Factors in Release of ADH

As early proposed by Gilman and Goodman (1937) and Verney (1947), some stimulus associated with negative water balance is probably the usual stimulus to A D H release. W a t e r deprivation results in the depletion of neurosecretory material in the neurohypophyses of m a n y mammals, though changes in the hypothalamus are not as marked (see review by Howe and Jewell, 1959). I n white rats, pituitary activity decreases from 215 m U . per gland after 48 hours of deprivation to 10 m U . after 120 hours (Dicker and Nunn, 1957), and after 10 days the neural lobe is histologically almost depleted of neurosecretory material. I n contrast, desert rodents such as Meriones meriones show little or no detectable change even after months on a dry diet (Howe and Jewell, 1959; Legait and Legait, 1962).

Osmotic pressure is an effective stimulus in dogs. Intracarotid injections of hypertonic saline result in inhibition of diuresis proportional to the degree of hypertonicity created. Only a 2 % increase in plasma osmotic

124 Robert Μ. Chew pressure is effective in reducing diuresis to 1 0 % of its maximum value (Verney, 1947). However, an osmoregulatory mechanism has not been demonstrated for any other m a m m a l ; efforts to provoke it in the r a t have failed (Brown and Ginsburg, 1954).

From the results of Verney (1947), verified by Zuidema and Clark (1957), the osmoreceptors would seem to be narrowly located in the vascular bed of the internal carotids. Neurons of the hypothalamic nuclei m a y them­

selves be osmoreceptors (Scharrer and Scharrer, 1954). Stimulation of the paraventricular nuclei in the goat causes A D H release (Andersson and McCann, 1955); electrical stimulation anywhere within a large area of the hypothalamus of the dog results in antidiuresis (Fang et al, 1961). However, the d a t a of Velikanova (1958) suggest t h a t there are other widely dis­

tributed osmoreceptors. He found t h a t antidiuresis could be provoked in dogs by intracarotid injections only if diuresis was not exceeding 5 ml. per minute. But, after transection of the spinal cord at T8, injection caused inhibition at any level of diuresis. Velikanova concluded t h a t when the water load is above a certain point, nerve impulses from overhydrated receptors outside the internal carotid vascular area are able to counteract the stimulation of the dehydrated receptors within the area.

Volume receptors m a y also be involved in release of A D H (Welt, 1956;

Zuidema et al, 1956; Wrong, 1957; Baratz and Ingraham, 1960; Share, 1962).

Release of A D H has been demonstrated following various emotional and stressful stimuli: in rats excited by forcible handling (Schnieden and Blackmore, 1954) and drinking 2 . 5 % saline (Scharrer and Scharrer, 1954);

in dogs excited by view of a cat, and during mild exercise (Klisiecki et al, 1933b); after a disagreeable subcutaneous faradic shock, and during nursing in the rabbit (Cross, 1951); during subcortical stimulation of the brain in m a n and rhesus monkeys, especially the amygdaloid complex (Dingman and Gaiton, 1959; Hayward and Smith, 1961). I n lactating white rats, A D H activity of the pituitary reaches a minimum ( 5 3 % of normal) on days 14-15 of lactation, while neurosecretory material is least at 18-22 days (Rennels, 1958). Goats, however, were never observed to release A D H after painful or emotional stimuli (Andersson and Persson, 1958).

Exposure to heat is followed by a release of A D H . This is possibly due to stimulation via the temperature receptors (Itoh, 1953), but Robinson and Macfarlane (1956) feel it is only the result of heat dehydration. They found in white rats t h a t repeated daily 2-hour heat exposures, causing loss of one-twelfth of B⁰ did not cause release of A D H , in spite of a 2.7° rise of T^r, but 4-hour exposures, with loss of one-sixteenth B⁰ did. Exposure of

sheep to T^a 40° results in A D H release in summer but not in winter. T h e A D H content of h u m a n serum increases in summer and decreases in winter, possibly in adjustment to seasonal changes in water loss (Yoshimura, 1958).

Histological d a t a suggest t h a t when rats are exposed to continuous light, more neurosecretory material is secreted and released t h a n normal, whereas continuous darkness suppresses secretion (Fiske and Greep, 1959).

Emotion, heat exposure, exercise, lactation—these are all events t h a t lead to increased loss of water, hence the physiological value of a correlated release of A D H .

Both the dog and the rat can maintain water balance after neurohypo-physectomy although they cannot deal with "water balance emergencies"

(Verney, 1947). Though the blood plasma m a y remain free of A D H activity for as long as a year after neurohypophysectomy in the dog (Blackmore and Chester, 1956), neurosecretory material is demonstrable in the hypo-thalamic nuclei (Scharrer and Scharrer, 1954). I n totally hypophysecto-mized white rats, the severed stalk becomes reorganized within 5^ months into tissue t h a t can store neurosecretory material and t h a t contains A D H (Billenstien and Leveque, 1955). R a t serum A D H activity returns to normal 30 days after hypophysectomy (Lloyd and Pierog, 1955). I t would be very interesting to observe water balance in desert rodents with normal high titer of A D H , following neurohypophysectomy or hypothalamic lesions.

4> Other Hormonal Influences

a. Adrenal cortical hormones (ACH). T h e concept t h a t water balance is achieved by opposing effects of t h e neurohypophysis and t h e adrenal cortex was originally developed by Silvette and Britton (1938a) from their work on opossums. This and recent work on the rat is reviewed by Jones (1956, 1957) and G a u n t et al. (1957).

For the rat it is clearly indicated t h a t A C H is necessary for the excretion of a water load; the mere absence of A D H is not sufficient. A D H in the absence of A C H has a natriuretic effect which is normally dominated by A C H in the intact animal. Although the plasma is quickly depleted of N a⁺ in adrenalectomized animals, N a⁺ values remain near normal if the neuro-hypophysis is also removed.

A C H is also important in regulating E C W volume when there is an isotonic increase of volume (Wrong, 1957).

T h e response of marsupials to adrenalectomy is essentially like t h a t of placentals, as shown by the work on Didelphis marsupialis (Silvette and Britton, 1936, 1938a,b; Britton and Silvette, 1937) and Setonyx brachyurus (Buttle et al., 1952). I n adrenalectomized placentals there is reduced

in-126 Robert Μ. Chew testinal absorption of water, increased excretion of sodium with accom­

panying loss of water and dehydration of the body, followed by reduced urine volume and hemoconcentration and greatly increased toxicity of water loads.

Adrenalectomized Gerbillus gerbillus can still excrete high urine con­

centrations, relative to nondesert rodents, and increase concentration further when given added salt, but normal urea concentrations cannot be reestablished by replacement therapy (Burns, 1956).

b. Oxytocin. A D H and oxytocin are released from the posterior pituitary nearly simultaneously in several situations (Abrahams and Pickford, 1954).

I n dehydration both A D H and oxytocin are depleted from the posterior lobe (Dicker and N u n n , 1957). Exogenous oxytocin alone causes an increase in osmolar clearance when the urine being formed is not too dilute, and A D H and oxytocin (1:20) produces both an antidiuretic effect and increased clearance (Dicker, 1957). Oxytocin preparations alone m a y increase water excretion of the rat (Croxatto et al., 1956), having a greater diuretic effect in thirsting t h a n in hydrated animals (Peters, 1959), and, while delaying the diuresis of a water load, increase the total amount finally excreted (Berde and Cerletti, 1956). Intravenous doses of synthetic oxytocin (100 mU./kg.) cause considerable diuresis in dogs (Horster et al., 1959). Adam-sons et al. (1956) and Lederis (1962) give analyses of A D H : oxytocin in t h e hypothalamic-hypophyseal tissues of the camel and dog, and review d a t a for other large mammals.

c. Epinephrine. In goats epinephrine can cause a brief (5-10-minute) polyuria if the kidney is not forming hypertonic urine at the time (Anders­

son, 1955). Langston and Guyton (1958) have demonstrated a dual effect in the dog. If blood pressure is held constant it is possible to observe a direct effect on the kidney resulting in reduced urine volume; however, this is normally masked by the effect of increased arterial pressure which increases G F R and t h u s urine volume. Epinephrine m a y also indirectly influence water metabolism through an effect on liver tissue. Medullecto-mized rats have a reduced capacity of the liver to inactivate vasopressin, an increased serum A D H activity, and, probably as a consequence, a lower t h a n normal diuretic response; all these are corrected by epinephrine injections (Toyomasu and Itoh, 1961).

d. Intermedin. Comparative studies of the anatomy of the pituitary glands of mammals suggest t h a t the relative development of the inter­

mediate lobe is related to the aridity of a species' environment and to its ability to tolerate dehydrating conditions (Legait and Legait, 1962). I n the desert rodents t h a t were examined, and in white mice, the pars inter­

media is 1 4 - 2 7 % of the total volume of the pituitary. I n mammals t h a t are

able to survive only a few weeks on a dry diet, the relative volume is 7 - 1 2 % , whereas in aquatic rodents and fruit-eating mammals it is as little as 0.2%.

T h e intermediate lobe is absent in cetaceans and sirenians.

I n Meriones crassus kept on a dry diet, there is an involution of t h e intermediate lobe, while the anterior pituitary remains unchanged and t h e posterior lobe increases slightly in size. Cytological changes suggest t h a t material elaborated by the intermediate cells is used up. However, the intermedin activity of t h e pituitary tissue has decreased only slightly in Μ.

crassus after 96 days, and antidiuretic activity is almost normal. I n white rats deprived of water, intermedin activity decreases during the first day and is negligible by the twentieth day. T h e intermediate lobe m a y play an indirect role in water metabolism by an effect on the metabolism of the amino acids t h a t constitute the hormones of the neurohypophysis (Legait and Legait, 1960).