Sodium Homeostasis, a Balance Necessary for Life.

Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin-angiotensin-aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.

Animal models for diabetes insipidus.

The hormone arginine vasopressin (AVP) is a nonapeptide synthesized by hypothalamic magnocellular nuclei and secreted from the posterior pituitary into the bloodstream. It binds to AVP receptor 2 in the kidney to promote the insertion of aquaporin channels (AQP2) and antidiuretic responses. AVP secretion deficits produce central diabetes insipidus (CDI), while renal insensitivity to the antidiuretic effect of AVP causes nephrogenic diabetes insipidus (NDI). Hereditary and acquired forms of CDI and NDI generate hypotonic polyuria, polydipsia, hyperosmolality, and hypernatremia. The AVP mutant (Brattleboro) rat is the principal animal model of hereditary CDI, while neurohypophysectomy, pituitary stalk compression, hypophysectomy, and mediobasal hypothalamic lesions produce acquired CDI. In animals, hereditary NDI is mainly caused by mutations in AVP2R or AQP2 genes, while acquired NDI is most frequently induced by lithium. We report here on the determinants of the intake and excretion of water and mineral salts and on the different types of DI in humans. We then describe the hydromineral characteristics of these animal models and the responses observed after administration of hypertonic NaCl or when they are fed with low-sodium diets. Finally, we report on the effects of drugs such as AVP analogues and/or oxytocin, another neuropeptide that increases sodium excretion in animal models and humans with CDI, and sildenafil, a compound that increases the expression and function of AQP2 channels in animal models and humans with NDI.

Effects of oxytocin administration on the hydromineral balance of median eminence-lesioned rats.

In the clinical setting, acute injuries in hypothalamic mediobasal regions, along with polydipsia and polyuria, have been observed in patients with cerebral salt wasting (CSW). CSW is also characterised by hypovolaemia and hyponatraemia as a result of an early increase in natriuretic peptide activity. Salt and additional amounts of fluid are the main treatment for this disorder. Similarly, experimental lesions to these brain regions, which include the median eminence (ME), produce a well-documented neurological model of polydipsia and polyuria in rats, which is preceded by an early sodium excretion of unknown cause. In the present study, oxytocin (OT) was used to increase the renal sodium loss and prolong the hydroelectrolyte abnormalities of ME-lesioned animals during the first few hours post-surgery. The objective was to determine whether OT-treated ME-lesioned animals increase their sodium appetite and water intake to restore the volume and composition of extracellular body fluid. Electrolytic lesion of the ME increased water intake, urinary volume and sodium excretion of food-deprived rats and also decreased urine osmolality and estimated plasma sodium concentration. OT administration at 8 hours post-surgery reduced water intake, urine output and plasma sodium concentration and also increased urine osmolality and urine sodium excretion between 8 and 24 hours post-lesion. From 24 to 30 hours, more water and hypertonic NaCl was consumed by OT-treated ME-lesioned rats than by physiological saline-treated-ME-lesioned animals. Food availability from 30 to 48 hours reduced the intake of hypertonic saline solution by ME/OT animals, which increased their water and food intake during this period. OT administration therefore appears to enhance the natriuretic effect of ME lesion, producing hydroelectrolyte changes that reduce the water intake of food-deprived animals. Conversely, the presence of hypertonic NaCl increases the fluid intake of these animals, possibly as a result of the plasma sodium depletion and hypovolaemic states previously generated. Finally, the subsequent increase in food intake by ME/OT animals reduces their need for hypertonic NaCl but not water, possibly in response to osmotic thirst. These results are discussed in relation to a possible transient activation of the ME with the consequent secretion of natriuretic peptides stored in terminal swellings, which would be augmented by OT administration. Electrolytic lesion of the ME may therefore represent a useful neurobiological model of CSW.

Animal models of Central Diabetes Insipidus: Human relevance of acquired beyond hereditary syndromes and the role of oxytocin.

The aim of this study was to review different animal models of Central Diabetes Insipidus, a neurobiological syndrome characterized by the excretion of copious amounts of diluted urine (polyuria), a consequent water intake (polydipsia), and a rise in the serum sodium concentration (hypernatremia). In rodents, Central Diabetes Insipidus can be caused by genetic disorders (Brattleboro rats) but also by various traumatic/surgical interventions, including neurohypophysectomy, pituitary stalk compression, hypophysectomy, and median eminence lesions. Regardless of its etiology, Central Diabetes Insipidus affects the neuroendocrine system that secretes arginine vasopressin, a neurohormone responsible for antidiuretic functions that acts trough the renal system. However, most Central Diabetes Insipidus models also show disorders in other neurobiological systems, specifically in the secretion of oxytocin, a neurohormone involved in body sodium excretion. Although the hydromineral behaviors shown by the different Central Diabetes Insipidus models have usually been considered as very similar, the present review highlights relevant differences with respect to these behaviors as a function of the individual neurobiological systems affected. Increased understanding of the relationship between the neuroendocrine systems involved and the associated hydromineral behaviors may allow appropriate action to be taken to correct these behavioral neuroendocrine deficits.

Opposite effects of oxytocin on water intake induced by hypertonic NaCl or polyethylene glycol administration.

Oxytocin (OT), a neurohormone, has been related to natriuretic and diuretic effects and also to water intake and sodium appetite. The objective of the present study was to determine the effect of subcutaneous OT administration on water intake and urine-related measures induced by the administration of hypertonic NaCl (experiment 1) or polyethylene glycol (PEG) (experiment 2). Experiment 1 showed that OT administration increases the urine volume, urinary sodium concentration, and natriuresis and reduces the water intake, water and sodium balances, and estimated plasma sodium concentration induced by hypertonic NaCl administration. Conversely, experiment 2 showed that OT administration increases the water intake and the antidiuretic response induced by PEG administration. These results show that the opposite effects of OT on the water intake induced by hypertonic NaCl or PEG administration are accompanied by differential regulatory effects, enhancing a natriuretic response in the first experiment and generating an antidiuretic reaction in the second experiment. This study suggests a differential regulatory effect of OT during states of intra- and extracellular thirst.

Inhibition of natriuresis in median eminence polydipsia: effects after intake of diets with different osmolalities and after hypertonic NaCl administration.

Lesions in the hypothalamic median eminence (ME) induce polydipsia and polyuria in male rats. A first experiment was designed to examine the effect of salt consumption (standard 0.25 percent Na+ vs. low-salt 0.04 percent Na+ diet) on the fluid-electrolytic balance (plasma sodium, urinary sodium excretion, urine osmolality) and water intake of ME polydipsic animals. In the first 6 h post-surgery, the natriuretic response was higher in ME-lesioned animals than in control groups. At 24 h post-surgery, however, less sodium was excreted by ME rats fed with a standard salt diet (ME/SS), despite showing no decrease in salt intake, and they evidenced an increase in plasma sodium concentration and water intake. Urine osmolality was significantly higher in control animals than in either ME-lesioned group. In experiment 2, hypertonic NaCl administration (2 ml/2M) increased the polydipsic behavior of ME-lesioned but not control rats (day 2). Animals deprived of food/salt showed a significant reduction (on day 2) in the initial (day 1) polydipsia, which increased on day 3 when the animals had access to a standard-salt diet. These results suggest that the reduced natriuretic response and the consequent sodium retention observed in ME animals may exacerbate the hydromineral imbalance of this polydipsic syndrome.

The D2/D3-receptor antagonist tiapride impairs concurrent but not sequential taste aversion learning.

Taste aversion learning (TAL) is a learning modality in which the animals reject a gustatory stimulus associated with the administration of noxious visceral substances. This learning can be established by concurrent or sequential procedures that involve different anatomical and functional mechanisms and may constitute distinct learning modalities. The dopaminergic system has been related to various learning processes and goal-directed behaviours. The present study examined the effect of the administration of tiapride, a D(2)/D(3) dopaminergic antagonist, on concurrent and sequential TAL. Results obtained showed that pre-treatment with tiapride blocks the acquisition of concurrent TAL but does not affect sequential TAL, including reversal learning tasks. These results demonstrate the involvement of the D(2)/D(3) dopaminergic receptors in the former but not the latter learning process. The dopaminergic system appears to participate in concurrent TAL, an "implicit" learning modality, but not in sequential TAL, which is considered a relational/explicit acquisition process.

Nucleus of the solitary tract and flavor aversion learning: relevance in concurrent but not sequential behavioral test.

Theories relating the nucleus of the solitary tract to taste aversion learning (TAL) have received their main support from immunohistochemical research. In the present study, a behavioral analysis was performed on the effect of lesions of the intermediate nucleus of the solitary tract (iNST) on concurrent and sequential flavor aversion learning tasks. Bilateral lesions of the iNST impaired concurrent flavor learning, in which animals must discriminate between two simultaneously presented flavors paired with intragastric administration of a noxious or innocuous substance, respectively. However, the same iNST lesions did not interrupt the development of sequential flavor aversion learning, in which each flavor is offered individually on consecutive alternate days. These results behaviorally confirm the relevance of the nucleus of the solitary tract in TAL and suggest a functional dissociation between the neural systems underlying concurrent and sequential flavor aversion learning.

Potentiated effect of systemic administration of oxytocin on hypertonic NaCl intake in food-deprived male rats.

Subcutaneous administration of oxytocin (OT) increases water intake and sodium/urine excretion in food-deprived male rats. This study analyzes the effect of OT administration (at 0830 and 1430h) on the consumption of water and hypertonic NaCl (1.5%). In the first experiment, injections of OT increased the intake of hypertonic NaCl (but not of water) in food-deprived rats but not in ad lib-fed animals during the second 12 h (2030 to 0830) of the treatment day. The net concentration of the fluid consumed by OT/deprived animals was close to isotonic. In the second experiment, the initial effect of OT administration was an increase in urine volume and urinary sodium excretion and concentration by food-deprived animals during the first 12 h (0830 to 2030). These findings suggest that in food-deprived animals, systemic administration of OT induces NaCl intake as a consequence of previous urine loss and urinary sodium excretion.

The natriuretic effect of oxytocin blocks medial tuberomammillary polydipsia and polyuria in male rats.

Lesions of the tuberomammillary complex, a neuroanatomical system closely related to the hypothalamic supraoptic and paraventricular nuclei, induce strong polydipsia in male rats. It was recently demonstrated that this increase in water intake is immediate, persistent, follows circadian rhythms and appears to be related to sodium regulation. The present study found that urine osmolality was significantly lower in tuberomammillary-lesioned animals vs. their respective controls at 8:00 h after surgery. Therefore, the aim of the present study was to examine the natriuretic effect of intraperitoneal oxytocin (OT) administration on medial ventral tuberomammillary nucleus (E3) polydipsia and polyuria of lesioned and control male rats. At 24:00 h post-lesion, OT blocked the hyperdipsic and polyuric responses of E3-lesioned animals but not those of non-lesioned controls, which did however significantly increase their water intake. Moreover, urinary osmolality and sodium excretion increased in E3 -lesioned animals that received OT but not in lesioned controls receiving physiological saline (992 +/- 187.19 vs. 215.83 +/- 23.39 mOsm/kg; 1.68 +/- 0.13 vs. 0.47 +/- 0.1 mEq/L). At 48:00 h post-lesion, OT administration also induced a higher intake of water and of simultaneously offered hypertonic NaCl (1.5%) in E3-lesioned animals. These results are interpreted in terms of the hypothalamic systems involved in sodium and water homeostasis.

NaCl preference and water intake effects of food availability in median eminence polydipsia.

Lesions in the median eminence (ME) produce a well-known neurological model of polydipsia and polyuria in rats. The effect of food availability (ad lib/deprivation) on the polydipsic/polyuric behaviour of animals was tested. As expected, all lesioned rats developed strong polyuria and polydipsia during the first postoperative 24h. This effect was maintained during day 2 when food was available ad lib (experiment A), but both polyuria and polydipsia were abolished when animals were deprived of food during the next 24h (day 3). Animals deprived of food from the first post-operative day (experiment B) showed a significant reduction in the initial polyuria and polydipsia (day 1) on day 2, but these effects were again observed on day 3 when food was available ad lib. Finally, when food-deprived animals were able to choose between a 1.5% sodium chloride solution and water (experiment C), they preferentially chose (82% of total liquid consumed) the hypertonic saline solution (day 1); during the next 24h (day 2), when only water was available, the polyuric/polydipsic effect was abolished but returned when food became available ad lib on day 3. Hence, the polyuria/polydipsia effect produced by ME lesions appears to be consistent during the first 24h but might later be related to the availability of standard food and is completely abolished under food deprivation conditions. Preference for the hypertonic solution supports the volemic component of this syndrome and demonstrates the need for appropriate amounts of hypertonic nutrients to be consumed during the first 24h.