Restricting dietary sodium reduces plasma sodium response to exercise in the heat.

Exercise-associated hyponatremia can be life-threatening. Excessive hypotonic fluid ingestion is the primary etiological factor but does not explain all variability. Possible effects of chronic sodium intake are unknown. The aim of this study was to determine whether dietary sodium affects plasma sodium concentration [Na+ ] during exercise in the heat, when water intake nearly matches mass loss. Endurance-trained men (n = 9) participated in this crossover experiment. Each followed a low-sodium (lowNa) or high-sodium (highNa) diet for 9 days with 24-h fluid intakes and urine outputs measured before experimental trials (day 10). The trials were ≥2 week apart. Trials comprised 3 h (or if not possible to complete, to exhaustion) cycling (55% VO2max ; 34 °C, 65% RH) with water intake approximating mass loss. Plasma [Na+ ], hematocrit, sweat and urine [Na+ ], heart rate, core temperature, and subjective perceptions were monitored. Urine [Na+ ] was lower on lowNa 24 h prior to (31 ± 24, 76 ± 30 mmol/L, P = 0.027) and during trials (10 ± 10, 52 ± 32 mmol/L, P = 0.004). Body mass was lower on lowNa (79.6 ± 8.5, 80.5 ± 8.9, P = 0.03). Plasma [Na+ ] was lower on lowNa before (137 ± 2, 140 ± 3, P = 0.007) and throughout exercise (P = 0.001). Sweat [Na+ ] was unaffected by diet (54.5 ± 40, 54.5 ± 23 mmol/L, P = 0.99). Heart rate and core temperature were higher on lowNa (P ≤ 0.001). Despite decreased urinary sodium losses, plasma sodium was lower on lowNa, with decreased mass indicating (extracellular) water may have been less, explaining greater heart rate and core temperature. General population health recommendations to lower salt intake may not be appropriate for endurance athletes, particularly those training in the heat.

Fluid deprivation increases isotonic NaCl intake, but not hypertonic salt intake, under normal and heated conditions in obese Zucker rats.

In the course of exposure to fluid deprivation and heated environment, mammals regulate their hydromineral balance and body temperature by a number of mechanisms including sweating, water and salt intakes. Here we challenged obese Zucker rats, known to have a predisposition to hypertension, with 0.9%NaCl alone or with 2%NaCl solution + water to drink under fluid deprivation and heated conditions. Food and fluid intakes, body weight, diuresis and natriuresis were measured daily throughout. Serum aldosterone levels and Na(+) concentration were also analyzed. Data showed that obese and lean rats presented similar baseline measurements of food, 0.9%NaCl and fluid intakes, diuresis and fluid balance; whereas hypertonic 2%NaCl consumption was almost absent. Before and during fluid deprivation animals increased isotonic but not hypertonic NaCl intake; the obese showed significant increases in diuresis and Na(+) excretion, whereas, total fluid intake was similar between groups. Heat increased isotonic NaCl intake and doubled natriuresis in obese which were wet on their fur and displayed a paradoxical increase of fluid gain. Fluid deprivation plus heat produced similar negative fluid balance in all groups. Body weight losses, food intake and diuresis reductions were amplified under the combined conditions. Animals exposed to 2%NaCl showed higher circulating levels of aldosterone and obese were lower than leans. In animals which drank 0.9%NaCl, obese showed higher serum levels of Na(+) than leans. We conclude that in spite of their higher sensitivity to high salt and heat obese Zucker rats can control hydromineral balance in response to fluid deprivation and heat by adjusting isotonic NaCl preference with sodium balance and circulating levels of aldosterone. This suggests a key hormonal role in the mechanisms underlying thermoregulation, body fluid homeostasis and sodium intake.

Gene cascades ensure physiological function from optimal health to developing diseases.

Optimal physiological function throughout life is assured by activation, inhibition and/or modulation of multiple gene cascades resulting in new protein synthesis (possible biomarker), increased or decreased production of existing proteins, and other regulatory activities that maintain the organism in a relative healthy state for survival. Changes in physiological health state demand further (rapid) production/activation/inhibition/modulation of proteins that should ensure continued physiological functions in the short term, but these changes may not necessarily be ideal for long term survival. Medications, or even way of life changes, may help to stabilise overall organism's survival but cannot necessarily repair or reverse changes in gene expression already endured nor return the organism to an initial optimal healthy state.

Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery.

BACKGROUND: The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. OBJECTIVE: The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. RESULTS: By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. CONCLUSION: Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.

Mineralocorticoid pretreatment enhances angiotensin II-induced neuronal excitation but not salt drinking in male Fischer rats.

Central administration of angiotensin (Ang) II stimulates thirst and sodium intake via the AT-1 receptor. Mineralocorticoid pretreatment enhances Ang II-induced drinking of hypertonic salt solutions (i.e. the synergy theory) in Wistar and Sprague-Dawley rats. Electrophysiological experiments using iontophoretic application of Ang II, and the AT-1 receptor specific nonpeptide antagonist losartan, have shown excitation of neurones in the preoptic/medial septum region of urethane anaesthetised male Wistar rats. Deoxycorticosterone acetate (DOCA) pretreatment further enhanced this neuronal excitation to Ang II and reduced the responses to losartan. This generated the hypothesis that DOCA-enhanced Ang II-induced neuronal excitation was necessary for the enhanced salt intake of synergy theory. We tested this hypothesis in Fischer 344 rats that are known to have a low basal salt appetite and reduced sensitivity for i.c.v. Ang II. We compared the effect of DOCA pretreatment on i.c.v. Ang II-induced water and 2% NaCl intake in behaving adult male, Fischer rats, as well as preoptic/medial septum region neuronal responses to Ang II and losartan, using a seven-barrelled micro-iontophoretic electrode sealed to a recording electrode in urethane anaesthetised, male Fischer rats. Two groups were used: one pretreated with DOCA (0.5 mg/day for 3 days) and the other comprising controls, treated with isotonic saline. Ang II applied iontophoretically increased activity in 31% of the spontaneously active neurones. Following DOCA pretreatment, the responsiveness to Ang II (when applied after aldosterone) was increased. By contrast, in the behaving animals, water and 2% NaCl intake in response to i.c.v. Ang II were not enhanced by DOCA pretreatment. These results do not support the working hypothesis but could be interpreted as evidence for the existence of two separately modulated central Ang II systems: one responding to mineralocorticoids with increased neuronal activity and the other responsible for the Ang II-induced sodium appetite in conscious rats.

DOCA stimulates salt appetite in Zucker rats: effect of dose, synergistic action with central angiotensin II, and obesity.

An enhanced sodium appetite is found in rats by the synergist interaction of peripheral mineralocorticoids, deoxycorticosterone acetate (DOCA), and central angiotensin II (AngII), the synergy theory. We used obese Zucker rats which have a predisposition to develop hypertension under appropriate salt conditions to examine this synergy response between AngII and different low doses of DOCA on 2% NaCl intake. Obese and lean Zucker rats on low sodium food were treated systemically with 0.5, 1 and 2 mg/kg/day of DOCA for 3 days, before receiving i.c.v. AngII (10 pmol) on the fourth day. Food, fluid intakes and urine outputs were measured daily throughout. Plasma aldosterone levels were also analysed. Results showed that AngII alone increased water but not salt intake, whereas all three doses of DOCA by themselves enhanced daily salt intake during the treatment period. The lowest dose of DOCA plus AngII did not stimulate an enhanced sodium consumption. The 1 mg/kg was the threshold dose of DOCA for a synergistic response, and with 2 mg/kg DOCA the obese rats consumed nearly 2-fold more hypertonic NaCl solution than the leans. Moreover, obese baseline plasma levels of aldosterone were more elevated than the lean rats. In conclusion, in adult Zucker rats a threshold level of mineralocorticoid is required for the salt stimulating action of central AngII. In the obese rat the synergistic effect is enhanced with higher doses of mineralocorticoid, suggesting that the plasma level of aldosterone could be a prominent factor, which may predispose the obese to salt-sensitivity and, possibly, subsequently to hypertension under appropriate conditions.

Mineralocorticoid modulation of central angiotensin-induced neuronal activity, water intake and sodium appetite.

Central angiotensin II (AngII) stimulates water and salt solution intake. Pretreatment with low-dose mineralocorticoid (DOCA) enhances this AngII-induced intake of salt solutions (the synergy theory) in Wistar and Sprague Dawley rats but not in Fischer rats. This response is mediated via the AT-1 receptor. Electrophysiological experiments using iontophoretic application of AngII and the AT-1 receptor-specific non-peptide antagonist losartan showed excitation of neurons in the preoptic/medial septum region of urethane-anesthetized male Wistar rats. DOCA pretreatment further enhances this neuronal excitation in response to AngII and reduces the responses to losartan. This generated the hypothesis that DOCA-enhanced AngII-induced neuronal excitation is the neural support for the synergy theory. AT-2 receptors modulate these intake responses depending on sodium in the diet, and diuretic-induced dehydration during pregnancy produces a higher salt intake in the offspring. AngII-induced salt and water intakes were tested in offspring from Sprague Dawley mothers with only 1.8% NaCl to drink in which half were treated with furosemide. The important observations were a) the AT-1 antagonist alone suppressed intakes in offspring from mothers not treated with furosemide, b) both AT-1 and AT-2 antagonists suppressed intakes in offspring from furosemide-treated mothers, and c) combined administration of AT-1 and AT-2 antagonists greatly suppressed water intake in offspring from mothers not treated with furosemide. These results suggest that AT-1 and AT-2 receptors have variable properties (receptor number and/or second messengers). Furthermore, the activity and function of these central AngII receptors depend on the background mineralocorticoid levels. The exact mechanism of this influence, however, remains to be determined.

Effects of prolonged exposure to CO2 on behaviour, hormone secretion and respiratory muscles in young female rats.

Atmospheric CO2 concentrations increased significantly over the last century and continuing increases are expected to have significant effects on current ecosystems. This study evaluated the behavioural and physiological (hormone status, muscle structure) effects of prolonged CO2 exposure in young female Wistar rats exposed at 700ppm of CO2 during 6h a day for 15days. Prolonged CO2 exposure, though not continuous, produced significant disturbances in behaviour with an increase in drinking, grooming and resting, and a reduction in rearing, jumping-play and locomotor activity. Furthermore, CO2 exposure was accompanied by increased plasma levels of corticosterone, suggesting that prolonged exposure to CO2 was stressful. The muscular structure can also be modified also when respiratory working conditions change. The expression of myosin heavy chain was significantly affected in the diaphragm and oral respiratory muscles: Masseter Superficialis and Anterior Digastric. Modified behaviour and hormonal changes both appear to be at the origin of the observed muscular adaptation.

Gender and obesity influence sodium intake and fluid regulation in Zucker rats following repeated sodium depletions.

The Zucker obese rat is an important model for the metabolic syndrome, which includes renal disease and salt-sensitive hypertension, suggesting abnormalities of body fluid regulation. Here, in Zucker rats, lean and obese, and of both sexes, we compared 48 h of sodium intake and fluid regulation responses with repeated depletions with furosemide to repeated control saline injections. Increased urine volume excretion was observed after each furosemide administration for the 4 groups and obese rats excreted more than the leans on the control days. Male obese rats did not excrete sodium nor increase intake of 2% NaCl following the first furosemide administration, whereas the other 3 groups did. Subsequent depletions increased 2% NaCl consumption and urinary sodium excretion in all groups. Males excreted more sodium in their urine than the females on the control days. Females showed an increase in 2% NaCl intake on control days. Water intake increased in the female leans after each depletion, increased in the males after the 2nd and 3rd depletion and increased in the obese females only after the 2nd depletion. These findings show clearly that there are gender- and weight-related differences in the response of Zucker rats to furosemide-induced depletion. However, the main differences occurred with the first depletion. With repeated depletions the rats adjusted sodium and fluid intake and excretion so that differences due to gender and body weight tended to disappear. Our findings caution against drawing conclusions about differences due to gender and body weight based on single treatments.

Endocrine and behavioural factors affecting water balance in sheep subjected to isolation stress.

The effect of stress on drinking, water balance and endocrine profile was studied using ten castrated rams. Individual sheep were exposed to 30-h periods of total isolation (psychological stress) or physical separation from their social group (control). Plasma was analysed for haematocrit, osmolality, electrolyte levels and concentrations of cortisol and arginine vasopressin. Isolation stress significantly reduced water intake, increased haematocrit and plasma concentration of cortisol, but did not alter osmolality or vasopressin concentration. The physiological effects of this self-imposed water restriction contrast with those obtained by depriving the sheep of water for 24 h under conditions that were not stressful, i.e. by keeping them grouped together. These results suggest that cortisol may act to defend plasma volume in sheep exposed to acute stress. The results also indicate that vasopressin probably should not be considered to be a 'stress hormone' in the sheep.

Vasopressin, but not oxytocin, is released in response to water deprivation in conscious goats.

Plasma samples obtained at 4-h intervals from goats for at least 24 h before and then during 24 h of deprivation of water were analysed by radioimmunoassay for vasopressin and oxytocin concentrations. The samples were also analysed for osmolality and sodium concentration. The differential effect of night/day versus day/night deprivation was also studied. During the two periods before the two deprivations osmolality varied in a regular manner, with low values occurring at 08.00 h. Sodium concentration followed osmolality, whereas vasopressin did not vary during the period before deprivation. During deprivation vasopressin increased along with osmolality and sodium concentration, with the beginning of the increase occurring after the morning feed. Oxytocin levels did not increase during the period of deprivation. These results do not support the hypothesis of general release of neurohypophysial hormones in response to osmotic stimuli but instead indicate there are species variations with respect to hormonal response to water deprivation.

Opioid influences on pituitary function in sheep under basal conditions and during psychological stress.

The effects of intravenous injections of naloxone (2 mg/kg), morphine (0.3 mg/kg) and saline vehicle on plasma concentrations of cortisol, prolactin, vasopressin and oxytocin were assessed in sheep (N = 10) when in their social groups (basal conditions) and during a period of isolation (psychological stress). Blood samples were collected by jugular venipuncture before and during the 60-min period following drug administration. Plasma hormone concentrations were determined by radioimmunoassay. Under basal conditions, cortisol levels were increased after naloxone (36-48%), but not after morphine or saline, and concentrations of prolactin, vasopressin and oxytocin did not change. Under stress conditions, (1) cortisol concentrations were elevated throughout the 60-min sampling period after naloxone or saline but for only 20 min after morphine; maximum increases observed were 161% (naloxone), 150% (saline) and 112% (morphine); (2) prolactin levels were raised after saline (85-129%) and morphine (55-61%) but were unchanged after naloxone; (3) vasopressin concentrations decreased transiently (43%) after saline but not following naloxone or morphine; and (4) oxytocin levels did not change after any treatment. These results indicate that endogenous and exogenous opioids modulate cortisol release in nonstressed sheep, and cortisol and prolactin secretion in sheep subjected to psychological stress. The nature of the anterior pituitary responses induced, together with the absence of a discernible effect on posterior pituitary function, suggest that the central opioid systems involved are similar in sheep and primates but different from those in the rat.

Neuronal responses to iontophoretically applied angiotensin II, losartan and aldosterone, as well as gustatory stimuli, in non-anesthetized control and desoxycorticosterone acetate-pretreated rats.

The neuronal mechanism of the sodium appetite initiated in rats by priming with a mineralocorticoid (desoxycorticosterone acetate (DOCA)) treatment and subsequent central angiotensin II (Ang II) was investigated using electrophysiological-iontophoretic techniques and sapid salt stimulation of the tongue in non-anesthetized restrained, DOCA-pretreated (0.5 mg/day s.c. for 3 days) or non-pretreated male Wistar rats. The rats were trained to drink water and a 1.6% NaCl solution while their heads were painlessly held in a stereotaxic apparatus with an attachment fixed to the skull. A total of 634 neurons (375 in non-pretreated and 259 in DOCA-pretreated rats) were recorded in the medial septum and median preoptic area during iontophoretic application of Ang II, aldosterone or losartan, or tongue application of the salty solution or water. Of the 151 neurons recorded in control rats during the application of the solutions on the tongue, one (0.7%) was found specifically excited and 16 (10.6%) inhibited by the sapid sodium. Similarly, of the 110 neurons tested in the DOCA-pretreated rats, 5 (4.5%) were found specifically excited and 8 (7.3%) inhibited by the sapid sodium. The number of neurons responding to the iontophoretically applied agents was not significantly changed by the DOCA pretreatment. Thus, the DOCA pretreatment significantly increased the number of preoptic neurons that were specifically excited by a salty solution applied on the tongue. These results suggest that hormonally induced changes in the gustatory responsiveness of ventral forebrain neurons may be part of the sequence that alters the hedonic valence of NaCl during sodium appetite.

Angiotensin II receptor subtype antagonists can both stimulate and inhibit salt appetite in rats.

In urethane-anaesthetised male Wistar rats iontophoretic application of the angiotensin II (Ang II) type 1 (AT-1) receptor specific nonpeptide antagonist losartan in the septo-preoptic continuum can produce neuronal excitation of short- and long-term duration which has been interpreted as removal of tonic Ang II-induced inhibition. Mineralocorticoid pretreatment, which increases neuronal sensitivity to Ang II to enhance salt appetite, also removes this losartan-induced long-term excitation. These results suggested steroid modulation of the AT-1 receptor and a complex involvement of Ang II in salt appetite. To investigate the role of the inhibitory action of central Ang II on salt appetite, we gave intracerebroventicular injections of a single, low dose (10 ng) of losartan in normal euhydrated rats and this produced, paradoxically, a progressive increase in salt intake (1.6 +/- 0.3 ml/day to 3.5 +/- 0.9 ml/day, n = 15, P < 0.05). Treatment of these salt enhanced rats with DOCA (0.5 mg/day, s.c., for 3 days) further increased the salt appetite, but then a second i.c.v. injection of the same dose of losartan significantly inhibited the enhanced salt appetite (4.7 +/- 0.7 to 1.3 +/- 0.4, n = 9, P < 0.05). These results provide evidence for a complex action of Ang II on the At-1 receptor mediating the generation of salt appetite that appears to involve either at least two functional subtypes of this AT-1 receptor, as already suggested by previous electrophysiological experiments, or one AT-1 receptor with several activation states.

Effects of DOCA pretreatment on neuronal sensitivity and cell responsiveness to angiotensin II, in the bed nucleus of the stria terminalis in the rat.

A previous study has shown that DOCA pretreatment altered the responsiveness of neurons to microiontophoretic administration of angiotensin II (AII) and aldosterone (Aldo). This result coincided with an increase in activity in the septo-preoptic region and a decrease in activity of the central nucleus of the amygdala. The latter region is anatomically linked to the bed nucleus of the stria terminalis (BNST). Single unit activity was recorded in the BNST in response to iontophoretic application of AII, non-peptide AII-receptor antagonists or Aldo in DOCA-pretreated and in non-pretreated rats. DOCA-pretreatment significantly decreased the responsiveness to AII (28 cells (18.5%) vs. 8 cells (14.0%) u = 0.018 for excitation and 3 cells (8.6%) vs. 0 cells 0%, u = 0.011 for inhibition, P < 0.05) and to Aldo (24 cells (21.4%) vs. 4 cells (10.2%), u = 0.026 for excitation, and 3 cells (2.6%) vs. 0 cells, u = 0.009 for inhibition, P < 0.05) of the neurons localised in the BNST. A significant decrease was found in the inhibitory responses to iontophoretic application of losartan, an AII type-1 receptor (AT-1) antagonist (u = 0.042, P < 0.05). No significant differences were recorded with iontophoretic application of PD 123319, a specific AII-type-2 (AT-2) receptor antagonist. Therefore AT-1 receptors are likely responsible for the decreased responsiveness of the BNST correlated with the decrease in the activity within the amygdala.

Osmoreceptor localization in the brain of the pigeon (Columba livia).

The area of the brain of pigeons that may be responsible for drinking following intravascular administration of osmotically effective solutes was investigated using infusions of water or isotonic and hypertonic solutions of NaCl or sucrose into various regions of the brains of conscious birds, and measuring the volume of water drunk. The preoptic area and the lateral hypothalamus were the only areas from which dose related drinking could be obtained in response to bilateral infusions of hypertonic NaCl or sucrose. Unilateral infusion of the hypertonic solutions rarely produced drinking. In contrast, water or isotonic NaCl, when infused unilaterally, in some cases caused some water intake. Drinking in response to intravenous infusion of hypertonic NaCl was not abolished by an 'apparent' lesion of the preoptic area. In several cases infusion of water or sucrose into the preoptic area caused a small volume of isotonic saline solution to be drunk. Thus the preoptic area and the lateral hypothalamus appear to be at least two of the areas involved in osmoregulation in the pigeon and may also be involved in sodium regulation.

Electrophysiological investigation of cells in the region of the anterior hypothalamus firing in relation to blood pressure and volaemic changes.

The anterior hypothalamus has been implicated in the higher centre control of blood pressure and more recently in hydromineral balance regulation. Using a glass recording electrode with and without a 7-barrelled iontophoretic electrode we investigated this region for blood pressure-sensitive cells. We used a ventral approach through the optic chiasma. We found 36 cells out of 91 tested that increased their firing rate in response to a spontaneous or induced decrease in blood pressure. Of these 19 increased firing in response to angiotensin II (AII) injected into the lateral cerebral ventricle and 10 of these increased firing in response to local iontophoretic application of AII. Cells responsive to an increase in blood pressure were never found. Thus cells in this area respond to hypovolaemia and hypotension as well as to AII, which could link this area with higher centre responsiveness to stimuli of extracellular thirst.