Introduction. The body's water balance is maintained primarily by regulating the osmolality of the body fluids. The loss of hypotonic fluid by the lungs and the skin tends to increase the osmolality and the intake of fluids by mouth tend to reduce the osmolality. The osmotic pressure of the extracellular fluid is maintained at a constant level primarily by regulation of water excretion by the kidney through the action of antidiuretic hormone (ADH).

A. ADH, also called vasopressin, is a nonapeptide that is produced in the magnocellular system of the hypothalamus, specifically within cells of the supraoptic and paraventricular nucleus (Fig. 7-1). The hormone is synthesized and packaged in neurosecretory granules with a protein, neurophysin. The granules flow along the axons of these cells to the nerve endings in the posterior pituitary where they are stored. ADH is released from the nerve endings by exocytosis in response to stimulation of the neurons.

Fig. 7-1. The negative feedback mechanism that regulates the
osmotic concentration of the extracellular fluid.

B. A negative-feedback reflex mechanism regulates the osmotic concentration of the ECF by controlling the secretion of ADH (Fig. 7-1). The stimulus is a rise in ECF osmotic concentration. The sensors are osmoreceptors located in the anterior hypothalamus near the neurons that manufacture ADH. These receptors are sensitive to changes in their intracellular volume or osmotic concentration caused by changes in the effective osmotic concentration of the fluid surrounding them. Axons of the receptors evidently impinge on the secretory neurons, and impulses are transmitted from the receptors to the secretory neuron endings in the posterior pituitary. The released ADH triggers increased water reabsorption. This, coupled with continued solute excretion, reduces the osmotic concentration of the ECF, providing the negative feedback to the osmoreceptors that induces a fall in the rate of ADH release.

Fig. 7-2. The relationship between the plasma osmotic concentration and plasma ADH concentration. The maximum effective concentration is that which causes the kidney to maximally concentrate the urine.

C. The range of plasma osmotic concentration that can change plasma ADH concentration from the threshold level to the maximum effective concentration is only 15 mosmole/kg H₂O, from 280 to 295 mosmole/kg H₂O (Fig. 7-2). This small variation in plasma osmolality acting through the ADH mechanism can cause the urine osmotic concentration and flow rate to vary from 50 mosmole/kg H₂O and 20 L/day to 1200 mosmole/kg H₂O and 0.8 L/day. At osmotic concentrations below 280 mosmole/kg H₂O, the level of ADH in plasma is relatively constant at about 0.5 picograms/ml (pg/ml, 10^-12 g/ml). When plasma osmolality rises above that threshold concentration of about 280 mosmole/kg H₂O, ADH secretion is stimulated (Fig. 7-2). The maximally effective concentration of ADH, that is, the concentration that brings about the maximum urine osmotic concentration, is reached when the plasma osmotic concentration rises to 294 to 295 mosmole/kg H₂O. The exquisite sensitivity of this feedback mechanism is such that a change of 1% in the plasma osmotic concentration (~3 mosmole/kg H₂O) causes a change in plasma ADH concentration of 1 pg/ml, which is sufficient to alter urine osmolality by about 250 mosmole/kg H₂O. In an individual weighing 70 kg, this change can be produced by drinking 400 to 450 ml or 14 oz of water.

D. Not all solutes are equally effective as osmotic stimuli for ADH secretion, NaCl and mannitol are very effective; urea is much less effective. A rise in blood glucose concentration in the presence of adequate insulin has no effect at all on ADH secretion. In the absence of insulin, it has a small stimulating effect. Physiologically, a change in NaCl concentration as the result of water loss is probably the most important stimulus.

QUESTIONS: 
1. How will the ADH regulatory mechanism respond to a 24 hr period in which there is no water intake?

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