AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Control of blood volume following hypovolemic challenge in vertebrates: Transcapillary versus lymphatic mechanisms.

Anurans have an exceptional capacity for maintaining vascular volume compared with other groups of vertebrates. They can mobilize interstitial fluids via lymphatic return at rates that are ten-fold higher than mammals. This extraordinary capacity is the result of coordination of specialized skeletal muscles and pulmonary ventilation that vary volume and pressure of subcutaneous lymph sacs, thus moving lymph to dorsally located lymph hearts that return lymph to the vascular space. Variation in the capacity to mobilize lymph within anurans varies with the degree of terrestriality, development of skeletal muscles, lung volume and lung compliance, and lymph heart pressure development. This ability enable anurans, which have the highest rates of evaporative water loss among terrestrial vertebrates, to withstand levels of dehydration far exceeding that of other vertebrates, and to successfully occupy virtually all terrestrial environments during their evolution. Maintenance of vascular fluid volume for all vertebrates can be achieved primarily by moving fluid from the interstitial space to the vascular space by transcapillary uptake and mobilization of interstitial (lymphatic) fluid. Transcapillary fluid uptake at the capillary level has been analyzed historically by Krogh and others from a Starling perspective and involves a balance of hydrostatic and oncotic forces. A complete evaluation of blood volume homeostasis also incorporates pressures and compliances of the vascular and interstitial spaces, but has been applied to only a few species. In this review we outline the current understanding of how anurans and other vertebrates maintain blood volume during hypovolemic challenges such as dehydration and hemorrhage which is crucial for maintaining cardiac output.

Colloids and the Microcirculation.

Colloid solutions have been advocated for use in treating hypovolemia due to their expected effect on improving intravascular retention compared with crystalloid solutions. Because the ultimate desired effect of fluid resuscitation is the improvement of microcirculatory perfusion and tissue oxygenation, it is of interest to study the effects of colloids and crystalloids at the level of microcirculation under conditions of shock and fluid resuscitation, and to explore the potential benefits of using colloids in terms of recruiting the microcirculation under conditions of hypovolemia. This article reviews the physiochemical properties of the various types of colloid solutions (eg, gelatin, dextrans, hydroxyethyl starches, and albumin) and the effects that they have under various conditions of hypovolemia in experimental and clinical scenarios.

Responses of distal nephron Na+ transporters to acute volume depletion and hyperkalemia.

We assessed effects of acute volume reductions induced by administration of diuretics in rats. Direct block of Na+ transport produced changes in urinary electrolyte excretion. Adaptations to these effects appeared as alterations in the expression of protein for the distal nephron Na+ transporters NCC and ENaC. Two hours after a single injection of furosemide (6 mg/kg) or hydrochlorothiazide (HCTZ; 30 mg/kg) Na+ and K+ excretion increased but no changes in the content of activated forms of NCC (phosphorylated on residue T53) or ENaC (cleaved γ-subunit) were detected. In contrast, amiloride (0.6 mg/kg) evoked a similar natriuresis that coincided with decreased pT53NCC and increased cleaved γENaC. Alterations in posttranslational membrane protein processing correlated with an increase in plasma K+ of 0.6-0.8 mM. Decreased pT53NCC occurred within 1 h after amiloride injection, whereas changes in γENaC were slower and were blocked by the mineralocorticoid receptor antagonist spironolactone. Increased γENaC cleavage correlated with elevation of the surface expression of the subunit as assessed by in situ biotinylation. Na depletion induced by 2 h of furosemide or HCTZ treatment increases total NCC expression without affecting ENaC protein. However, restriction of Na intake for 10 h (during the day) or 18 h (overnight) increased the abundance of both total NCC and of cleaved α- and γENaC. We conclude that the kidneys respond acutely to hyperkalemic challenges by decreasing the activity of NCC while increasing that of ENaC. They respond to hypovolemia more slowly, increasing Na+ reabsorptive capacities of both of these transporters.

Syndrome of inappropriate anti-diuresis induces volume-dependent hypercalciuria.

Hyponatremia is associated with bone demineralization. We hypothesized that, during hyponatremia, calciuria and calcium balance depend on volemic status. We evaluated calciuria in patients with hyponatremia, secondary to SIAD or hypovolemia. Patients with SIAD exhibited a volemic expansion that was associated with hypercalciuria. Calciuria was proportional to markers of volemia. INTRODUCTION: Chronic mild hyponatremia has been associated with bone demineralization of unknown mechanisms. During chronic hyponatremia, arginine-vasopressin secretion can result from hypovolemia or from syndrome of inappropriate anti-diuresis (SIAD) that leads to a slightly volemic expansion. Since volemia determines renal calcium excretion and balance, we evaluated calcium homeostasis in patients with chronic hyponatremia, related to SIAD or to hypovolemia. METHODS: We retrospectively included all patients referred to our Department between May 2006 and May 2014 for hyponatremia, resulting from SIAD or chronic hypovolemia. None had edema, cirrhosis, cardiac, or renal insufficiency. Exploration included estimation of volemia, extracellular fluid volume (ECFV) measurement with inulin, and calcium homeostasis. RESULTS: In total, the SIAD and hypovolemic groups included 22 and 7 patients, respectively. The SIAD group exhibited signs of increased volemia: higher glomerular filtration rate, higher fractional excretion of uric acid, and lower plasma renin. ECFV exceeded that of the hypovolemic group and was above usual values. There was no difference between the two groups regarding plasma calcium, PTH, and vitamin D. However, in the SIAD group, calciuria was higher than in the hypovolemic group, reaching levels of hypercalciuria. Furthermore, there was a positive correlation between calciuria and markers of volemia. CONCLUSIONS: Our results show that SIAD results in a volemic expansion tendency that is associated with a decrease in renal calcium reabsorption and thus hypercalciuria, whereas in the hypovolemic group, calciuria was not increased. Therefore, renal loss of calcium and bone demineralization in SIAD patients could be partly induced by volemic expansion.

PlanHab: hypoxia exaggerates the bed-rest-induced reduction in peak oxygen uptake during upright cycle ergometry.

The study examined the effects of hypoxia and horizontal bed rest, separately and in combination, on peak oxygen uptake (V̇o2 peak) during upright cycle ergometry. Ten male lowlanders underwent three 21-day confinement periods in a counterbalanced order: 1) normoxic bed rest [NBR; partial pressure of inspired O2 (PiO2 ) = 133.1 ± 0.3 mmHg]; 2) hypoxic bed rest (HBR; PiO2 = 90.0 ± 0.4 mmHg), and 3) hypoxic ambulation (HAMB; PiO2 = 90.0 ± 0.4 mmHg). Before and after each confinement, subjects performed two incremental-load trials to exhaustion, while inspiring either room air (AIR), or a hypoxic gas (HYPO; PiO2 = 90.0 ± 0.4 mmHg). Changes in regional oxygenation of the vastus lateralis muscle and the frontal cerebral cortex were monitored with near-infrared spectroscopy. Cardiac output (CO) was recorded using a bioimpedance method. The AIR V̇o2 peak was decreased by both HBR (∼13.5%; P ≤ 0.001) and NBR (∼8.6%; P ≤ 0.001), with greater drop after HBR (P = 0.01). The HYPO V̇o2 peak was also reduced by HBR (-9.7%; P ≤ 0.001) and NBR (-6.1%; P ≤ 0.001). Peak CO was lower after both bed-rest interventions, and especially after HBR (HBR: ∼13%, NBR: ∼7%; P ≤ 0.05). Exercise-induced alterations in muscle and cerebral oxygenation were blunted in a similar manner after both bed-rest confinements. No changes were observed in HAMB. Hence, the bed-rest-induced decrease in V̇o2 peak was exaggerated by hypoxia, most likely due to a reduction in convective O2 transport, as indicated by the lower peak values of CO.

The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia.

Tolerance to central hypovolemia is highly variable, and accumulating evidence suggests that protection of anterior cerebral blood flow (CBF) is not an underlying mechanism. We hypothesized that individuals with high tolerance to central hypovolemia would exhibit protection of cerebral oxygenation (ScO2), and prolonged preservation of CBF in the posterior vs. anterior cerebral circulation. Eighteen subjects (7 male/11 female) completed a presyncope-limited lower body negative pressure (LBNP) protocol (3 mmHg/min onset rate). ScO2 (via near-infrared spectroscopy), middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv) (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Subjects who completed ≥70 mmHg LBNP were classified as high tolerant (HT; n = 7) and low tolerant (LT; n = 11) if they completed ≤60 mmHg LBNP. The minimum difference in LBNP tolerance between groups was 193 s (LT = 1,243 ± 185 s vs. HT = 1,996 ± 212 s; P < 0.001; Cohen's d = 3.8). Despite similar reductions in mean MCAv in both groups, ScO2 decreased in LT subjects from -15 mmHg LBNP (P = 0.002; Cohen's d=1.8), but was maintained at baseline values until -75 mmHg LBNP in HT subjects (P < 0.001; Cohen's d = 2.2); ScO2 was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.02; Cohen's d ≥ 1.1). Similarly, mean PCAv decreased below baseline from -30 mmHg LBNP in LT subjects (P = 0.004; Cohen's d = 1.0), but remained unchanged from baseline in HT subjects until -75 mmHg (P = 0.006; Cohen's d = 2.0); PCAv was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.01; Cohen's d ≥ 0.94). Individuals with higher tolerance to central hypovolemia exhibit prolonged preservation of CBF in the posterior cerebral circulation and sustained cerebral tissue oxygenation, both associated with a delay in the onset of presyncope.

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

NEW FINDINGS: 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.

White blood cell concentrations during lower body negative pressure and blood loss in humans.

NEW FINDINGS: What is the central question of this study? Is lower body negative pressure a useful surrogate to study white blood cell responses to haemorrhage in humans? What is the main finding and its importance? We found that lower body negative pressure appears to be a useful surrogate to study the early white blood cell mobilization response during blood loss. Hypovolaemia has been associated with an immune response that might be secondary to sympathoexcitation. We tested the hypothesis that simulated hypovolaemia using lower body negative pressure (LBNP) and real hypovolaemia induced via experimental blood loss (BL) cause similar increases in the white blood cell concentration ([WBC]). We measured [WBC] and catecholamine concentrations in 12 men who underwent an LBNP and a BL protocol in a randomized order. We compared 45 mmHg of LBNP with 1000 ml of BL; therefore, [WBC] and catecholamine concentrations were plotted against central venous pressure to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Mean regression line slopes were similar for total [WBC] (LBNP 183 ± 4 µl-1  mmHg-1 versus BL 155 ± 109 µl-1  mmHg-1 , P = 0.15), neutrophils (LBNP 110 ± 2 µl-1  mmHg-1 versus BL 96 ± 72 µl-1  mmHg-1 , P = 0.15) and lymphocytes (LBNP 65 ± 21 µl-1  mmHg-1  versus BL 59 ± 38 µl-1  mmHg-1 , P = 0.90). Mean regression line slopes for adrenaline were similar (LBNP 15 ± 5 pg ml-1  mmHg-1 versus BL 16 ± 4 pg ml-1  mmHg-1 , P = 0.84) and were steeper during LBNP for noradrenaline (LBNP 28 ± 6 pg ml-1  mmHg-1 versus BL 9 ± 6 pg ml-1  mmHg-1 , P = 0.01). These data indicate that central hypovolaemia elicits a relative leucocytosis with a predominantly neutrophil-based response. Additionally, our results indicate that LBNP models the stimulus-response relationship between central venous pressure and [WBC] observed during BL.

The type-1 cannabinoid receptor modulates the hydroelectrolytic balance independently of the energy homeostasis during salt load.

Hydroelectrolytic imbalances, such as saline load (SL), trigger behavioral and neuroendocrine responses, such as thirst, hypophagia, vasopressin (AVP) and oxytocin (OT) release and hypothalamus­pituitary­adrenal (HPA) axis activation. To investigate the participation of the type-1 cannabinoid receptor (CB1R) in these homeostatic mechanisms,male adult Wistar rats were subjected to SL (0.3MNaCl) for four days. SL induced not only increases in the water intake and plasma levels of AVP, OT and corticosterone, as previously described, but also increases in CB1R expression in the lamina terminalis, which integrates sensory afferents, aswell as in the hypothalamus, the main integrative and effector area controlling hydroelectrolytic homeostasis. A more detailed analysis revealed that CB1R-positive terminals are in close apposition with not only axons but also dendrites and secretory granules of magnocellular neurons, particularly vasopressinergic cells. In satiated and euhydrated animals, the intracerebroventricular administration of the CB1R selective agonist ACEA (0.1 µg/5 µL) promoted hyperphagia, but this treatment did not reverse the hyperosmolality-induced hypophagia in the SL group. Furthermore, ACEA pretreatment potentiated water intake in the SL animals during rehydration as well as enhanced the corticosterone release and prevented the increase in AVP and OT secretion induced by SL. The same parameters were not changed by ACEA in the animals whose daily food intake was matched to that of the SL group (Pair-Fed). These data indicate that CB1Rs modulate the hydroelectrolytic balance independently of the food intake during sustained hyperosmolality and hypovolemia.

Dehydration affects cardiovascular nitric oxide synthases and caveolins in growing rats.

PURPOSE: During the postnatal stage, cardiovascular nitric oxide (NO) system and caveolins (cav) may be regulated differentially in response to hypovolemic state induced by water restriction. Our aim was to examine the effects of water restriction on NO synthases (NOS) and cav in the atria, ventricle and aorta of growing rats. METHODS: Male Sprague-Dawley rats aged 25 and 50 days were divided into (n = 15): WR: water restriction 3 days; WAL: water ad libitum 3 days. Systolic blood pressure, NOS activity and NOS/cav protein levels were measured. RESULTS: Dehydration induced a larger increase in SBP in WR25 group. Ventricular NOS activity, endothelial NOS (eNOS) and neuronal isoform (nNOS) of WR25 pups were increased, and both cav were decreased. In the WR50 group, NOS activity remained unchanged. In the atria, NOS activity, eNOS and nNOS decreased in WR25 associated with increased cav-1; in the WR50 group, NOS activity was increased without changes in NOS isoforms. In the aorta of WR25, NOS activity and inducible NOS (iNOS) were decreased; NOS activity was unchanged in WR50, despite the decreased levels of eNOS and increased iNOS, cav-1 and cav-3. CONCLUSIONS: NO system adjustments in cardiovascular system under osmotic stress in vivo depend on postnatal age, being eNOS and nNOS, the isoforms that determine NOS activity in cardiac tissue in 25-day-old pups. Changes in cav abundance during hypovolemic state may contribute to age-related NO production.

Tissue oxygen saturation and finger perfusion index in central hypovolemia: influence of pain.

OBJECTIVES: Tissue oxygen saturation and peripheral perfusion index are proposed as early indirect markers of hypovolemia in trauma patients. Hypovolemia is associated with increased sympathetic nervous activity. However, many other stimuli, such as pain, also increase sympathetic activity. Since pain is often present in trauma patients, its effect on the indirect measures of hypovolemia needs to be clarified. The aim of this study was, therefore, to explore the effects of hypovolemia and pain on tissue oxygen saturation (measurement sites: cerebral, deltoid, forearm, and thenar) and finger photoplethysmographic perfusion index. DESIGN: Experimental study. SETTING: University hospital clinical circulation and research laboratory. SUBJECTS: Twenty healthy volunteers. INTERVENTIONS: Central hypovolemia was induced with lower body negative pressure (-60 mm Hg) and pain by the cold pressor test (ice water exposure). Interventions were performed in a 2×2 fashion with the combination of lower body negative pressure or not (normovolemia), and ice water or not (sham). Each subject was thus exposed to four experimental sequences, each lasting for 8 minutes. MEASUREMENTS AND MAIN RESULTS: Measurements were averaged over 30 seconds. For each person and sequence, the minimal value was analyzed. Tissue oxygenation in all measurement sites and finger perfusion index were reduced during hypovolemia/sham compared with normovolemia/sham. Tissue oxygen saturation (except cerebral) and perfusion index were reduced by pain during normovolemia. There was a larger reduction in tissue oxygenation (all measurement sites) and perfusion index during hypovolemia and pain than during normovolemia and pain. CONCLUSIONS: Pain (cold pressor test) reduces tissue oxygen saturation in all measurement sites (except cerebral) and perfusion index. In the presence of pain, tissue oxygen saturation and perfusion index are further reduced by hypovolemia (lower body negative pressure, -60 mm Hg). Thus, pain must be considered when evaluating tissue oxygen saturation and perfusion index as markers of hypovolemia in trauma patients.

The impact of inspiratory pressure on stroke volume variation and the evaluation of indexing stroke volume variation to inspiratory pressure under various preload conditions in experimental animals.

PURPOSE: Stroke volume variation (SVV) measures fluid responsiveness, enabling optimal fluid management under positive pressure ventilation. We aimed to investigate the effect of peak inspiratory pressure (PIP) on SVV under various preload conditions in experimental animals and to ascertain whether SVV indexed to PIP decreases the effect. METHODS: Mild and moderate hemorrhage models were created in nine anesthetized, mechanically ventilated beagle dogs by sequentially removing 10 and then an additional 10 ml/kg of blood, respectively. In all the animals, PIP was incrementally increased by 4 cmH2O, from 5 to 21 cmH2O. SVV was measured by arterial pulse contour analysis. Stroke volume was derived using a thermodilution method, and central venous pressure and mean arterial pressure were also measured. RESULTS: SVV increased according to PIP with significant correlation at baseline, with mild hemorrhage and moderate hemorrhage. PIP regression coefficients at baseline and in the mild and moderate hemorrhage models were 0.59, 0.86, and 1.4, respectively. Two-way repeated-measures analysis of variance showed that PIP and the degree of hemorrhage had a significant interaction effect on SVV (p = 0.0016). SVV indexed to PIP reflected the hemorrhage status regardless of PIP changes ≥9 cmH2O. CONCLUSIONS: PIP is significantly correlated with SVV, even under hypovolemia, and the effect is enhanced with decreasing preload volumes. Compared with SVV, the indexed SVV was less susceptible to higher inspiratory pressures.

[Optimization of infusion therapy in patients with ovarian cancer].

We investigated the clinical observations and the results of a comprehensive survey of 70 patients with ovarian cancer stage III-IV aged 30 to 70 years with the presence of endotoxemia. Integral assessment of prognosis and severity of the condition was performed according to SAPS II and SOFA. Infusion program included a preliminary correction of hypovolemia prior to surgery on the operating table in equal parts, HES and balanced crystalloid solutions, with in- creased infusion of 15% of blood volume based on the method of anesthesia. In the early postoperative period, infusion programs were complemented by various embodiments of metabolic correction. Patients of group-1 (n = 35) received remaxol in a dose of 800 mI/day. Patients of group-2 (n = 35) received ademethionine (heptral) 800 mg/day. Analysis of the results revealed that premorbid background in patients with ovarian cancer stage III-IV was characterized by hypovolemia, phenomena hepatopathy, and endotoxemia, and mixed forms of hypoxia of varying severity. Differentiated approach to the choice of pathogenesis-based perioperative infusion according to premorbid condition, anesthesia and blood loss contributed to the elimination of hypovolemia, favored efficient oxygen delivery and consumption, the ade- quacy of tissue oxygenation. Remaxol inclusion in the perioperative infusion programs in patients with ovarian cancer enhanced their clinical efficiency, reduced cytolytic and cholestatic syndromes, recovered of protein and synthetic liver function, reduced the appearance of mixedforms of hypoxia and endogenous intoxication.

Tissue oxygen saturation during hyperthermic progressive central hypovolemia.

During normothermia, a reduction in near-infrared spectroscopy (NIRS)-derived tissue oxygen saturation (So2) is an indicator of central hypovolemia. Hyperthermia increases skin blood flow and reduces tolerance to central hypovolemia, both of which may alter the interpretation of tissue So2 during central hypovolemia. This study tested the hypothesis that maximal reductions in tissue So2 would be similar throughout normothermic and hyperthermic central hypovolemia to presyncope. Ten healthy males (means ± SD; 32 ± 5 yr) underwent central hypovolemia via progressive lower-body negative pressure (LBNP) to presyncope during normothermia (skin temperature ≈34°C) and hyperthermia (+1.2 ± 0.1°C increase in internal temperature via a water-perfused suit, skin temperature ≈39°C). NIRS-derived forearm (flexor digitorum profundus) tissue So2 was measured throughout and analyzed as the absolute change from pre-LBNP. Hyperthermia reduced (P < 0.001) LBNP tolerance by 49 ± 33% (from 16.7 ± 7.9 to 7.2 ± 3.9 min). Pre-LBNP, tissue So2 was similar (P = 0.654) between normothermia (74 ± 5%) and hyperthermia (73 ± 7%). Tissue So2 decreased (P < 0.001) throughout LBNP, but the reduction from pre-LBNP to presyncope was greater during normothermia (-10 ± 6%) than during hyperthermia (-6 ± 5%; P = 0.041). Contrary to our hypothesis, these findings indicate that hyperthermia is associated with a smaller maximal reduction in tissue So2 during central hypovolemia to presyncope.

Comparison of cardiovascular aquaporin-1 changes during water restriction between 25- and 50-day-old rats.

PURPOSE: Aquaporin-1 (AQP1) is the predominant water channel in the heart, linked to cardiovascular homeostasis. Our aim was to study cardiovascular AQP1 distribution and protein levels during osmotic stress and subsequent hydration during postnatal growth. METHODS: Rats aged 25 and 50 days were divided in: 3d-WR: water restriction 3 days; 3d-WAL: water ad libitum 3 days; 6d-WR+ORS: water restriction 3 days + oral rehydration solution (ORS) 3 days; and 6d-WAL: water ad libitum 6 days. AQP1 was evaluated by immunohistochemistry and western blot in left ventricle, right atrium and thoracic aorta. RESULTS: Water restriction induced a hypohydration state in both age groups (40 and 25 % loss of body weight in 25- and 50-day-old rats, respectively), reversible with ORS therapy. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups, being evident in cardiomyocytes membrane only in 50-day-old 3d-WR group, which presented increased protein levels of AQP1; no changes were observed in the ventricle of pups. In vascular tissue, AQP1 was present in the smooth muscle of pups; in the oldest group, it was found in the endothelium, increasing after rehydration in smooth muscle. No differences were observed between control groups 3d-WAL and 6d-WAL of both ages. CONCLUSION: Our findings suggest that cardiovascular AQP1 can be differentially regulated in response to hydration status in vivo, being this response dependent on postnatal growth. The lack of adaptive mechanisms of mature animals in young pups may indicate an important role of this water channel in maintaining fluid balance during hypovolemic state.

Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and ß-adrenergic activity.

1, 25-Dihydroxycholechalciferol (calcitriol) and 19-nor-1, 25-dihydroxyvitamin D2 (paricalcitol) are vitamin D receptor (VDR) agonists. Previous data suggest VDR agonists may actually increase renin-angiotensin activity, and this has always been assumed to be mediated by hypercalcemia. We hypothesized that calcitriol and paricalcitol would increase plasma renin activity (PRA) independently of plasma Ca(2+) via hypercalciuria-mediated polyuria, hypovolemia, and subsequent increased ß-adrenergic sympathetic activity. We found that both calcitriol and paricalcitol increased PRA threefold (P < 0.01). Calcitriol caused hypercalcemia, but paricalcitol did not. Both calcitriol and paricalcitol caused hypercalciuria (9- and 7-fold vs. control, P < 0.01) and polyuria (increasing 2.6- and 2.2-fold vs. control, P < 0.01). Paricalcitol increased renal calcium-sensing receptor (CaSR) expression, suggesting a potential cause of paricalcitol-mediated hypercalciuria and polyuria. Volume replacement completely normalized calcitriol-stimulated PRA and lowered plasma epinephrine by 43% (P < 0.05). ß-Adrenergic blockade also normalized calcitriol-stimulated PRA. Cyclooxygenase-2 inhibition had no effect on calcitriol-stimulated PRA. Our data demonstrate that vitamin D increases PRA independently of plasma Ca(2+) via hypercalciuria, polyuria, hypovolemia, and increased ß-adrenergic activity.

Effects of angiotensin II on kinase-mediated sodium and potassium transport in the distal nephron.

PURPOSE OF REVIEW: The aim is to review the recently reported effects of angiotensin II (Ang II) on sodium and potassium transport in the aldosterone-sensitive distal nephron, including the signaling pathways between receptor and transporter, and the (patho)physiological implications of these findings. RECENT FINDINGS: Ang II can activate the sodium chloride cotransporter (NCC) through phosphorylation by Ste20-related, proline-alanine rich kinase (SPAK), an effect that is independent of aldosterone but dependent on with no lysine kinase 4 (WNK4). A low-sodium diet (high Ang II) activates NCC, whereas a high-potassium diet (low Ang II) inhibits NCC. NCC activation also contributes to Ang-II-mediated hypertension. Ang II also activates the epithelial sodium channel (ENaC) additively to aldosterone, and this effect appears to be mediated through protein kinase C and superoxide generation by nicotinamide adenine dinucleotide phosphate oxidase. While aldosterone activates the renal outer medullary potassium channel (ROMK), this channel is inhibited by Ang II. The key kinase responsible for this effect is c-Src, which phosphorylates ROMK and leaves WNK4 unphosphorylated to further inhibit ROMK. SUMMARY: The effects of Ang II on NCC, ENaC, and ROMK help explain the renal response to hypovolemia which is to conserve both sodium and potassium. Pathophysiologically, Ang-II-induced activation of NCC appears to contribute to salt-sensitive hypertension.

Intestinal Na+ loss and volume depletion in JAK3-deficient mice.

BACKGROUND/AIMS: The Janus kinase 3 JAK3 participates in the signaling of immune cells. Lack of JAK3 triggers inflammatory bowel disease, which in turn has been shown to affect intestinal activity of the epithelial Na(+) channel ENaC and thus colonic sodium absorption. At least in theory, inflammatory bowel disease in JAK3-deficient mice could lead to intestinal salt loss compromizing extracellular volume maintenance and blood pressure regulation. The present study thus explored whether JAK3 deficiency impacts on colonic ENaC activity, fecal Na(+) exretion, blood pressure and extracellular fluid volume regulation. METHODS: Experiments were performed in gene-targeted mice lacking functional JAK3 (jak3(-/-)) and in wild type mice (jak3(+/+)). Colonic ENaC activity was estimated from amiloride-sensitive current in Ussing chamber experiments, fecal, serum and urinary Na(+) concentration by flame photometry, blood pressure by the tail cuff method and serum aldosterone levels by immunoassay. RESULTS: The amiloride (50 µM)-induced deflection of the transepithelial potential difference was significantly lower and fecal Na(+) excretion significantly higher in jak3(-/-) mice than in jak3(+/+) mice. Moreover, systolic arterial blood pressure was significantly lower and serum aldosterone concentration significantly higher in jak3(-/-) mice than in jak3(+/+) mice. Both, absolute and fractional renal Na(+) excretion were significantly lower in jak3(-/-) mice than in jak3(+/+) mice. CONCLUSIONS: JAK3 deficiency leads to impairment of colonic ENaC activity with intestinal Na(+) loss, decrease of blood pressure, increased aldosterone release and subsequent stimulation of renal tubular Na(+) reabsorption.

[Hyponatremia in cancer patients].

Hyponatremia is one of the most common electrolyte disturbances in cancer patients. Patients with extremely severe symptomatic hyponatremia need treatment with the administration of hypertonic saline. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a significant cause of cancer-related hyponatremia. A prospective study at a dedicated cancer hospital in Belgium demonstrated that SIADH was the most common cause of hyponatremia (30.4%). Ectopic ADH production by malignant cells (especially in small-cell lung cancer), several anticancer drugs (cyclophosphamide, ifosfamide, vincristine, cisplatin, et al.), stress from surgery, pain, and nausea, may cause SIADH in cancer patients. The second most common cause of hyponatremia in the Belgian investigation was sodium depletion (28.7%). In addition to gastrointestinal losses of sodium (vomiting, diarrhea), salt wasting syndrome (SWS) must be considerd as a cause of sodium depletion. Cerebral salt wasting syndrome (CSWS) with severe central nervous system diseases and renal salt wasting syndrome (RSWS) with cisplatin administration are especially important. Although identifying SWS or SIADH as the cause of hyponatremia is difficult, the treatment strategy for SWS is basically different from that for SIADH. Fluid restriction is generally prescribed for the hyponatremia associated with SIADH, and fluid replacement is indicated for the volume depletion associated with SWS. Furthermore, central nervous system disease and cisplatin administration, may cause both SWS and SIADH. This fact complicates the differential diagnosis, and careful management is necessary.