The Role of Antidiuretic Hormone

I t is clear t h a t A D H functions to increase the permeability of the distal convoluted tubules and the collecting ducts to water; however, the specific action of A D H is not established. As indicated by the work of Koefoed-Johnsen and Ussing (1953) on toad skin, the hormone m a y increase mem-brane pore size and t h u s allow a greatly increased flow of water.

A D H m a y also influence permeability by an effect involving the inter-cellular cement in the collecting ducts. Ginetzinsky (1958) and Zaks and Titova (1959) describe conspicuous histological differences between the kidneys of diuretic, normal, and antidiuretic rats. Ginetzinsky (1958) also observed hyaluronidase in the urine of water-conserving mammals. This author proposes t h a t A D H stimulates an apocrine secretion by the epithel-ium of the collecting ducts which contains hyaluronidase, and t h a t this enzyme then depolymerizes the intercellular cement of the ducts, making t h e m much more permeable and allowing rapid reabsorption of water.

Observations supporting this hypothesis have been made by Dicker and Eggleton (1960. 1961), Krestinskaya (1961), Ginetzinsky and Vasil'eva (1961), and Stolarczyk and Manitus (1962). However, Berlyne refutes any relationship between the amount of hyaluronidase in the urine and the degree of hydration of the animal (Berlyne, 1960; Ginetzinsky and Berlyne, 1961). Several researchers have not been able to duplicate the histological findings of Ginetzinsky (Ginetzinsky, 1962).

118 Robert Μ. Chew The thickening of intercellular cement and basal membranes t h a t occurs in potassium-deficient animals, coincident with a reduced concentrating ability of the kidneys, is suggestive of the importance of the intercellular materials (Hollander et al., 1957; Oliver et al, 1957; Giebisch and Lozano, 1959).

Kashiwagi (1959) proposes t h a t vasopressin accelerates water absorption in renal tubules because of its effect in activating carbonic anhydrase within these cells.

2. Kidney Structure and Concentrating Ability

According to the current concept of nephron functioning, it should follow t h a t the maximum concentration of the urine is directly related to the length of the multiplier system, i.e., the thickness of the medulla, especially as it is prolonged into one or more papillae. The comparative study of mammalian kidneys by Sperber (1944) shows t h a t obvious papillae are present only in small mammals, i.e., the species t h a t have a more difficult water balance problem because of their greater ratio of evaporative surface to body mass. Small mammals t h a t inhabit semiarid or arid habitats typically have a very long papilla which projects into the upper end of the ureter. The larger mammals t h a t inhabit arid regions have thicker medullary layers t h a n those from mesic regions. T h e comparative d a t a of Table V I I I B , show a close correlation between relative medullary thickness and the concentrating ability of the kidneys. The relative numbers of nephrons with long loops of Henle (which penetrate deeply into the medulla) and of nephrons with short loops do not seem to have a significant effect on con­

centrating ability (B. Schmidt-Nielsen and O'Dell, 1961). As is to be ex­

pected, desert rodents have thick medullae, long papillae, and highly concentrated urine whereas the mountain beaver (Aplodontia rufa), which lives in a habitat t h a t makes water conservation unnecessary, has a thin medulla and cannot form a very hyperosmotic urine (Dolph et al., 1962).

Vimtrup and Schmidt-Nielsen (1952) found t h a t the histology of the kidney of Dipodomys is basically similar to t h a t of the white rat. Bentley (1955) gives an analysis of kidney structure in Setonyx brachyurus. Vogel (1959) gives comparative d a t a on kidney size, glomerular size, and filtration rate for a variety of domestic mammals.

3. Urea and Urine Concentration

This topic has been reviewed by B. Schmidt-Nielsen (1958). Urea ac­

cumulates in the interstitial fluid of the medulla, possibly by an active process as well as passively, and augments the concentration gradient due to electrolytes. A low-protein diet can reduce the concentrating ability of

the kidney, possibly because the accumulation of urea in t h e medulla is reduced (Levinsky and Berliner, 1959a). I n most mammals the maximum urine concentration t h a t can be achieved on a particular feeding regimen depends upon the relative amounts of urea and electrolyte present in the blood and, hence, in the glomerular filtrate. A higher osmolality of the urine is achieved when more urea is excreted, as in a urea or protein-loaded animal (Crawford et al, 1959; Radford, 1959). M o s t mammals have a greater ability to osmotically concentrate urea t h a n NaCl. However, this is not true of the beaver, pig, and Psammomys obesus (B. Schmidt-Nielsen et αΙ.^} 1961). In these species, the osmotic concentration of urea in t h e urine varies inversely with the degree of salt loading, and the total urine concentration is the same in both salt- and urea-loaded animals.

A t least some ruminants are able to conserve urea when they are de­

hydrated or on a low protein diet. Bos taurus, when fed a diet 1 2 % crude protein and given water, excretes 36.1 gm. of urea nitrogen per day, which is 7 0 % of the total nitrogen intake; animals on 4 % crude protein and with­

out water excrete 2.3 gm. of urea nitrogen per day, which is only 1 5 % of nitrogen intake. Bos indicus reduces its urea excretion to a lesser degree under the same conditions (Livingston et al., 1962). Urea excretion is also very low in camels and Merino sheep when t h e y are dehydrated; plasma urea m a y increase threefold in Merinos kept 6 days without water at high environmental temperatures (Macfarlane et al., 1961). Urea retention should aid in increasing urine concentration, a n d hence water conservation, and also save on the water otherwise needed for excretion of urea.

4. Tolerance of Drinking Salt Solutions

A mammal's kidneys do not have to be able to excrete a urine t h a t is more concentrated t h a n saline drinking water in order for the animal to

" m a k e a water profit" on the saline intake, since other water intakes (in food, from metabolism) provide a certain "unobligated urinary w a t e r " into which the salt of the drinking solution can be taken up (see Wolf et al., 1959;

Becker and Ginn, 1962). However, the slack in the osmotic space cannot be very great in an animal given air-dry food and saline drinking water, and the ability to survive on concentrated solutions certainly indicates unusual capacity of the kidneys t o concentrate urine.

M a m m a l s of arid regions have received particular attention in this regard.

T h e Mongolian gerbil (Meriones unguiculatus) can maintain normal body weight on 0.8 Μ N a C l and can derive some benefit from 1.0 Μ N a C l (Winkelmann and Getz, 1962). Citellus leueurus maintains itself on 0.8 Μ N a C l (Hudson, 1962) and Setonyx brachyurus can maintain water balance on 0.43 M, b u t not on 0.57 Μ (equivalent to sea water) (Bentley, 1955).

120 Robert Μ. Chew A 0.26 Μ NaCl drinking solution has no adverse effect on the general health of most Merino sheep (Peirce, 1957); growing heifers can maintain themselves in winter on 0.26 Μ NaCl, but are adversely affected by 0.21 Μ in the summer (Weeth and Haverland, 1961).

P a r t of the success of survival on saline solutions is in the drinking response to the solution; this m a y be the result of an adaptation to an environmental situation. Peromyscus rubidus, which inhabit salt marshes, survive in poor condition when drinking sea water, of which they drink 5 5 % less volume per day t h a n of fresh water; while, P. gambelii, from a mountain habitat, drink 3 9 0 % more sea water t h a n fresh water and die after 12-67 days (Fisler, 1962). Meriones unguiculatus drinks less of 0.2-0.6 Μ NaCl solutions t h a n of distilled water (Winkelmann and Getz, 1962).

The ability to survive the intake of highly saline solutions involves not only an exceptional ability of the nephrons to reabsorb water, but also an exceptional inhibition of the reabsorption of NaCl. Salt excretion without accompanying urine-concentrating ability will result in osmotic diuresis and, initially, extracellular dehydration. While, salt retention, in spite of concentrating ability, will lead to intracellular dehydration and electrolyte shifts. I t has not been determined for any m a m m a l just which of these phenomena is the limiting factor in their tolerance of saline solutions. The degree to which the two are independent is also not clear. Hudson (1962) found t h a t Citellus leucurus shows no significant increase in serum electro­

lyte after m a n y days drinking 0.6 Μ NaCl. A 1 0 % increase in serum osmotic concentration develops after 22 days on 0.8 Μ N a C l ; a similar increase occurs after 5-7 days without water at T^a 22°.

5. The Urinary Bladder and Water Reabsorption

I t is questionable if the urinary bladder plays an important role in water reabsorption. Howell and Gersh (1935) reported absorption of water from the bladder of one dry-fed Dipodomys agilis, but K. Schmidt-Nielsen and Vimtrup (1952) were not able to verify this with dry-fed D. deserti.

Johnson et al. (1951) found a considerable two-way exchange of water in the dog bladder (4 m m .³ per square centimeter per minute). Although there was no net exchange, the magnitude of the water movements indicates considerable possible absorption in any m a m m a l in which outward move­

ment of water is differentially greater t h a n inward movement. Levinsky and Berliner (1959b) found a decrease in urine urea of up to 4 0 % , and a consequent decrease in urine osmolarity, when urine is perfused through the ureter and bladder of dogs, at low rates of flow comparable to urine flows of animals on low-protein diets. Electrolytes passively pass through the wall of isolated dog bladder at rates depending on concentrations,

gradients, time, p H , and volume (Rapaport et al, 1960). The bladder clearly is not an impermeable reservoir, and bladder urine is not necessarily the same as tubule urine.

D . Hormonal Factors in Urine Volume Regulation

Urine flow is controlled by the kind and titer of hormones, particularly A D H and A C H , in circulation. External and internal factors t h a t control or alter these titers are t h u s directly involved in water balance.