Vasopressin administration to neonatal rats reduces antidiuretic response in adult kidneys

Peptides,

Vol. 4, pp. 827-832, 1983. ~ Ankho International Inc. Printed in the U.S.A.

Vasopressin Administration to Neonatal Rats Reduces Antidiuretic Response in Adult Kidneys G A l L E. H A N D E L M A N N ,

I J A M E S T. R U S S E L L

Laboratoo, o f Cell Biology, N I M H , Bethesda, M D 20205 HAROLD GAINER

Laboratory o f Neurobiology and N e u r o i m m u n o l o g y , N I C H D , Bethesda, M D 20205 ROBERT ZERBE AND MOHAMMED

BAYORH

Laboratory o f Clinical Science, N I M H , Bethesda, M D 20205 R e c e i v e d 3 J u n e 1983 HANDELMANN, G. E., J. T. RUSSELL, H. GAINER, R. ZERBE AND M. BAYORH. Vasopressin administration to neonatal rats reduces antidiuretic response in adult kidneys. PEPTIDES 4(6) 827-832, 1983.--Neonatal rats who had been given injections of vasopressin on days I-7 after birth exhibited polyuria as adults. In vivo antidiuresis bioassays demonstrated that their kidneys were deficient in their ability to concentrate urine in response to stimulation with vasopressin. The kidneys also showed a reduction in vasopressin-induced cyclic AMP production, although parathyroid hormone- and calcitonin-induced levels were normal. This suggests a specific deficit in vasopressin receptor-adenylate cyclase function. In contrast, the neonatal treatment had no effect on the sensitivity of the adult vasculature to the hypertensive effects of vasopressin. These results show that short exposures to high levels of vasopressin early in development can produce a long-term defect in vasopressin responsiveness that is specific to the kidney. Vasopressin

Kidney

Development nephron. The second is to cause vasoconstriction. In neonatal rats, AVP is similarly secreted in response to dehydration [1, 18, 19], but the response of the kidney to the hormone is not fully developed, in part due to the lower receptor content of the neonatal kidney [28,33]. Little is known about the development of the pressor response to AVP. In order to determine whether neonatal exposure to high levels of AVP could influence the development of the kidney, we injected neonatal rats with AVP during a period of rapid development of the kidney, the first week after birth [15, 28, 40]. When the rats were mature, their water intake, urine volume, and blood pressure were measured. In addition, the sensitivity of the kidney and vasculature to the actions of AVP were measured by physiological assay. In addition, the ability of AVP to stimulate adenylate cyclase activity in the kidney was investigated, as AVP-induced cyclic AMP production is important in the mechanisms of osmoregulation (for reviews see [12,22]).

I N C R E A S I N G evidence indicates that hormones play a different role in the developing animal than they do in the adult. While in the adult they activate the cells of their target organs to perform various functions, in the immature organism they tend to organize the cells so that they develop into a functional unit. This phenomenon has been well established for the gonadal hormones, which are responsible for sexual differentiation and maturation (see [6,41] for reviews). By manipulating the amount and type of gonadal hormones present in the neonatal rat, the later function of the reproductive organs, as well as sexual behavior, can be permanently altered. Similar effects have been shown for other hormones. Thyroxine, for example when administered to neonates negatively influences growth of the thyroid, independent of effects on total body growth [2, 14, 32], while A C T H administration causes hypertrophy of the adrenal glands [30]. The present experiments investigated the possibility that another neuropeptide hormone, vasopressin (AVP), influences the development of its target organs. In the adult rat, AVP is secreted from the posterior pituitary in response to increases in plasma osmotic pressure or decreases in plasma volume. Two actions of pituitary AVP have been identified. One is to increase reabsorption of water from the distal tubule and collecting duct of the kidney

METHOD

Subjects and Peptide Treatment Three litters of Osborne-Mendel rats were cross-fostered

tRequests for reprints should be addressed to Dr. Gail Handelmann. Lab. Cell Biology, NIMH, Bldg. 10 Rm. 4N312, Bethesda, MD 20205.

827

828

H A N D E L M A N N ET AL. TABLE 1 DAILY WATER I N T A K E AND U R I N E V O L U M E , IN ml A D U L T RATS+ T R E A T E D WITH VASOPRESSIN ON DAYS 1-7 AFTER BIRTH (MEAN + S.E.M.)

Treatment

(n)

Water Intake

p

Urine Volume

p

PBS (control) Epinephrine (40 pg/100 g) Arginine Vasopressin (40 ktg/100 g) Lysine Vasopressin (40 ktg/100 g)

(6) (6)

30.2 _+ 2.3 25.2 + 2.0

-0.1

5.8 + 0.3 5.3 + 0.4

(6)

33.3 _+ 1.0

0.1

10.0 + 1.0

0.01"

(6)

35.4 _+ 1.6

(1.05"

11.8 + 1.4

0.01"

-0.1

*Statistically different from control by Student's t-test, p<0.05. ",Rats tested for seven consecutive days beginning day 40 after birth.

and the litters culled to 8 pups each. Beginning the day after birth (neonatal day I) and ending neonatal day 7, each pup received daily subcutaneous injections of one of the following preparations, dissolved in phosphate-buffered saline (PBS): (11 arginine vasopressin (AVP, Calbiochem, 395 U/rag; 40/xg/100 g body weight); (2) lysine vasopressin (Ferring, 200 U/mg; 40 ~g/100 g); (3) epinephrine (Sigma; 40 /,tg/100 g); (4) PBS alone. The assignment of pups within a litter to treatment groups was done at random. Each mother raised pups of a variety of treatments. The pups were weaned on day 23. These rats were used for measurement of water balance and antidiuresis in response to AVP. Other litters in which the pups were injected with either AVP or PBS were used for measurement of blood pressure and cAMP formation in the kidney. Bioassays Water balance. After day 40, the rats were housed individually in metabolic cages. Water intake and urine excretion were measured daily for seven consecutive days. A VP-stintulated vasopressor response. Each rat was anesthetized with halothane, pithed, and the mean arterial blood pressure was monitored as previously described [17]. After resting blood pressure was determined, standard doses of AVP were administered via the femoral vein. A VP-induced atttidiuresis. The effect of standard doses of AVP on urine volume and osmolarity was measured in continuously hydrated, anesthetized rats. The procedure was similar to one described previously [8]. Each rat was anesthetized with sodium thiopental (15 mg/100 g body weight; Abbott, Chicago, IL), and continuously hydrated with a hypoosmotic glucose-saline solution via the femoral vein. The rat was initially hydrated to 10% of its body weight in one hour, then perfused continuously with an hourly volume equivalent to 5% of its body weight to insure a constant rate of water clearance by the kidneys. Urine samples were collected from the bladder every ten minutes using an LKB fraction collector. The volume of each sample was measured, and the samples were capped to prevent evaporation before the osmolarity was measured by freezing point depression, using an Advanced Instruments osmometer. When a consistent baseline was established, standard doses of AVP ranging from l0 to 1000/,LU dissolved in the hydrating solution were administered via the femoral vein. After the

injection of each dose, 4 or 5 samples were collected to allow the volume and osmolarity of the urine to return to baseline before the next dose. A VP-Stimulated c A M P Formation At 90 days of age or more, the rats were decapitated and their kidneys rapidly removed and placed in ice cold Robinson's solution [11]. The kidneys were decapsulated and sliced into 250 p,m thick sections with a Sorvall tissue chopper. Six adjacent sections were removed and divided among three round-bottomed polyethylene test tubes, each containing 2 ml of Robinson's solution, in an incubator bath at 37°C. Each tube was continuously aerated with a gas mixture of 95% oxygen and 5% carbon dioxide. After a 15 minute incubation, the slices were transferred to fresh Robinson's solution. Two slices from each kidney were placed in medium containing 1 /xM AVP (0.2 U/ml), 250 p,M parathyroid hormone (PTH; 10 U/ml), 29 nM calcitonin (CT; 1 /xg/ml), or medium without hormone. These doses of hormone have been shown to stimulate maximal cAMP formation in rat kidney tissue [9,21]. The slices were incubated for 30 minutes with continuous aeration, then removed from the medium and frozen on dry ice. The frozen sections were homogenized by sonication in 1 ml of 6% TCA and extracted four times with water-saturated ether. The samples were lyophilized, resuspended in 0.05 M sodium acetate buffer (pH 6.2), and the cAMP content was measured by radioimmunoassay (New England Nuclear RIA Kit). Protein content of the samples was measured by the method of Lowry et al. [26]. Cyclic AMP content was expressed in terms of picomoles per mg protein. RESULTS

There was no difference in the mortality or rate of growth between the treatment groups. Their weights did not differ when measured at day 7 or 40. Water Balance The daily water intake and urine volume for each treatment group is shown in Table 1. The rats treated after birth with either form of vasopressin produced about twice as much urine daily as the PBS- or epinephrine-treated rats. Their water intake was also slightly greater, although the

KIDNEY RESPONSE TO VASOPRESSIN

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TABLE 2 INCREASES

IN M E A N A R T E R I A L P R E S S U R E IN R E S P O N S E (A m m H g , M E A N +_ S . E . M . )

TO VASOPRESSIN

Vasopressin Dose (/xg/kg Body Weight) Treatment

n

0.03

0.10

0.30

1.00

Neonatal PBS Neonatal AVP

6 6

10 _+ 2 11 + 1

26 _+ 7 28 -+ 5

85 _+ 6 83 -+ 8

89 _+ 7 83 _+ 8

200 10-

• NEONATAL AVP O NEONATAL SALINE

>I'-

150

~; 2 0 -

< ,...I <

O >

O9 0

~ 30-

_z 100-

re"

n"

U.l

O9 <

? -

I.Ll

O9 < 40U.I n-"

¢r

W

Z

I.Ll

50

~50 • N E O N A T A L AVP

60-

10

O N E O N A T A L SALINE

10

50

I

I

t

I

100

200

400

1000

[ A V P ] , ~U 70 10

~ 50

J 100

~ 200

~ 400

d 1000

[AVP],MU FIG. 1. Percent decrease in volume of 10 minute urine samples obtained after intravenous injection of AVP in bioassay of diuresis. The doses of AVP are shown in/zU per injection. The mean baseline volume of the AVP-treated and control rats was 0.98_+0.1 ml/10 rain (n 6) and 1.07___0.06 ml/10 min (n 6), respectively.

i n c r e a s e was only statistically different f r o m t h e c o n t r o l v a l u e in t h e c a s e o f the rats t r e a t e d with lysine v a s o p r e s s i n . T h e s e results indicate that the n e o n a t a l v a s o p r e s s i n h a d a l o n g - t e r m effect o n diuresis in t h e rat. T h e effect was p r o b ably not d u e to the v a s o p r e s s o r activity o f v a s o p r e s s i n , bec a u s e e p i n e p h r i n e , w h i c h also has v a s o p r e s s o r activity, did n o t p r o d u c e the s a m e effect. ( T h e n e o n a t a l rats i n j e c t e d with A V P s h o w e d a c l e a r b l a n c h i n g r e s p o n s e following the injections b e g i n n i n g o n d a y 2. T h e rats injected with e p i n e p h r i n e b l a n c h e d b e g i n n i n g t h e first d a y o f injection, n e o n a t a l d a y 1. This suggests that although the n e o n a t a l v a s c u l a t u r e is c a p a b l e o f v a s o c o n s t r i c t i o n at day 1, t h e A V P - m e d i a t e d p r e s s o r r e s p o n s e is not f u n c t i o n a l until d a y 2.)

FIG. 2. Percent increase in osmolarity of l0 minute urine samples obtained after intravenous injections of AVP in bioassay of diuresis. The mean baseline osmolarity for the AVP-treated and control rats was 314-+40 mosm/1 and 328_+71 mosm/I, respectively.

Vasopressor Response T h e t w o g r o u p s did not differ in t h e i r resting arterial pressure or, as s h o w n in T a b l e 2, in the A V P - s t i m u l a t e d inc r e a s e s in arterial p r e s s u r e at a n y dose. T h e s e results indicate t h a t e x p o s u r e to high levels o f v a s o p r e s s i n o n n e o n a t a l d a y s 1-7 d o e s not affect t h e sensitivity o f the v a s c u l a t u r e to AVP.

A VP-Stimulated Antidiuresis In r e s p o n s e to A V P , urine v o l u m e d e c r e a s e s a n d o s m o larity i n c r e a s e s . A s s h o w n in Fig. 1, at e a c h dose of A V P the c o n t r o l rats s h o w e d a g r e a t e r d e c r e a s e in urine v o l u m e t h a n did the A V P - t r e a t e d rats. Similarly, the c o n t r o l rats s h o w e d a g r e a t e r i n c r e a s e in urine o s m o l a r i t y at e a c h d o s e o f 100/xU or g r e a t e r (Fig. 2). T h e o s m o l a r i t y o f the urine o f the A V P t r e a t e d rats r e a c h e d a plateau at a b o u t 20% a b o v e b a s e l i n e , while t h e urine o s m o l a r i t y o f t h e c o n t r o l rats rose to a b o u t

830

HANDELMANN E T A L . TABLE 3 cAMP C O N T E N T OF K I D N E Y SLICES: H O R M O N E - S T I M U L A T E D I N C R E A S E S O V E R BASAL L E V E L S (pmol/mg PROTEIN/30 M I N U T E S : MEAN + S.E.M.)

Hormone Treatment

(n)

Neonatal PBS

(9)

Neonatal AVP

(10)

A VP

PTH

Cq

1.6 ~: 0.4

1.6 + 0.3

2.6 + 1.1

0.7 ~: 0.1 ~+

2.1 +: 0.3

2.8 + 0.6

*Statistically different from Neonatal PBS, Student's t-test, p<0.01.

200% of baseline at the highest dose of AVP. These results indicate a reduced ability of the kidneys of the AVP-treated rats to respond to AVP in adulthood. A VP-Induced +AMP Formation

In the absence of AVP or other hormones, kidney slices from control and neonatally treated rats contained 6.7_+0.6 and 5.4_+0.7 pmol/mg protein, respectively. These values are not statistically different, and are comparable to those found in kidney tissue by other techniques (for example [9, 27, 29]. In the control rats' kidneys, both AVP and PTH stimulated formation of about 1.6 pmol of cAMP over baseline, while CT stimulated about 2.6 pmol (Table 3). In the kidneys of the AVP-treated rats, however, AVP stimulated formation of only 0.7 pmols, while PTH and CT induced formation of normal amounts. This suggests that the effect of neonatal AVP administration is associated with a reduction in the AVP receptor-mediated formation of cAMP. The lack of change in PTH- or CT-stimulated cAMP suggests that the effect is specific to the AVP receptor complex in the kidney tubules. DISCUSSION

These experiments demonstrate that a short exposure of the neonatal rat to high levels of an endogenous peptide hormone, vasopressin, has a long-lasting deleterious effect on the vasopressin-mediated osmoregulatory function of the kidney. The insensitivity of the kidneys to AVP, caused by the neonatal treatment, appears to be related to a deficit in the AVP-receptor mediated formation of cAMP. This deficit in cAMP formation could be due to either a reduced number of AVP receptors, decreased binding efficiency of the receptors, or an impairment of the receptor-adenylate cyclase coupling. Furthermore, such deficits may be secondary to abnormal morphological development, such as a shortening of the convoluted tubules [10] or abnormal growth of the epithelium of the ascending limb [24]. The fact that PTH- and CT-stimulated adenylate cyclase was unaffected by the treatment, however, suggests that the effect was specific to the AVP receptor complex. Previous experiments suggested that exposure to high levels of AVP might influence the developing kidney. For example, Brattleboro rats given daily doses of 500 mU during the first month after birth showed higher water intake and lower urine osmolarity than did untreated Brattleboro rats six weeks after the treatment was stopped [42]. This may also indicate an impairment of the AVP receptor-adenylate cyclase complex, despite the fact that Brattleboro rats lack AVP, as oxytocin has been proposed to mediate some

amount of water balance in these rats [3, 16]. Oxytocin interacts with the AVP receptor [34] and causes formation of hypertonic urine in normal rats and rats with hereditary diabetes insipidus [3,16]. As circulating levels of oxytocin in the Brattleboro rat are several times higher than in normal rats, the peptide may be responsible for a small amount of water reabsorption. In another experiment, the offspring of pregnant rats treated with a synthetic AVP analog, dDAVP, showed a transient alteration in their capacity to produce hypertonic urine [25]. The fact that prenatal treatment caused a transient impairment while postnatal treatment caused a permanent one may indicate a critical period for the developmental effect on the kidney. In this experiment, the AVP treatment did not influence the sensitivity of the vasculature to AVP. There may be a different developmental period during which the vasculature is susceptible to peptide influences, or it may not be susceptible at all. Physiologically, the vasculature is less sensitive to AVP than the kidney; antidiuresis can be produced by plasma levels that have no effect on blood pressure [38]. The doses of AVP required to influence the development of the vasculature may therefore be higher than those that influence the kidney. Pharmacologically, the AVP receptor of the vasculature differs from that of the kidney. The vascular receptor has a different affinity profile for various structural analogs of AVP [7,39]. In addition, it has been suggested that the vascular receptor is primarily linked to calcium influx and not to adenylate cyclase [13,31]. Whether such differences could determine susceptibility to the developmental effect remains to be investigated. There are a number of conditions in which the developing kidney might be exposed to abnormally high levels of AVP, either because of a pathological condition or because of high maternal levels. In humans, inappropriate secretion of AVP may be associated with tumors, hemorrhage, and neurological, pulmonary, and endocrine diseases [4]. In addition, st large number of common therapeutic drugs release AVP from the pituitary, including analgesics, diuretics, and tricyclic compounds [4]. Finally, cigarette-smoking is a potent releaser of AVP, through inhalation of nicotine [20,36]. Increasing attention is being focused on the developmental effects of peptide hormones. For example, several neuropeptides, including MSH, [met] enkephalin, and betaendorphin, have long-lasting effects on behavior when administered to neonates [5, 23, 37]. These effects may be due to alterations in the sensitivity of neural systems to peptide neurotransmitters. A related effect has recently been shown for a non-peptide neurotransmitter, dopamine. When dopamine antagonists are administered to pregnant rats, the oft~pring have fewer brain dopamine receptors [35]. This

K I D N E Y R E S P O N S E TO V A S O P R E S S I N

831

effect could be due to either an a b s e n c e o f the n o r m a l ligand o r to o c c u p a t i o n o f the r e c e p t o r by the a n t a g o n i s t . T h e results o f the p r e s e n t e x p e r i m e n t s , along with t h e s e p r e v i o u s

results, raise the possibility that a d m i n i s t r a t i o n o f n e u r o p e p tides during d e v e l o p m e n t has long-lasting effects on the sensitivity o f their various target organs to t h o s e p e p t i d e s .

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HANDELMANN

El" A L .

41. Watterson, R. L. (Ed.) Hormones in Development, Chicago: Univ. Chicago Press, 1956. 42. Wright, W. A. and C. L. Kutscher. Vasopressin administration in the first month of life: effects on growth and water metabolism in hypothalamic diabetes insipidus rats. Pharmac'ol Biochem Behav 6: 505-509, 1977.