Chapter 37
Water and Salt Intake and Body Fluid Homeostasis
Body fluids are the watery matrix in which the biochemical reactions of cellular metabolism occur. The concentration of substrates in cellular fluid is a key factor in determining the rate at which those reactions take place. All tissues depend on circulating blood to deliver the nutrients needed to support cellular metabolism and to carry away unwanted metabolites for excretion. Thus, the maintenance of solute concentrations or osmolalities—osmotic homeostasis—and the regulation of plasma volume—volume homeostasis—are essential functions in the physiology of animals.
When normal body fluid osmolality or plasma volume is threatened, various physiological and behavioral responses are stimulated to maintain or restore the basal state adaptively. For example, during water deprivation, animals decrease water lost in urine to prevent dehydration from worsening and they consume water to replace the fluid they have lost. Similarly, hemorrhage stimulates the urinary conservation of water and sodium as well as the ingestion of water and NaCl. Water retention and sodium retention are accomplished through actions of the antidiuretic hormone arginine vasopressin (AVP) and the antinatriuretic hormone aldosterone, whereas water ingestion and NaCl ingestion are motivated by thirst and salt appetite. These complementary responses are mediated and coordinated by the brain.
This chapter describes the various mechanisms by which the signals for fluid homeostasis are detected and integrated by the central nervous system. However, we first present a brief overview of body fluid physiology to provide a context in which to consider the regulated functions.
Body Fluid Physiology
Water is the largest constituent of the body. It contributes 55 to 65% of the body weight of animals, including humans, varying mostly in relation to the amount of body fat. Total body water is distributed between intracellular fluid (ICF) and extracellular fluid (ECF) compartments, with approximately two-thirds in the former and one-third in the latter. The ECF can be further subdivided into the interstitial fluid surrounding the cells and the intravascular fluid within blood vessels. The intravascular fluid, the plasma (or serum) of blood, averages 7 to 8% of total body water, or 20 to 25% of the ECF.
Fluid compartments differ not only in their volumes but also in the solutes they contain. Specifically, membrane-bound Na+-K+ pumps move Na+ outside the cells and K+ inside. Despite the differences in solute composition, the osmotic pressure, which reflects the concentrations of all solutes in a fluid compartment, is equivalent between ECF and ICF compartments. This equilibrium occurs because water is driven across cell membranes by osmosis from a relatively dilute compartment into one with a higher solute concentration until the osmotic pressures are equivalent on both sides of the cell membrane.
Multiple Mechanisms Help Maintain Blood Volume and Pressure
The distribution of fluid between intravascular and interstitial fluid compartments is determined by a balance between the hydrostatic pressure of the blood, which is maintained by cardiac output and arteriolar vasoconstriction, and the opposing osmotic pressure contributed by plasma proteins. Although those proteins contribute only 1 to 2% to overall plasma osmolality, the permeability of capillary membranes to such large molecules is low; therefore, proteins exert a pressure differential (of approximately 15–20 mm Hg), called the colloid osmotic (oncotic) pressure, that tends to pull interstitial fluid into the circulation. Figure 37.1 summarizes the forces governing transcapillary fluid transfer between the two extracellular compartments, a phenomenon first described by the English physiologist Starling (1896). Note that according to this arrangement, interstitial fluid acts as a reservoir for plasma. The Starling equilibrium is such that when blood pressure falls, as after hemorrhage, interstitial fluid moves into the circulation, thereby helping restore plasma volume. The reverse occurs when saline is added to the blood because plasma proteins are then diluted and the oncotic pressure they provide diminishes, allowing fluid to flow into the interstitial space.
Figure 37.1 Starling forces governing transcapillary fluid transfer. At the arteriolar end of the capillary, the difference between the intravascular hydrostatic pressure (Pc) and the interstitial hydrostatic pressure (Pi) exceeds the oppositely oriented difference between the intravascular oncotic pressure (πc) and the interstitial oncotic pressure (πi); the resultant pressure gradient drives capillary fluid into the interstitial space (Jv1). As fluid leaves the capillary, Pc decreases due to fluid loss and πc increases due to hemoconcentration. Consequently, at the venous end of the capillary, interstitial fluid is pulled back into the vascular space (JV2). Numerical values indicate approximate net pressure differences (in mm Hg) between intravascular and interstitial spaces. Relative sizes of P and π are indicated by arrow length. Note that fluid accumulating in the interstitial space ultimately returns to the blood via the lymphatic system (not shown).
Blood pressure also is maintained by two other mechanisms intrinsic to the cardiovascular system. First, although the arteries that receive the cardiac output of blood have thick walls to preserve blood pressure, the veins are thin-walled, distensible vessels. After a moderate hemorrhage, veins collapse, redistributing blood to arteries that cannot collapse and thus remain full. Consequently, arterial blood pressure is not compromised and the blood deficit occurs primarily on the venous side of the circulation. Conversely, fluid accumulates in the veins when blood volume is expanded, again without much effect on arterial blood pressure. This property is called the capacitance or compliance of the vascular system. Second, the filtration of blood in the glomeruli of the kidneys is determined in large part by blood pressure in the renal arteries. A drop in blood pressure reduces the glomerular filtration rate (GFR) and decreases urine formation, whereas a rise in blood pressure elevates GFR and promotes urinary fluid loss. This normal function of the kidneys is so efficient that the development of hypertension always implicates renal dysfunction as a contributing factor because the kidneys failed to adjust to the elevated blood pressure by increasing fluid excretion in urine.
Summary
Body fluid homeostasis is directed at achieving stability in the osmolality of body fluids and the volume of plasma. Such homeostatic regulation is promoted by several mechanisms intrinsic to the physiology of body fluids and the cardiovascular system. Nevertheless, changes in body fluid osmolality and plasma volume may be so large that additional mechanisms must be recruited to maintain homeostasis. These other responses involve the central control of water and sodium excretion in urine through the actions of specific hormones, and the central control of water and NaCl consumption motivated by thirst and salt appetite.
Osmotic Homeostasis
Osmolality is an expression of concentration—that is, a ratio of the total amount of solute dissolved in a given weight of water:
Dehydration and the consequent need for water occur whenever this ratio is elevated, whether by a decrease in its denominator or by an increase in its numerator. In fact, both changes occur naturally and often: Body water decreases as a result of water deprivation or the loss of dilute fluids to accomplish evaporative cooling (e.g., sweating), and it increases as a result of solute load (e.g., the consumption of NaCl in foods).
The water loss associated with dehydration is borne by the ECF and the ICF in proportion to their sizes because the osmolality of fluid in the two compartments remains in equilibrium. In contrast, the increase in plasma osmolality that results from a solute load results only in cellular dehydration because the water leaving cells by osmosis expands ECF volume. Thus, a solute load is a more abrupt, less complex treatment than water deprivation for stimulating AVP secretion and thirst, the two main osmoregulatory responses of the brain.
Arginine Vasopressin Is the Antidiuretic Hormone
AVP is a nine amino acid peptide that is synthesized in the magnocellular neurons in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) of the hypothalamus. The peptide is cleaved enzymatically from its prohormone and transported along axons projecting from the hypothalamus to the nearby posterior lobe of the pituitary gland (neurohypophysis). There, AVP is stored within neurosecretory granules until specific stimuli, such as an increase in the effective osmolality of body fluids, activate its secretion into the bloodstream. The importance of AVP in maintaining water balance is underscored by the fact that its stores in the pituitary contain sufficient hormone to enable maximal antidiuresis when dehydration is sustained for more than a week.
The circulating hormone acts on a subset of AVP receptors (the V2 subtype) in the kidney to increase water permeability of the collecting ducts of nephrons through insertion of water channels, called aquaporins, into the apical membranes of tubular epithelial cells. Antidiuresis occurs when water moves out of the distal convoluted tubule and collecting duct by osmosis. As secondary responses to the increased net water reabsorption, urine flow decreases and urine osmolality increases. See Box 37.1 for more on renal water channels.
Box 37.1 Water Channels
Water conservation by the kidney is dependent on its ability to concentrate the urine. Urine is concentrated through the combined actions of the loop of Henle and the collecting duct of the kidney. The loop of Henle generates a high osmolality in the renal medulla via a mechanism known as the countercurrent multiplier system. AVP acts in the collecting duct to increase water permeability, thereby allowing osmotic equilibration between the urine and the hypertonic interstitium of the renal medulla. The net effect of this process is to extract water from the urine into the medullary interstitial blood vessels, resulting in increased urine concentration and decreased urine volume.
AVP produces antidiuresis by virtue of its effects on the epithelial principal cells of the collecting duct in the kidney, which are endowed with AVP receptors of the V2 type. It has long been known that binding of AVP to G protein-coupled V2 receptors causes cAMP generation via activation of adenylate cyclase. However, the intracellular mechanisms responsible for the subsequent increased water reabsorption across the collecting duct cells were elucidated only after the discovery of aquaporins, which are a widely expressed family of water channels that facilitate rapid water transport across cell membranes.
Many different aquaporin water channels are expressed in various body tissues, including the brain. Several of these channels have been localized in the kidney. Aquaporin-1 is expressed constitutively in the proximal tubule and thin descending limb of the loop of Henle and is believed to be responsible for reabsorption of a large fraction of the water filtered by the glomerulus. The other three water channels, aquaporin-2, -3, and -4, are expressed in collecting duct principal cells, target cells for the action of AVP to regulate collecting duct water permeability. Aquaporin-2 is the only water channel known to be expressed in the apical membrane (i.e., the side bordering the tubular lumen, through which urine flows) of collecting duct principal cells and is also abundant in intracellular vesicles located below the apical membrane. Aquaporin-2 is the major AVP-regulated water channel and mediates water transport across the apical plasma membrane of the principal cells of the collecting ducts. In contrast, aquaporins-3 and -4 are expressed at high levels in the basolateral plasma membranes (i.e., the side bordering the blood) of principal cells and are responsible for the constitutively high water permeability of the basolateral plasma membrane.
There are at least two ways by which AVP regulates osmotic water permeability in the collecting duct: short-term and long-term regulation (Knepper, 1997). Short-term regulation is associated with increases in water permeability within a few minutes of AVP exposure, an effect that is rapidly reversible. AVP triggers this response by binding to the V2 receptor and increasing intracellular cyclic AMP levels by activating adenylate cyclase. The increase in collecting duct water permeability is a consequence of fusion of aquaporin-2-containing intracytoplasmic vesicles with the apical plasma membranes of the principal cells, a process that increases apical water permeability by markedly increasing the number of water-conducting pores in the apical plasma membrane. Dissociation of AVP from the V2 receptor allows intracellular cAMP levels to decrease, and the water channels are reinternalized into the intracytoplasmic vesicles, thereby terminating the increased water permeability. By virtue of the subapical membrane localization of the aquaporin-containing vesicles, they can be quickly shuttled into and out of the membrane in response to changes in intracellular cAMP levels. This mechanism therefore allows minute-to-minute regulation of renal water excretion through changes in ambient plasma AVP levels. Long-term regulation of collecting duct water permeability represents a sustained increase in collecting duct water permeability in response to prolonged high levels of circulating AVP. This response requires at least 24 h to elicit and is not as rapidly reversible. This conditioning effect is due largely to the ability of AVP to induce large increases in the abundance of aquaporin-2 and -3 water channels in the collecting duct principal cells. Greater total expression of the number of aquaporin-2 and -3 water channels, when combined with the short-term effect of AVP to shift aquaporin-2 into the apical plasma membrane, allows the collecting ducts to achieve extremely high water permeabilities during conditions of prolonged dehydration, thereby further enhancing the urine concentrating capacity in response to elevated levels of circulating AVP.
With refinement of radioimmunoassays for AVP, the unique sensitivity of the hormone to small changes in osmolality has become apparent, as has the remarkable sensitivity of the kidney to small changes in plasma AVP levels. Circulating AVP is linearly related to plasma osmolality above a threshold of 1 to 2% (Fig. 37.2). Urine osmolality, in turn, is related linearly to AVP levels from 0.5 to 5–6 pgml−1, in association with increases in plasma osmolality to only 4% above the threshold for AVP secretion (Fig. 37.3). However, because urine volume is related inversely to urine osmolality, small increases in plasma AVP concentration (e.g., from 0.5 to 2 pgml−1) have the effect of decreasing urine flow much more than subsequent larger increases (e.g., from 2 to 5 pgml−1; Fig. 37.3). This relationship emphasizes the marked physiological effects of small initial changes in plasma AVP levels. The net result of these relations among plasma osmolality, AVP secretion, urine volume, and urine osmolality is a finely tuned regulatory system that adjusts the rate of free water excretion according to plasma osmolality via changes in pituitary hormone secretion.
Figure 37.2 Plasma concentrations of AVP as a function of changes in plasma osmolality, blood volume, or blood pressure in humans. The arrow indicates the plasma AVP concentration at basal plasma osmolality, volume, and blood pressure.
Modified with permission from Robertson (1986).
Figure 37.3 Relationship of plasma osmolality, plasma AVP concentrations, urine osmolality, and urine volume in humans. Note that small changes in plasma AVP concentrations have larger effects on urine volume at low plasma AVP concentrations than at high plasma AVP concentrations. Modified with permission from Robinson (1985).
Thirst Is Another Effective Osmoregulatory Response to Dehydration
Accompanying the excretion of concentrated urine is reabsorption of conserved water, which can considerably dilute remaining body fluids. Thirst, and the water intake it provokes, is a much more rapid and less limited response to dehydration than antidiuresis. Thirst may be defined as a strong motivation to seek, to obtain, and to consume water in response to deficits in body fluids. Like AVP secretion, thirst can be stimulated by cellular dehydration caused by increases in the effective osmolality of ECF (Gilman, 1937). Studies in animals consistently indicate that drinking behavior is elicited by 1 to 3% increases in plasma osmolality above basal levels, and analogous research has revealed that similar thresholds must be reached to produce thirst in humans (Robertson, 1986). This arrangement, in which the threshold for drinking is slightly higher than that for secretion of AVP (Fig. 37.3), ensures that ongoing behavior is not disrupted by thirst unless the buffering effects of osmosis and antidiuresis are insufficient to maintain osmoregulation. It also ensures that dehydration does not become severe before thirst is stimulated. See Box 37.2 for more on how the neurohypophysis controls the volume of water in the body.
Box 37.2 Diabetes Insipidus
The disease diabetes insipidus (DI), in which the secretion of AVP is impaired or absent, illustrates the crucial role of AVP in controlling the volume of water in the body. An eighteenth century Scottish physician, William Cullen, named the disease diabetes insipidus, or insipid urine, to distinguish it from diabetes mellitus, or sweet urine, in which abnormally high concentrations of glucose in the blood result in glucose appearing in the urine.
AVP is the only known antidiuretic substance in the body. In its absence, the kidney is unable to concentrate urine maximally to conserve water. The result is a continued excretion of copious amounts of very dilute urine. Patients with severe cases of DI, in whom the ability to excrete AVP is completely lost, can excrete up to 25 liters of urine each day. Such patients urinate almost hourly, which renders the completion of even simple tasks and activities of daily living, including sleeping, exceedingly difficult.
Patients with DI can quickly become dehydrated if their urinary fluid losses are not replaced by drinking water. Fortunately, thirst remains intact in most patients with DI because lesions that destroy the magnocellular neurons in the SON and PVN that synthesize AVP generally leave intact the osmoreceptors in the anterior hypothalamus as well as the higher brain centers that control thirst. Consequently, extreme thirst is one of the hallmarks of this disease, leading to the characteristic symptoms of polydipsia (excessive drinking) and polyuria (excessive urination). If drinking water is unavailable, or if a person with DI is unable to drink, then the unreplaced urinary water loss leads to dehydration and death in the absence of medical intervention.
DI can be caused when tumors and infiltrative diseases of the hypothalamus destroy the magnocellular neurons that produce AVP. Because four nuclei contain magnocellular neurons, and 10 to 20% of AVP-producing neurons are sufficient for normal urine concentration, brain lesions that cause DI are generally large. Less commonly, DI is idiopathic (of unknown cause), most likely from an autoimmune basis. DI can also be genetic, transmitted as an autosomal-dominant trait. Some patients with DI do not have any defect in AVP secretion but rather have defects in the V2 AVP receptors in the kidney that respond to circulating AVP. These cases are called nephrogenic (of kidney origin) DI.
The treatment for DI of hypothalamic origin, like that of other endocrine deficiency disorders, is replacement of the deficient hormone, in this case AVP. The short half-life of AVP in the circulation allows mammals to have minute-to-minute control of their urine output. However, longer-acting synthetic analogs of AVP are more convenient for treatment because they need not be taken as frequently as short-acting drugs (Robinson, 1985). These agents can restore urinary concentration and allow a person with DI to lead a more normal life.
Also like AVP secretion, water intake increases linearly in proportion to increases in the effective osmolality of ECF. The dilution of body fluids by ingested water complements the retention of water that occurs during antidiuresis, and both responses occur when drinking water is available. However, there may be marked individual differences in whether dehydrated subjects respond to their need for water promptly by drinking or more slowly by increasing renal water conservation (Kanter, 1953). AVP secretion and urine osmolality are more elevated when an induced increase in plasma osmolality is not compensated for by water intake (e.g., because drinking water is not available). Conversely, water intake in response to a solute load increases in animals after their kidneys are removed or their capability to secrete AVP is compromised, thereby precluding rapid excretion of the load in concentrated urine.
Rapid Inhibitory Feedback Control of Drinking
When dehydrated, many animals drink water very quickly, stopping long before the ingested water actually rehydrates them. This anticipatory satiety appears to be mediated by a neural message communicated from the oropharynx to the brain in association with the act of swallowing. The main experiments were done in dogs with implanted gastric fistulas (Thrasher, Nistal-Herrera, Keil, & Ramsay, 1981). When the fistula was closed, ingested water flowed normally from the stomach into the small intestine and was absorbed; water-deprived dogs drank rapidly, stopped 15 min before their plasma osmolalities began to decrease, and did not resume drinking as their stomach emptied because plasma osmolalities had returned to normal. In contrast, when the fistula was left open, ingested water drained out from the stomach, never entering the intestine and thus never being absorbed; the dogs drank normal amounts, stopped drinking, and after 10 to 20 min resumed drinking. In another study, when the dogs were not allowed to drink but water was introduced into the stomach through the fistula, thus bypassing the oropharynx, the gastric load did not affect water intake until it had been absorbed.
These seminal observations are consistent with a temporary satiety being produced by the act of water consumption, with a more long-lasting satiety occurring only after absorption of the ingested water and rehydration of the dog. AVP secretion is affected in parallel, showing that physiological and behavioral components of osmoregulation are influenced similarly. Ingestion of a concentrated NaCl solution instead of water produced the same temporary satiety and inhibition of AVP secretion, but after the saline was absorbed, the increase in plasma osmolality stimulated more drinking and AVP secretion than occurred at first. In similar experiments, people responded the same way but rats appear to have a different mechanism of rapid feedback, perhaps involving peripheral osmoreceptors.
Osmoreceptor Cells Stimulate AVP Secretion and Thirst
All body cells lose water by osmosis when the effective osmolality of ECF is increased. Thus, cells that provoke AVP secretion and thirst do not have unique osmosensitive properties (unlike retinal photoreceptor cells, for example, which are uniquely responsive to light). Instead, the exceptional feature of osmoreceptor cells is thought to be their neural circuitry, which activates the central systems for AVP secretion and thirst when the cells are dehydrated.
Destruction of osmoreceptor neurons should eliminate detection of increased plasma osmolality and thus the AVP secretion and thirst responses that are elicited by dehydration. In fact, ample research has confirmed that certain brain lesions eliminate AVP secretion and thirst responses. Such studies also have revealed that osmoreceptor cells (Johnson & Buggy, 1978; Thrasher, Keil, & Ramsay, 1982) appear to be located in the vascular organ of the lamina terminalis (OVLT) and areas of the adjacent anterior hypothalamus, near the anterior wall of the third cerebral ventricle (Fig. 37.4). Surgical destruction of that area of the brain in animals abolishes the AVP secretion and thirst responses to hyperosmolality but not their responses to other stimuli. The same conclusion was drawn after a study of people who were unable to osmoregulate when water deprived or when given an NaCl load; these patients were found to have focal brain tumors that destroyed the region around the OVLT.
Figure 37.4 Summary of the main anterior hypothalamic pathways that mediate secretion of arginine vasopressin (AVP) and oxytocin (OT). The vascular organ of the lamina terminalis (OVLT) is especially sensitive to hyperosmolality. Hyperosmolality also activates other neurons in the anterior hypothalamus, such as those in the subfornical organ (SFO) and median preoptic nucleus (MnPO), and magnocellular neurons, which are intrinsically osmosensitive. Circulating angiotensin II (AII) activates neurons of the SFO, an essential site of AII action, as well as cells throughout the lamina terminalis and MnPO. In response to hyperosmolality or AII, projections from the SFO and OVLT to the MnPO activate excitatory and inhibitory interneurons that project to the supraoptic nucleus (SON) and paraventricular nucleus (PVN) to modulate direct inputs to these areas from the circumventricular organs. Cholecystokinin (CCK) acts primarily on gastric vagal afferents that terminate in the nucleus of the solitary tract (NST), but at higher doses it can also act at the area postrema (AP). Although neurons apparently are activated in the ventrolateral medulla (VLM) and NST, most oxytocin secretion appears to be stimulated by monosynaptic projections from A2/C2 cells, and possibly also noncatecholaminergic somatostatin/inhibin b cells, of the NST. Baroreceptor-mediated stimuli, such as hypovolemia and hypotension, are more complex. The major projection to magnocellular AVP neurons appears to arise from A1 cells of the VLM that are activated by excitatory interneurons from the NST. Other areas, such as the parabrachial nucleus (PBN), may contribute multisynaptic projections. Cranial nerves IX and X, which terminate in the NST, also contribute input to magnocellular AVP neurons. It is unclear whether baroreceptor-mediated secretion of oxytocin results from projections from VLM neurons or from NST neurons. AC, anterior commissure; OC, optic chiasm; PIT, anterior pituitary.
The location of osmoreceptor cells in the OVLT is consistent with the results of pioneering investigations in which hyperosmotic solutions injected into blood vessels perfusing the anterior hypothalamus stimulated AVP secretion in dogs (Verney, 1947). The OVLT and surrounding areas of the anterior hypothalamus were subsequently implicated by studies in rats. After systemic injections of hypertonic NaCl solution, modern immunocytochemical techniques were used to detect early gene products in cells associated with the production of new protein. Dense staining in the OVLT (and in AVP-secreting cells in the hypothalamus) indicated that it had been strongly stimulated by the experimentally induced dehydration and closely paralleled pituitary AVP secretion (Hoffman, Smith, & Verbalis, 1993).
The neural pathways connecting the OVLT with magnocellular AVP-secreting cells in the hypothalamic SON and PVN have been identified, whereas the neural circuits in the forebrain that control thirst are less well known. Early reports identified the lateral hypothalamus as a “thirst center” because its destruction in rats eliminated the drinking response, but not the associated AVP secretion, to increased osmolality of body fluids. However, later investigations showed that the critical damage was not to hypothalamic cells but to dopamine-containing fibers that coursed through the area. The induced disruption of behavior was not specific to drinking but instead reflected a general inability of the brain-damaged animals to initiate movement (Stricker, 1976). Indeed, the syndrome of behavioral dysfunctions seen in these animals generally resembled that of Parkinson’s disease, which has also been attributed to the loss of dopaminergic fibers in the brain. (See Chapter 36 for the same reinterpretation of the inability of rats to eat normally after dopamine-depleting lesions of the lateral hypothalamus.) More recent studies using functional magnetic resonance imaging of the brain have implicated the anterior cingulate cortex as a likely area involved in thirst perception (Egan et al., 2003).
Natriuresis and Inhibition of Solute Intake Also Promote Osmotic Homeostasis during Dehydration
When body fluid is hyperosmolar, adaptive behavior includes not only drinking and conserving water (thereby increasing the denominator in the ratio that represents body fluid osmolality) but also excreting NaCl and avoiding the consumption of additional osmolytes (thereby decreasing the numerator of that ratio). Endogenous natriuretic agents promote urinary sodium loss after an administered NaCl load or a period of imposed water deprivation. One such agent is the hormone atrial natriuretic peptide (ANP), which is synthesized in the atria of the heart and released when increased intravascular volume distends the atria. Another is the hormone oxytocin. Like AVP, oxytocin is synthesized in magnocellular neurons in the PVN and SON and secreted from the posterior pituitary in proportion to induced hyperosmolality (Stricker & Verbalis, 1986). In rats, oxytocin is as potent in stimulating natriuresis as AVP is in stimulating antidiuresis (Verbalis, Mangione, & Stricker, 1991), by acting directly in the kidneys and indirectly by eliciting secretion of ANP.
Salt loads are also known to decrease the intake of osmolytes, whether in the form of NaCl solution or food, complementing the stimulation of thirst and the secretion of AVP and oxytocin. However, because destruction of the OVLT eliminates the two latter effects but not the dehydration-induced reduction in NaCl intake, osmo- or Na+ receptors located outside the basal forebrain must mediate the inhibition of NaCl and food intake. Possible sites for such cells include the hepatic portal vein and the area postrema, both of which have been suspected of having Na+ receptor functions. In addition, cells in the hepatic portal vein are well situated to detect the sodium content of ingested food and to modulate its intake accordingly.
Diuresis and Inhibition of Water Intake Promote Osmotic Homeostasis during Overhydration
Osmoregulation is required not only under conditions of dehydration but also during periods of acute overhydration and hypoosmolality, as may result when beverages are consumed in excess of water needs or when AVP levels are non-osmotically elevated. Such consumption may occur not because of thirst but, for example, because of the palatability of or chemical substances in the beverages (e.g., caffeine, alcohol). (See Box 37.3 on water intoxication.) Unlike excess food, which is stored as triglycerides in adipose tissue, excess water is not stored for later use but instead is excreted in urine. When plasma osmolality is below normal, circulating levels of AVP are reduced and, in consequence, the kidneys excrete dilute urine and thereby raise plasma osmolality. The major behavioral contribution of osmotic dilution to osmoregulation is inhibition of free water intake; the ingestion of osmolytes in food and NaCl is not stimulated by osmotic dilution.
Box 37.3 Water Intoxication
Overhydration that leads to retention of excess water is commonly called water intoxication. This can be caused by two mechanisms: excessive ingestion of fluids in volumes greater than the ability of the kidneys to excrete water or impaired kidney water excretion. In many cases, both mechanisms contribute to the water retention. Ingestion of dilute fluids normally causes slight decreases in plasma osmolality, which are sufficient to reduce circulating AVP concentrations to levels that allow the kidneys to excrete the ingested water in dilute urine, thereby maintaining osmotic homeostasis. The capacity of mammalian kidneys to excrete excess fluid is very large, in humans ranging from 800 to 1,000 ml/h, or 19 to 24 L/d. Humans rarely ingest fluids at these large volumes; however, this does occur in patients with schizophrenia, who drink compulsively for reasons not related to thirst, or during periods of forced water consumption as has occurred during fraternity hazing or freshwater drowning. More commonly, water retention occurs when the water excreting capacity of the kidney is limited by increased plasma AVP levels. This can occur because of physiological nonosmotic stimuli that cause AVP secretion, such as hypovolemia, or because of pathological AVP secretion caused by a variety of disease processes, including tumors that synthesize and secrete AVP or central nervous system disorders that interfere with normal regulation of AVP secretion, which is called the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Verbalis, 2007).
The metabolic consequence of excess water retention is a dilution of the osmolality of body fluids, or hypoosmolality, and a commensurate dilution of the extracellular fluid (ECF) sodium concentration to low levels, or hyponatremia. The physiological consequence of lowered ECF osmolality is an imbalance of osmolality across the intracellular fluid (ICF) and ECF compartments. In response, water will move across cell membranes from the ECF to the ICF until osmotic equilibrium is again achieved. This water movement results in swelling of all cells throughout the body. In most organs this is well tolerated, but the brain is enclosed in a rigid bony skull that limits the degree of brain swelling, or cerebral edema, to approximately 8%, which is the space occupied by cerebrospinal fluid within the skull. Once this limit is reached, the brain herniates through the openings at the base of the brain, which compresses the brainstem respiratory regulatory center leading to cessation of breathing and death. This pathological process is the cause of death in cases of water intoxication that develops rapidly, as in individuals engaging in endurance exercise events such as marathon races, who ingest too much fluid relative to their reduced urine excretory capacity as a result of exercise-induced stimulation of AVP secretion (Noakes et al., 2005). Individuals with lesser degrees of cerebral edema nonetheless can develop neurological manifestations ranging from disorientation to seizures, obtundation, and coma, a syndrome called hyponatremic encephalopathy (Fraser & Arieff, 1997).
However, such dire consequences do not develop in most patients with hypoosmolality and hyponatremia because the brain is able to adapt to hypoosmolality via a process called brain volume regulation (Verbalis, 2010). In response to hypoosmolality-induced cell swelling, the brain loses electrolytes and small molecules culled from the ICF and ECF spaces, thereby decreasing brain water content back toward normal levels. This process generally requires 24–48 hours in both experimental animals and humans. The marked variability in the presenting neurological symptoms of hyponatremic patients can be understood in the context provided by this process of brain volume regulation. Most of the severe neurological symptoms associated with hyponatremia are thought to reflect the cerebral edema that occurs as a consequence of osmotic water movement into the brain. However, once the brain has volume adapted through solute losses, thereby reducing the cerebral edema, neurological symptoms are not as prominent and in some cases may even be totally absent. On the other hand, even patients with chronic hyponatremia appear to be at risk from deleterious complications as a result of the cellular solute losses that allow survival during hypoosmolar conditions. These include altered neurocognition, gait instability, increased falls and bone loss leading to bone fractures, and a debilitating demyelinating disorder called central pontine myelinolysis if the hyponatremia is corrected too rapidly.
Summary
Osmoregulation during dehydration in animals and humans is accomplished by a combination of physiological responses, resulting in antidiuresis and natriuresis, and the behavioral response of increased water intake. Osmoreceptor cells critical for mediating these functions have been identified in the basal forebrain. These neurons respond to very small increases in plasma osmolality, and the effector systems they control correct any increase in plasma osmolality. In addition, an early stimulus must exist, generated by peripheral osmo- or Na+ receptor cells, which signals the brain in anticipation of subsequent rehydration. Other osmo- or Na+ receptor cells appear to mediate the inhibition of NaCl and food intake, which also contributes to osmoregulation during dehydration. Conversely, diuresis and inhibition of water intake promote osmoregulation during overhydration, whereas excitation of NaCl or food intake does not.
Volume Homeostasis
Like osmotic dehydration, loss of blood volume (hypovolemia) stimulates several adaptive compensatory responses appropriate for restoring circulatory volume. The physiological contributions to volume regulation have been studied extensively in laboratory animals subjected to a controlled loss of blood. Because behavior is compromised by the anemia and hypotension that result from extensive hemorrhage, researchers studying thirst in rats often instead produce hypovolemia by subcutaneous injection of a colloidal solution. Such treatment disrupts the Starling equilibrium in capillaries near the injection site because the extravascular colloid opposes the oncotic effect of plasma proteins. Consequently, fluid leaches out of capillaries and remains in the interstitial space. Ingested fluid is also drawn into the interstitial space by the colloid so the total fluid volume required to correct the plasma volume deficit may be substantial. Water does not move from the cells by osmosis, however, because the osmolality of the injected colloidal solutions actually is similar to that of cells.
After colloid injections, rats conserve water and Na+ in urine and increase their consumption of water and saline solution (Stricker, 1981). When given an isotonic NaCl solution to drink, these rats ingest volumes appropriate to their needs. When given separate bottles of water and concentrated NaCl solution, remarkably the rats drink appropriate amounts of each to create an isotonic fluid mixture. These observations raise several questions: How do the hypovolemic rats detect their plasma volume depletion? How are their thirst and salt appetite coordinated so that they consume the desired isotonic mixture of fluid? How are these two behavioral responses integrated with the complementary physiological responses of water and Na+ conservation in urine? Research has provided answers to these and related questions, which are discussed in the following sections.
Neural and Endocrine Signals of Hypovolemia Stimulate AVP Secretion
An appropriate physiological response to volume depletion should include water conservation and urine concentration. In fact, like plasma hyperosmolality, hypovolemia is an effective stimulus for AVP secretion (Robertson, 1986; Stricker & Verbalis, 1986). However, AVP secretion does not occur until blood loss exceeds 10% of total blood volume, meaning AVP secretion is much less sensitive to hypovolemia than to increases in ECF osmolality (Fig. 37.2). The effects of hypovolemia and osmotic dehydration are additive; that is, a given increase in osmolality causes greater secretion of AVP when animals are hypovolemic than when they are euvolemic (Fig. 37.5).
Figure 37.5 The relationship between the osmolality of plasma and the concentration of vasopressin (AVP) in plasma depends on blood volume and pressure. The line labeled N shows plasma vasopressin concentration across a range of plasma osmolality in an adult with normal intravascular volume (euvolemic) and normal blood pressure (normotensive). Lines to the left of N show the relationship between plasma vasopressin concentration and plasma osmolality in adults whose low intravascular volume (hypovolemia) or blood pressure (hypotension) is 10, 15, and 20% below normal. Lines to the right of N are for volumes and blood pressures 10, 15, and 20% above normal.
Modified with permission from Robertson (1986).
Loss of blood volume is first detected by stretch receptors in the great veins entering the right atrium of the heart. These stretch receptors provide an afferent vagal signal to the nucleus of the solitary tract (NST) in the brainstem (Chapter 36). Still larger decreases in blood volume may also lower arterial blood pressure and reduce the stretch of receptors in the walls of the carotid sinus and aortic arch. That information is integrated in the NST with neural messages from the low-pressure, venous side of the circulation. Note that these sensory neurons are not actually baroreceptors (literally, pressure receptors); although commonly they are referred to as such, they are more accurately described as stretch receptors.
The ascending pathway between the NST in the brainstem and the SON and PVN in the hypothalamus includes noradrenergic fibers arising from A1 cells in the ventrolateral medulla. Volume depletion stimulates AVP secretion via other pathways as well. In addition, the kidneys secrete renin during hypovolemia, a response mediated in part by sympathetic neural input to β-adrenergic receptors on cells that secrete renin. Renin is an enzyme that initiates a cascade of biochemical steps that result in the formation of angiotensin II (AII) (Fig. 37.6), an extremely potent vasoconstrictor. AII stimulates AVP secretion by acting in the brain at the subfornical organ (SFO) (Ferguson & Renaud, 1986), which is located in the dorsal portion of the third cerebral ventricle. Because this circumventricular organ lacks a blood–brain barrier, its AII receptors can detect very small increases in the blood levels of AII. Neural pathways from the SFO to the SON and PVN in the hypothalamus mediate AVP secretion and may use AII as a neurotransmitter. Another pathway from the SFO goes to the OVLT, perhaps providing an opportunity for the integration of information about volume states and osmotic concentration.
Figure 37.6 The renin–angiotensin cascade. Baroreceptors in the aortic arch, carotid sinus, and renal afferent arterioles sense hypovolemia and then cause the kidneys to secrete the enzyme renin. Renin cleaves angiotensinogen, which is synthesized by the liver, to produce angiotensin I. The angiotensin-converting enzyme, primarily in the lungs, cleaves angiotensin I to produce angiotensin II (AII), a peptide made of eight amino acid residues. AII is a potent vasoconstrictor and one of several stimulants of aldosterone secretion. Stimulation of aldosterone secretion from the adrenal cortex, along with possible direct intrarenal effects of AII, promotes renal conservation of sodium ions, complementing the pressor effect of AII in stabilizing arterial pressure and volume. ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; pOsm, plasma osmolality.
Neural and Endocrine Signals of Hypovolemia Also Stimulate Thirst
In addition to the antidiuresis and vasoconstriction produced by the secretion of AVP and activation of the renin–angiotensin system, colloid treatment increases water intake in rats (Fitzsimons, 1961). Once 5 to 10% of the normal plasma volume has been lost, the water intake elicited by hypovolemia increases linearly in relation to further deficits in plasma volume. This stimulus for water intake and the effect of an NaCl load on thirst are additive. The stimulus of thirst during hypovolemia appears to be the same as the signal for AVP secretion—that is, a combination of neural afferents from cardiovascular baroreceptors and endocrine stimulation by AII (Fitzsimons, 1969). Each signal can stimulate water intake in the absence of the other. For example, water intake by hypovolemic rats is not diminished by destruction of the NST and loss of neural input from baroreceptors, nor is it eliminated by the loss of AII resulting from bilateral removal of the kidneys (Fitzsimons, 1961). Presumably, colloid treatment would not elicit thirst in rats subjected concurrently to bilateral nephrectomy and NST lesions.
Intravenous infusion of AII strongly stimulates thirst in rats and most other animals studied in the laboratory (including humans). AII adds to the thirst stimulated by an osmotic load when the two treatments are combined. There had been considerable controversy about whether AII functions as a normal physiological stimulus of thirst because the doses of AII required to stimulate significant water intake produce blood levels of AII well above the physiological range. However, such doses also increase arterial blood pressure, and it has been shown that this acute hypertension inhibits thirst and limits the induced water intake. For example, drinking was enhanced considerably when the hypertensive effects of AII were blunted by simultaneous administration of vasodilating agents (Robinson & Evered, 1987).
Osmotic Dilution Inhibits Thirst and AVP Secretion during Hypovolemia
Hypovolemic rats need isotonic saline, not water alone, to repair their plasma volume deficits. When the rats drink only water, about two-thirds of the ingested volume moves into cells by osmosis and much of what remains extracellular is captured by the colloid. Thus, most of the water that is consumed does not remain in the vascular compartment, and the volume deficit within the vascular compartment persists. This situation may be contrasted with the negative feedback control of osmoregulatory thirst in which the dehydration of osmoreceptor cells causes thirst and ingested water repairs dehydration, eliminating the stimulus for thirst.
Rather than repairing the volume deficit, the water consumed by hypovolemic rats causes a second serious challenge to body fluid homeostasis: osmotic dilution. The animals cannot readily eliminate this self-administered water load because hypovolemia reduces GFR and thereby diminishes urinary excretion independent of AVP. Therefore, when water is the only drinking fluid available, an appropriate response of colloid-treated rats would be to stop drinking and thereby limit the secondary problem of osmotic dilution. In experiments, colloid-treated rats actually do stop drinking water despite persistent hypovolemia, and the stimulus for the inhibition of thirst has been found to be osmotic dilution of body fluids (Stricker, 1969). A 4 to 7% decrease in osmolality is sufficient to stop drinking that has been motivated by a 30 to 40% loss of plasma volume. Thus, the osmoregulatory system appears dominant in the control of thirst. Comparable data demonstrate the same to be true of AVP secretion in colloid-treated rats: osmotic dilution inhibits AVP secretion even in severely hypovolemic rats (Stricker & Verbalis, 1986).
Hypovolemia Also Stimulates Aldosterone Secretion and Salt Appetite
As mentioned earlier, hypovolemic animals need to consume and retain water and NaCl, not just water. Appropriately, colloid-treated rats drink NaCl solution and conserve Na+ in urine. Renal Na+ retention is mediated largely by aldosterone secreted from the adrenal cortex, although Na+ conservation also occurs in association with the decrease in GFR. The central nervous system does not innervate the adrenal cortex, as it does the adrenal medulla. However, a neural influence on aldosterone secretion is provided indirectly because AII is a very potent stimulus of aldosterone secretion, and renin secretion from the kidneys during hypovolemia is stimulated in part by the sympathetic nervous system (Fig. 37.6). The secretion of aldosterone is also stimulated by another peptide hormone, adrenocorticotrophic hormone (ACTH), which is secreted from the anterior lobe of the pituitary gland in response to corticotropin-releasing hormone (CRH). The release of CRH from the PVN is triggered by various stressors, including activated cardiovascular baroreceptors. Yet another stimulus of aldosterone secretion is increased plasma levels of K+, which can develop as a consequence of reduced GFR and an associated decrease in urinary K+ excretion. The effects of these three independent stimuli of aldosterone secretion are additive. Aldosterone has also been found to stimulate salt appetite in animals, which therefore complements its renal effects to cause sodium conservation. (See Box 37.4 on salt appetite after adrenocortical dysfunction.)
Box 37.4 Salt Appetite After Adrenocortical Dysfunction
Fifty years ago, a 4-year-old boy was brought to the Johns Hopkins University Hospital in Baltimore with the peculiar behavior of eating large amounts of table salt. The child heavily salted all his food, even juice, and often consumed salt directly from its container. His parents tried unsuccessfully to keep him from ingesting salt and brought him to the hospital in the hope that his strange behavior could be understood and stopped. The physicians were able to prevent the boy from having access to NaCl, but they were shocked when he died a few days later. An autopsy revealed that the child had bilateral tumors in his adrenal glands. In retrospect, it seems clear that he could not secrete aldosterone and therefore lost Na+ in urine uncontrollably. Like patients with diabetes insipidus, who excrete a copious amount of dilute urine and drink comparable volumes of water in compensation (see Box 37.2 on diabetes insipidus), this boy evidently was consuming salt as an adaptive compensation to his recurrent need for sodium (Wilkins & Richter, 1940). He died when that response was prevented.
Rats increase their consumption of NaCl after surgical removal of their adrenal glands, by amounts proportional to the sodium loss in urine (Richter, 1936). The stimulus for this salt appetite appears to be a combination of elevated circulating levels of AII and reduced activity in a central oxytocinergic inhibitory system. In humans, however, a comparable salt appetite is not as common in patients with Addison disease, whose adrenocortical dysfunction causes them to lose Na+ in urine excessively. Nor is salt appetite usually stimulated in people who lose excessive amounts of Na+ in perspiration. No explanation is available for why an adaptive salt appetite appears readily in laboratory animals but not in humans, but this difference may be related, in part, to factors associated with herbivorous versus carnivorous eating behaviors.
The onset of salt appetite induced in rats by colloid treatment is curiously delayed relative to the appearance of thirst. That is, water intake increases within 1 to 2 h after colloid treatment whereas the intake of NaCl solution does not increase until at least 5 h later (Stricker, 1981). Investigations showed that the delay is caused both by the gradual appearance of an excitatory stimulus of salt appetite (i.e., AII) and by the gradual disappearance of an inhibitory stimulus for NaCl intake (i.e., central secretion of oxytocin). When rats are maintained on Na+-deficient diet for a few days instead of standard Na+-rich laboratory chow, NaCl intake appears very rapidly after colloid treatment—even before thirst. Those results have been attributed in part to the suppression of central oxytocin secretion and in part to the increased blood levels of AII and aldosterone observed then; indeed, the latter two hormones are known to act synergistically in the stimulation of salt appetite.
Aldosterone and other mineralocorticoids appear to act directly on neurons in the NTS with mineralocorticoid receptors, which have the important additional property of containing an enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) that inactivates glucocorticoids (which also bind to those receptors) and thereby allows the receptors specificity to mineralocorticoids. These HSD2-containing cells are activated by all treatments that elicit salt appetite in rats but are quickly inactivated once saline has been consumed (Geerling, Engeland, Kawata, & Loewy, 2006). In addition, it seems relevant that rats with discrete lesions of the area postrema, which sends inhibitory neural input to those cells in the NTS, consumed prodigious amounts of concentrated NaCl solution whereas rats with area postrema lesions that invaded the NTS had much smaller saline intakes.
Analogous to the control of thirst, presystemic signals appear to inhibit salt appetite in association with gastrointestinal distension and increased plasma osmolality. The visceral signals appear to project through the vagus to the NTS and area postrema and then to the parabrachial nucleus (PBN), and, in this regard, lesions of peripheral sensory fibers or of the viscerosensory input to the PBN led to remarkably large intakes of NaCl solution by rats. In contrast, the inhibition of salt appetite associated with increased plasma osmolality has been attributed to central secretion of oxytocin.
Central Oxytocin Inhibits Salt Appetite
Recall that hypovolemic rats ordinarily drink water before they consume saline and, in doing so, thereby cause an osmotic dilution of body fluids. That dilution inhibits secretion of pituitary AVP and oxytocin, either of which effects might have removed an inhibitory stimulus for salt appetite. In other studies, rats showed a strong inverse relationship between intake of NaCl and plasma levels of oxytocin (but not AVP), suggesting that circulating oxytocin was an inhibitory stimulus of salt appetite. However, in tests of this hypothesis, an intravenous infusion of physiological doses of oxytocin did not decrease NaCl intake in hypovolemic rats, nor did infusion of an oxytocin receptor blocker increase NaCl intake. These findings were clarified by the observation that, coincident with the secretion of oxytocin from magnocellular neurons, oxytocin was released from parvicellular neurons projecting centrally from the PVN. Thus, plasma oxytocin may have been a peripheral marker of the centrally acting oxytocin that mediated the inhibition of salt appetite in rats (Blackburn, Verbalis, & Stricker, 1992). This hypothesis has been strongly supported by the results of a series of investigations. For example, salt appetite in hypovolemic rats was eliminated by a systemic injection of naloxone, an opioid receptor antagonist that disinhibits oxytocin secretion, and this effect was blocked by the prior injection of an oxytocin receptor antagonist directly into the cerebrospinal fluid. Conversely, NaCl ingestion in response to hypovolemia or AII was potentiated by diverse treatments that inhibit the secretion of oxytocin. In addition to osmotic dilution, these treatments included systemic injection of ethanol, maintenance on a sodium-deficient diet (instead of the standard laboratory diet rich in Na+), and peripheral administration of mineralocorticoid hormones such as aldosterone. Thus, excitatory and inhibitory components together regulate NaCl intake in a dual-control system in the brain. See Box 37.5 on the control of thirst and salt appetite during hypovolemia in rats.
Box 37.5 Thirst and Salt Appetite During Hypovolemia in Rats
Hypovolemia elicits two endocrine effects in the excitation of salt appetite in rats—acute stimulation by a peptide hormone (AII) and more gradual stimulation by a steroid hormone (aldosterone). However, hypovolemia and AII each provide conflicting stimuli for salt appetite, since each signal also stimulates central oxytocin secretion, which mediates inhibition of salt appetite. The coordination of thirst and salt appetite stimulated by hypovolemia-induced colloid treatment in rats can be conceptualized as follows (Fig. 37.7). The combination of hypovolemia and AII stimulates thirst but provides a mixed stimulus of salt appetite. Thus, the animals at first drink water; however, by doing so, they dilute their body fluids, and the osmotic dilution eventually becomes large enough to inhibit thirst. Osmotic dilution has the additional effect of reducing central oxytocin secretion, which in turn disinhibits salt appetite, and the rats begin to drink concentrated NaCl solution. The ingested solute raises plasma osmolality and thereby removes the dilution-induced inhibition of thirst and oxytocin secretion. Consequently, the rats stop drinking saline and resume drinking water. Osmotic dilution again develops, thirst is again inhibited, and salt appetite is again disinhibited. And thus the hypovolemic animals, stimulated by neural and endocrine signals of hypovolemia, alternate their intakes of the two fluids while maintaining the concentration of body fluids near isotonic. Water and Na+ are conserved in urine until the deficit in plasma volume is repaired, at which point the stimuli for adaptive physiological and behavioral responses disappear, and normal body fluid volume and tonicity are restored. Because the same neural and endocrine signals of hypovolemia stimulate thirst, salt appetite, and AVP and oxytocin secretion, these responses are integrated.
Figure 37.7 Schematic diagram of the mechanisms controlling thirst and salt appetite in hypovolemic rats. Solid arrows indicate stimulation and unfilled arrows indicate inhibition. The combination of the effects of blood-borne AII on the brain and neural baroreceptor signals to the brainstem stimulates hypovolemic animals to drink water and concentrated saline solution. The rats alternately drink the two fluids in amounts that ultimately add up to a volume of isotonic saline sufficient to repair the volume deficit. When the animals have access to only one fluid, the water and salt intakes are limited by activation of the appropriate inhibitory osmoregulatory pathways. When rats drink isotonic saline instead of water and concentrated saline, neither inhibitory pathway is activated and consequently intake is continuous.
In addition, presystemic signals may participate in the control of water and saline consumption. For example, distension of the stomach and small intestine by ingested fluid may inhibit further drinking despite continued deficits of plasma volume. Similarly, osmotic dilution detected by visceral osmoreceptors may inhibit intake of water, whereas osmotic concentration may inhibit intake of hypertonic NaCl solution. Thus, both systemic and presystemic signals, providing information about the concentration and volume of body fluid and of ingested fluid, respectively, appear to be available to the hypovolemic animal. The integration of these signals by the brain is critical in the control of water and saline intakes and determines the volume of each fluid that is consumed.
Central oxytocinergic neurons can inhibit salt intake and food intake (Chapter 36). Thus, when osmotic dehydration activates oxytocinergic neurons, the intake of food and salt is inhibited and hyperosmolality is thereby prevented. From this perspective, food is a source of osmolytes (not just of calories) and NaCl solution provides osmolytes without calories. Inhibition of intake of osmolytes complements the natriuretic effect of pituitary oxytocin in supporting osmoregulation.
Salt Appetite Is Also Inhibited by Atrial Natriuretic Peptide
The role of oxytocin in osmoregulation has become apparent only during the last decade or so, and the identification of other peptide hormones as important factors in the homeostasis of body fluids may be anticipated. One likely candidate is atrial natriuretic peptide. Like oxytocin, ANP is secreted by neurons within the brain, and when administered directly into the cerebrospinal fluid it inhibits an experimentally induced salt appetite in rats, perhaps by opposing the actions of AII. Moreover, destruction of ANP receptors in the brain eliminates the inhibition of salt appetite caused by an NaCl load (Blackburn, Samson, Fulton, Stricker, & Verbalis, 1995). Further work will be needed to understand the role of ANP-containing neurons in the central control of salt intake and the relationship of the neurons with other systems that participate in the regulation of water and NaCl intake.
Summary
Regulation of blood volume, like osmoregulation, is accomplished by a combination of physiological responses to hypovolemia, resulting in antidiuresis and antinatriuresis, and the complementary behavioral responses of increased water and NaCl intake. Cardiovascular baroreceptor cells detect hypovolemia and send neural signals to the brainstem, which communicates to the hypothalamus and forebrain structures mediating neurohypophyseal AVP and oxytocin secretion, as well as thirst. AII also appears to stimulate these responses while additionally stimulating salt appetite and supporting blood pressure as a potent vasoconstrictor. However, AII and hypovolemia both increase central oxytocin secretion, which mediates inhibition of NaCl intake, so for salt appetite to emerge this effect must be inhibited (as by osmotic dilution of body fluids, resulting from the renal retention of ingested water). The integration of these stimuli ensures that behavioral and physiological responses occur simultaneously, and their redundancy allows these vital regulatory processes to occur even when one stimulus is lost due to injury or disease. More generally, studies of water and NaCl ingestion provide insights into how the brain controls motivation, and how peptide and steroid hormones interact with neural signals in the control of behavior.
References
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Suggested Readings
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