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De Luca LA Jr, Menani JV, Johnson AK, editors. Neurobiology of Body Fluid Homeostasis: Transduction and Integration. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Neurobiology of Body Fluid Homeostasis: Transduction and Integration.

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Chapter 15Homeostasis and Body Fluid Regulation

An End Note

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Homeostasis is accepted universally as a synonym of equilibrium or stability in biological systems and commonly used to describe activities of cells, organs, individuals, and society (Abbott 2003; Cannon 1929; Palagi and Mancini 2011). Tradition and universal acceptance easily preclude more explanations about the concept of homeostasis, being unlikely that the reading of this book has caused much doubt about its meaning.

However, the universal use and attribution of a control mechanism based exclusively on negative feedback have raised objections to the term homeostasis (e.g., Berridge 2004; Sterling 2012). It is not our intent to review and discuss here the foundations of the many objections raised about homeostasis. We would like to recall the original concept instead, showing how appropriate and valid it is in the context of neural and endocrine mechanisms that regulate the composition of body fluid and produce homeostasis in mammals.


We may identify the article of Walter Cannon published in Physiological Reviews (1929) as a landmark to the original definition of homeostasis. Cannon based on Claude Bernard considered homeostasis as steady states maintained by mechanisms peculiar to living beings. He also emphasized that the existence of such states derives from a constant internal environment. Bernard defined internal environment as the fluid matrix made of blood and lymph or, by extension, the extracellular fluid (ECF) (Cannon 1929; Guyton and Hall 2000; Takei 2000). It should be clear from (Cannon’s 1929) article, and from the reports of other authors, who later adopted the original concept (e.g., Guyton and Hall 2000; Takei 2000), that the constancy of the ECF constitutes the essence of the concept of homeostasis. Cannon referred specifically to the constancy of physical–chemical constituents of the ECF as varying within narrow limits. He called those constituents homeostatic categories. Among such categories, we may find temperature, water, osmolarity, and sodium, all related to mechanisms discussed in previous chapters.

Cannon considered a living being as an open system with automatic reactive mechanisms. Reactive mechanisms were assumed by Cannon to correct large fluctuations, thereby maintaining each homeostatic category within narrow and constant limits. Let us take sodium as an example. Its normal concentration in the human blood varies about 7% within a range of 138–146 mmol/L (Guyton and Hall 2000). As illustrated throughout this book, several autonomic, neuroendocrine, and behavioral mechanisms are associated with the homeostasis of this ion.


Powerful multiple homeostatic mechanisms maintain sodium concentration and osmolarity of the ECF of most bony fishes and amphibians, and birds and mammals, to about one-third that of the sea. Such mechanisms operate to avoid either desiccation or overhydration, and their appearance in evolution was important for vertebrate conquest of the terrestrial environment (Guyton and Hall 2000; Kültz 2012; Takei et al. 2000).*

Responses to sodium loss or gain provide an example of how different types of mechanisms contribute to body fluid homeostasis. Homeostatic mechanisms in general may operate in a reaction mode, usually involving negative feedback, or through a combination of reaction with prediction or anticipation (Carpenter 2004; Moore-Ede 1986).

The concept of reactive or negative feedback mechanisms regulating sodium availability in body fluids is ingrained in the field. Studies that began with Curt Richter about the same time Cannon defined homeostasis (Moran and Schulkin 2000) inspired pioneer work searching for brain reactive mechanisms that control both ingestion and renal excretion of sodium (Covian et al. 1975). Such paradigm of reactive mechanisms is the foundation of productive investigation about mechanisms of body fluid homeostasis as shown by many examples throughout this book.

Another paradigm that has been increasingly investigated involves anticipation. Anticipatory mechanisms that control sodium intake were initially indicated by the finding that history of repeated sodium depletions enhances sodium intake (Falk 1966). Later it was demonstrated that angiotensin II and aldosterone, hormones secreted or produced in response to sodium depletion, also act by modifying the behavior, increasing the intensity of both need-induced and need-free sodium intake (Sakai et al. 1989).

The implications of the effects of those hormones for neural and behavioral plasticity, particularly for the behavior of sodium intake, were already discussed in previous chapters (e.g., Chapters 4, 13, and 14). We would like to call attention to the fact that changes in sodium intake as a function of episodic sodium depletion must result from plastic changes in the mechanisms that produce the behavior. Such changes are not predicted from mechanisms that only react to alterations in body sodium, but have been interpreted as an anticipated response to future dehydration (Epstein 1991; Fessler 2003).

Now, the fact that the neural and behavioral mechanisms that produce sodium homeostasis are plastic does not mean that the normal sodium range is necessarily modified. For example, whereas repeated episodes of sodium depletion enhances sodium intake, they alter neither plasma sodium concentration nor indicators of blood volume in rats (Sakai et al. 1989). Another example to illustrate the same point derives from congenital adrenal hyperplasia associated with salt waste. Adult humans bearing this pathology have an enhanced sodium appetite positively correlated with history of perinatal hyponatremia, but they also have normal serum sodium concentration (Kochli et al. 2005).

So, we may conclude that sodium or body fluid homeostasis occurs in the face of plastic neural and behavioral alterations. This teaches us that homeostatic mechanisms (reactive, anticipatory, or both) should not be confounded with the product of their operation (the maintenance of the homeostatic categories within narrow values).


In this section, we further discuss how clear-cut observations that support homeostasis and reactive mechanisms may evolve to more complex situations that only apparently contradict homeostasis. The contradiction disappears if we take into account Cannon’s definition and control mechanisms that involve more than simple negative feedback. In order to show complex situations compatible with homeostasis, we will use two major examples of mechanisms and behaviors associated with the regulation of osmotic and ionic concentration of the ECF.

Consider first what is called osmometric theory of thirst as a major example. Cellular and behavioral studies suggest that hypertonicity of the ECF activate osmoreceptors located outside the blood–brain barrier by shrinkage of their intracellular volume [intracellular fluid (ICF)] (Bourque 2008; Fitzsimons 1961; Kutscher 1966; Liedtke 2007; Schoorlemmer et al. 2000). A linear function between water intake and the osmotic load, and the termination of drinking by the exact amount of water necessary to dilute the load (Fitzsimons 1961) suggests a direct negative feedback in operation. The theory elegantly suggests that a cellular-dehydrated animal behaves like an osmometer, by drinking water as a linear function of the amount of the osmotic load detected by the osmoreceptors—interestingly, the termination of drinking begins in advance to the correction of the ECF tonicity (Carpenter 2004; Stricker and Hoffmann 2006). As a corollary to the theory, if the cellular-dehydrated rat behaves strictly like an osmometer, it should ingest only water when allowed choices of fluids. However, as we will see next, it does not ingest only water.

When confronted in the laboratory with a free choice of multiple bottles, one bottle containing water and the others containing different mineral solutions, the cellular-dehydrated rat, similar to the extracellular-dehydrated rat, ingests less water and selects to ingest solutions containing minerals (Constancio et al. 2011; David et al. 2008a; Pereira et al. 2005). The chosen minerals are preferentially sodium—mainly in the form of sodium bicarbonate—or potassium.

Such nuances in mineral intake may derive from mechanisms evolved in the wild where water with dissolved minerals, and not pure water, is apparently the norm (Blake et al. 2011). Yet, whatever the actual reason there is for a cellular-dehydrated animal to ingest sodium or potassium, recall that ion excess is dealt with through increased excretion by normal kidneys (Fitzsimons 1961; Kutscher 1966; Schoorlemmer et al. 2000). So, osmotic concentration of the ECF is readjusted to predisturbance levels by a combination of behavior and renal function.

This is why we should not be misled by looking separately at the intake or at the renal output of an ion and forgetting what happens to the ECF. For example, circadian urine potassium excretion of humans may differ about 60–70% from low to high peak levels (Moore-Ede 1986). In general human population, however, the concentration of potassium in the ECF varies within a range of 25% variation (Guyton and Hall 2000), far smaller than the variations in renal potassium excretion. Moreover, if we examine potassium concentration in the ECF under laboratory-controlled conditions we may find signs of tighter regulation. For example, in either pregnant or nonpregnant goats, circadian plasma potassium concentration may differ about 7–8% from low to high peak levels, even considering larger concurrent changes in hormones that control renal potassium excretion (Skotnicka 2003).

A second major example suggests that the control of osmotic and sodium homeostasis is more complex than a simple negative feedback when it occurs along with mechanisms that regulate the volume of ECF. An introduction to such complexity involving the simultaneous regulation of both ICF and ECF in terms of control theory may be found elsewhere (Carpenter 2004). Here, we only would like to recall some neural and endocrine mechanisms to illustrate the same point.

What would an animal that has double dehydration, of both ICF and ECF, do first—drink water or ingest salt? If your answer is to drink water, you may be right. The powerful dipsogen angiotensin II, mentioned throughout this book, is produced in response to dehydration of the ECF. The same angiotensin II also induces sodium appetite (Sakai et al. 1989). However, there is a delay in the production of sodium appetite, operationally defined as increased ingestion of hypertonic NaCl, related with the time length of dehydration. The dilution hypothesis suggests that angiotensin II produces water intake (thirst) first; sodium appetite comes next as the ingested water dilutes the ECF and removes an inhibition produced by angiotensin II itself (Stricker and Verbalis 1990). According to the hypothesis, the mechanism seems to be protecting an already dehydrated animal from further cellular dehydration by preventing excess ingestion of osmolytes. A protective mechanism against cellular dehydration is also suggested by several studies with the lateral parabrachial nucleus (LPBN; Chapters 3, 9, 10, and 11).

Initial work established in the mid-1990s that a dipsogenic dose of angiotensin II injected in the lateral cerebral ventricles also immediately produces hypertonic NaCl intake, in a two-bottle choice test, in rats that received bilateral injection of a serotonergic antagonist in the LPBN region (Menani et al. 1996). A similar result was obtained in the early phase of sodium depletion when sodium appetite is still absent and usually only thirst is present (Menani et al. 2000). Later, it was shown that serotonergic antagonism in the LPBN of rats with quickly induced sodium appetite, as produced by a combination of furosemide plus low dose of captopril (see Chapter 14 for different procedures to induce sodium appetite), enhanced only hypertonic NaCl intake, with no effect on isotonic NaCl intake (David et al. 2008b). Although these results suggest a protection mechanism selective to hypertonic NaCl, the mechanism is perhaps not that simple because recent preliminary data suggest that the blockade of serotonin receptors in the LPBN may also enhance isotonic NaCl intake of cellular-dehydrated rats (David et al., unpublished data).

The main point here is to emphasize that a behavioral mechanism may apparently involve “errors”—for example, animals’ choice for dissolved minerals when cellular-dehydrated—not predicted by the osmometric theory, and perhaps not even predicted if we assume that homeostasis results from a simple, direct, negative feedback. The mechanism to achieve osmotic, sodium or potassium homeostasis and the aforementioned examples naturally involve not only brain pattern generators that command the behavior to initiate and terminate the ingestion of minerals and water, but also effector systems such as the kidney. The brain and the kidney may operate through feedback and feedforward mechanisms that result in homeostasis. Therefore, it is not too much to say again that, although the homeostatic mechanism as proposed by Cannon (1929) fits mostly a reactive, direct negative feedback, there are other mechanisms that make homeostasis possible to occur (Carpenter 2004; Moore-Ede 1986). The definition of homeostasis has its own validity independently from the type of animal machinery that produces it.


We have drawn some examples from body fluid homeostasis to address the concept of homeostasis under the definition proposed originally by (Walter Cannon 1929). The definition refers particularly to the constancy of physical–chemical constituents (homeostatic categories) of the ECF in a changing external environment. Whatever control mechanism ingrained in the animal machinery, reactive or predictive, to produce it, homeostasis is valid as long as we apply Cannon’s definition. In this context, homeostasis remains a valid concept to describe the state of body fluids of mammals as regulated by neural and endocrine mechanisms.


Research of the authors and the preparation of this book were supported by CAPES, CNPq, FAPESP, FAPESP-PRONEX, FUNDUNESP, PROPe-UNESP, and PROPG-UNESP.


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This contrasts with the flexible osmotic concentration of the ECF found in aquatic invertebrates (e.g., Freire et al. 2008)—which hardly fits Cannon’s definition of homeostasis.

© 2014 by Taylor & Francis Group, LLC.
Bookshelf ID: NBK200958PMID: 24829984


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