will increase even during volume depletion [1]. In these few patients, bilateral nephrectomy (BN) is an option for treatment [2]. We evaluated 16 haemodialysis patients [aged 37 (22–69) years, female 44%] in whom BN was performed due to severe or malignant hypertension with poor response to antihypertensive treatment (refractory hypertension). All patients were on haemodialysis in our dialysis centre during the years 1984–2008. Mean BP was significantly elevated even though the patients received ≥ 4 antihypertensive drugs. The aim of our retrospective study was to evaluate the efficacy and the frequency of needed BN. We compared BPs before and every 3 months following BN for an entire year. At 12 months after BN, mean systolic BP decreased from 194 ± 18 to 132 ± 12 mmHg, and diastolic BP decreased from 118 ± 10 to 82 ± 9 mmHg (P < 0.005). Near-normal BP values were observed within a mean of 2–3 months after BN. BP persistently decreased in 14 cases after nephrectomy, but rebounded in two cases because of hypervolaemia due to 10% body weight gain during intradialytic intervals. In these two cases, intensified ultrafiltration caused a prompt decrease in BP. In three subjects, hypotension occurred after BN (BP < 120/70 mmHg), and intradialytic ultrafiltration had to be decreased. Five patients required continuation of one antihypertensive drug. While in our centre, antihypertensive therapy was more intense during the last years of the study with 5.8 (5–6) daily antihypertensive agents compared with only 4.4 (4–5) in the years 1984–89 (NS). The clinical condition and quality of life improved in all of our patients. In nine patients, antihypertensive treatment was no longer necessary, and five patients required continuation of only one antihypertensive agent. Previous studies showed similar significant improvements in hypertension after BN [2], although a case report described persistent hypotension after BN in a 4-month-old infant [3]. According to the literature, BN is infrequently used as treatment for intractable hypertension. The prevalence of BN varies between 0% and 7% in most countries [4]. In our centre, refractory hypertension has become a rare indication for BN, and the incidence of BN was continuously decreasing during our observation period. For example, the incidence rate (n/year) decreased from 1.2 during the first five years (1984–89), to 1.0 and 0.4 during the next two 5-year periods, and was only 0.2 during 2003–08 (P < 0.05). The reduced frequency of BN was explained by the use of more effective antihypertensive medication during the last years; however, this difference was not significant because of small patient group sizes. Reductions in BN were also due to more frequent treatments with ACE inhibitors/AII blockers (9% in the first five years versus 33% during the last five years). In conclusion, we found that BN effectively lowered BP in cases that were extremely refractory to hypertension therapy. Despite this, the frequency of needed BN in haemodialysis patients appears to be decreasing. The lower frequency of BN may be associated with recent intensified antihypertensive therapy and a much greater use of ACE inhibitors during the last decade. Conflict of interest statement. None declared.

Long space missions, gene therapy, and the vital role of magnesium: a three-pronged plan for the next 50 years

Since pharmaceuticals cannot be used in space until liver and kidney dysfunctions are corrected, and with invariable malabsorption, it appears there is no alternative other than to use subcutaneous magnesium (Mg) replacements in the presence of deficiencies and use of gene therapy. I suggest beginning with the correction of as many as four gene deficiencies: atrial natriuretic peptide (ANP), nitric oxide (NO), vascular endothelial growth factor (VEGF), and erythropoietin (EPO), all as well as Mg related to perfusion and angiogenesis. There is no evidence of significant lunar radiation levels in the absence of a solar storm. It could then be determined whether this has resulted in correction of liver and kidney dysfunction. If this persists, serial additions of gene therapy will be required determining the effect of each individual gene trial on organ function. Microgravity and endothelial gaps with leaks trigger reduced plasma volume. Partial correction by use of a plasma volume substitute and development of a delivery device may reduce complexity of gene therapy. Research would be conducted both on Earth and in microgravity, with the development of subcutaneous pharmaceuticals and Mg, and a space walk-reliable subcutaneous silicon device, given that no replenishable subcutaneous device is presently available. A three-pronged approach provides a plan for the next 50 years: A. complete correction of a Mg deficit; B. partial replacement with plasma volume substitutes, and C. multiple gene factor strategy.

The impact of maternal protein restriction during rat pregnancy upon renal expression of angiotensin receptors and vasopressin-related aquaporins

BackgroundMaternal protein restriction during rat pregnancy is known to impact upon fetal development, growth and risk of disease in later life. It is of interest to understand how protein undernutrition influences the normal maternal adaptation to pregnancy. Here we investigated the mechanisms regulating renal haemodynamics and plasma volume during pregnancy, in the context of both normal and reduced plasma volume expansion. The study focused on expression of renal angiotensin receptors (ATR) and vasopressin-related aquaporins (AQP), hypothesising that an alteration in the balance of these proteins would be associated with pregnancy per se and with compromised plasma volume expansion in rats fed a low-protein diet.MethodsFemale Wistar rats were mated and fed a control (18% casein) or low-protein (9% casein) diet during pregnancy. Animals were anaesthetised on days 5, 10, 15 and 20 of gestation (n = 8/group/time-point) for determination of plasma volume using Evans Blue dye, prior to euthanasia and collection of tissues. Expression of the ATR subtypes and AQP2, 3 and 4 were assessed in maternal kidneys by PCR and western blotting. 24 non-pregnant Wistar rats underwent the same procedure at defined points of the oestrous cycle.ResultsAs expected, pregnancy was associated with an increase in blood volume and haemodilution impacted upon red blood cell counts and haemoglobin concentrations. Expression of angiotensin II receptors and aquaporins 2, 3 and 4 was stable across all stages of the oestrus cycle. Interesting patterns of intra-renal protein expression were observed in response to pregnancy, including a significant down-regulation of AQP2. In contrast to previous literature and despite an apparent delay in blood volume expansion in low-protein fed rats, blood volume did not differ significantly between groups of pregnant animals. However, a significant down-regulation of AT2R protein expression was observed in low-protein fed animals alongside a decrease in creatinine clearance.ConclusionRegulatory systems involved in the pregnancy-induced plasma volume expansion are susceptible to the effects of maternal protein restriction.