Adults ingest between 1.5 and 2.5 L of fluid a day. Another 300 to 400 mL are produced daily via metabolic reactions. Daily outputs exactly balance these inputs in healthy individuals: 1.0 to 2.0 L excreted in urine, 100 mL excreted in the feces, 50 mL excreted in sweat, and approximately 1000 mL excreted through exhalation of air and surface evaporation. Insensible fluid loss refers to the loss of fluid from respiration, evaporation, sweat, and other drainage. As highlighted in Figure 19-2, fluid ingestion and urine excretion are the only variables under the precise control of neural and hormonal stimuli.

Although the amount of fluid we drink each day is influenced by dietary and social influences, the ultimate control over whether we ingest an adequate
amount of fluid is exerted by the thirst center located in the hypothalamus at the level of the third ventricle. Thirst is sensed by hypothalamic osmoreceptors that increase their rate of firing with increased plasma osmolarity (i.e., decreased water concentration). When activated, these osmoreceptors, along with neighboring cells that sense blood pressure, signal the hypothalamus to increase the release of antidiuretic hormone (ADH, also called vasopressin) from the posterior pituitary gland (see Chapters 9, 13, and 18). ADH has two major effects. The first and most important is to increase the permeability of the renal collecting ducts of the kidney to water (see Chapter 18). Increased permeability of the collecting ducts allows water to be reabsorbed out of the urine back into the blood, thereby diluting the plasma back toward normal (and so reducing the stimulus for ADH release). The second effect of ADH is to act as a pressor, an agent causing a rise in blood pressure; its other name is vasopressin. In this role, ADH causes a constriction of vascular smooth muscle and an increase in blood pressure (see Chapter 13). The increase in blood pressure also reduces the stimulus for continued release of ADH.

A second hormone, angiotensin II, also has a direct effect on the cells of the hypothalamus to increase the sensation of thirst. It, too, is an important dipsogenic (thirst-stimulating) hormone.

As the major extracellular ion in the body, sodium is responsible in large part for determining plasma osmolality and is also important in maintaining membrane potential and neural conductance. The regulation of plasma sodium is mainly achieved by the kidney, which freely filters and then reabsorbs at least 98% of filtered sodium. The remaining 2% is reabsorbed or excreted into the urine, depending on the presence or absence of the hormone aldosterone; increased aldosterone increases sodium reabsorption back into the blood by acting at the level of the distal tubule of the kidney (see Chapter 18). Low levels of aldosterone lead to the excretion of all or some of the final 2% of sodium in the urine.

Aldosterone is secreted from the adrenal cortex following stimulation by the hormone angiotensin II. A brief summary of this hormonal system, presented in detail in Chapter 18, is as follows: Angiotensin II is produced after a cascade of reactions initiated by the hormone renin released from the juxtaglomerular cells of the kidney. Renin is released in response to low plasma sodium and low blood pressure. As a result of an increase in angiotensin II levels, aldosterone release is stimulated, and sodium balance and blood pressure return toward normal; this process is an excellent example of a negative feed-back cycle.

Sodium output also occurs through small amounts lost in the sweat and in the feces. In times of excessive sweating or diarrhea, depletion of sodium from these routes can be life threatening.

Sodium ingestion is influenced by taste as well as by a homeostatic drive (salt appetite) to maintain sodium balance. Humans and other animals have a drive to ingest salt that is triggered by low plasma sodium. Humans and other animals also show a distinct preference for salt ingestion, a circumstance that for a minority of humans may contribute to salt-sensitive hypertension.

Potassium, the major intracellular ion in the body, plays a vital role in determining cell membrane potential. Although extracellular potassium concentration is low, potassium level in the extracellular fluid is carefully regulated, because changes in extracellular concentration can result in life-threatening disturbances in neural and cardiovascular function. Potassium can shift between the intracellular and extracellular compartments, depending on various neural and hormonal influences and the pH of the extracellular fluid. For example, beta-adrenergic nervous stimulation and insulin secretion both increase the movement of potassium intracellularly by stimulation of the Na⁺/K⁺ pump. In contrast, decreasing the pH of the plasma may increase the movement of potassium out of the cell.

The source of potassium in the body is that ingested in the diet. Excretion of potassium is primarily through the urine, with a small amount lost in the
sweat and the feces. The major controlling factor over total body stores of potassium is the hormone aldosterone.

As described in Chapter 18, the maintenance of potassium balance is achieved by the kidney. Potassium is freely filtered across the glomerulus and then at least 80% is reabsorbed. If excess potassium has been ingested in the diet, the kidney can also secrete potassium into the urine to return to balance. If potassium is deficient in the diet, none is secreted into the urine and all is reabsorbed. Increased secretion (and so excretion) occurs in response to stimulation of the distal tubules of the kidney by the hormone aldosterone. Aldosterone is released from the adrenal cortex in response to angiotensin II, as described previously. Aldosterone release is also, to a lesser extent, stimulated directly by low plasma potassium and by an increase in the pituitary hormone adrenocorticotropin (ACTH).

Calcium is primarily an intracellular ion, with nearly 99% of its total body stores in bone and most of the remaining 1% stored intracellularly in other tissues. A very small amount of extracellular calcium either circulates bound to albumin; is complexed to nonorganic substances such as citrate, phosphate, or sulfate; or exists in an ionized form. Calcium in the ionized form is important for muscle contraction and a variety of enzymatic reactions. It is also required for most steps of the coagulation pathway. Calcium is ingested in the diet, filtered, reabsorbed, and excreted by the kidney. It is not secreted.

The control of serum calcium results primarily from changes in the secretion of parathyroid hormone from the parathyroid gland (see Chapter 9); decreased serum calcium stimulates increased parathyroid hormone secretion. Increased parathyroid hormone then acts in one of three ways to return serum calcium back toward normal: it (1) increases renal reabsorption of calcium; (2) stimulates bone breakdown to release bone calcium; or (3) stimulates the activation of vitamin D, thereby increasing calcium reabsorption across the gut. A second hormone, calcitonin, secreted from specialized cells of the thyroid gland, also exerts control over serum calcium levels. Calcitonin is released in response to increased serum calcium, and it acts to reduce serum calcium by causing a decrease in bone breakdown. Calcitonin also decreases calcium reabsorption by the kidney, further lowering serum levels. Serum calcium is inversely related to serum phosphate.

Phosphate is an intracellular ion that is vital for most metabolic reactions and is an essential component of ATP, DNA, and RNA. Phosphate also serves as a hydrogen ion buffer in plasma and urine. Approximately 85% of phosphate is stored in bone, with 14% in all other cells; less than 1% is extracellular. Phosphate is ingested in the diet and, in proportion to its ingestion, is filtered and excreted
in the urine. In the serum, it varies inversely with calcium. With renal failure, phosphate levels rise precipitously and result in low serum calcium levels.

Magnesium is primarily an intracellular ion that is stored in bone (50%), in body cells (49%), and in blood (1%). Magnesium is required for a variety of enzymatic reactions and is an important ion for DNA synthesis and RNA transcription, for translation, and for protein synthesis. Magnesium can bind to calcium receptors, either turning on the calcium response (mimicking) or blocking the effects of calcium. Magnesium is ingested in the diet and is filtered and excreted in the urine.

pH is a reflection of the ratio of acid to base in extracellular fluid. The pH in serum can be measured with a pH meter, or one can calculate it by measuring serum bicarbonate and carbon dioxide concentrations and placing these values into the Henderson-Hasselbalch equation, as shown in the following equation:

In this equation, HCO₃⁻ is the concentration of bicarbonate in the serum, and CO₂ is the concentration of dissolved carbon dioxide in the serum. The pK refers to the negative logarithm of the dissociation constant, K. The dissociation constant is a fixed value for the bicarbonate/carbon dioxide system at normal body temperature. It reflects the degree to which bicarbonate and carbon dioxide dissociate to accept or donate a hydrogen ion. For the bicarbonate/carbon dioxide system, pK is 6.1.

The pH reflects the hydrogen ion concentration of the solution. The greater the hydrogen ion concentration, the greater the acidity of the solution and the lower the pH. In contrast, the higher the pH, the lower the hydrogen ion concentration, and the more basic the solution.

An acid is any substance capable of liberating a hydrogen ion. Examples of acids include the substances in bold in the following formulas, all of which are shown giving up a hydrogen ion:

An acid can be strong or weak, depending on the degree to which it breaks down to liberate hydrogen ions. For example, hydrogen chloride (HCl) rapidly and totally breaks down into hydrogen and chloride ion; therefore, it is considered a strong acid. In contrast, few lactic acid molecules break down to hydrogen ion and lactate; therefore, lactic acid is considered a weak acid. The double arrow in each equation indicates that the reactions are reversible.

In each reaction above showing the dissociation (breakdown) of an acid, the substance produced in addition to the hydrogen ion is considered a base. A base is any substance that can accept a hydrogen ion, thereby taking it out of solution. Because each of these reactions is reversible, each substance produced with the hydrogen ion can rejoin with it and move the reaction in the opposite direction. Thus, these substances can be considered bases. These reactions are rewritten in the following formulas with the base in bold:

A base can be strong or weak, depending on the degree to which it accepts a hydrogen ion. Most acids and bases found in the body are weak.

Weak acids and weak bases make good buffers. A buffer is a substance that can either take free hydrogen ions from a solution or release hydrogen ions to a solution, thereby preventing large fluctuations in pH. There are three important buffer systems in the body: the bicarbonate-carbonic acid buffer system, the phosphate buffer system, and the hemoglobin buffer system.

The lungs rid the body of carbon dioxide. Although carbon dioxide itself is not an acid, it becomes one when it joins with water to form carbonic acid (Equation 19-2). The minute-by-minute regulation of plasma pH is controlled by an increase or decrease in the rate of respiration, thereby increasing or decreasing the exhalation of carbon dioxide. This system is possible because of the sensitivity of the respiratory center in the brain to free hydrogen ions (see Chapter 14), which usually vary in accordance with carbon dioxide.