J. Physiol. (1979), 292, pp. 407-420

407

With 5 text-figure8 Printed in Great Britain

SODIUM, POTASSIUM AND WATER METABOLISM IN THE RABBIT: THE EFFECT OF SODIUM DEPLETION AND REPLETION

BY SHEILA A. GRACE*, K. A. MUNDAY AND A. R. NOBLE From the Department of Physiology and Pharmacology, University of Southampton, Southampton S09 3TU (Received 28 September 1978) SUMMARY

1. Dietary sodium depletion and subsequent repletion was studied in rabbits. Potassium intake was maintained constant. 2. During sodium depletion and repletion blood pressure, packed cell volume, food consumption and body weight remained at control values. 3. Decreased sodium excretion was observed in both urine and faeces during sodium depletion and the physiological control of these changes is discussed in relation to the renin-angiotensin-aldosterone system. 4. Potassium excretion during sodium depletion initially fell as a result of reduced urine volume and gradually returned to normal. Urine potassium concentration remained constant. 5. Faecal excretion of potassium rose by 63 % during sodium depletion and there was a rise from a control value of 17-25 % in the proportion of total potassium excretion accounted for by the faecal component. 6. Water consumption and urine volume both decreased in the initial phase of sodium depletion and then returned to control levels. 7. It is important to consider both urinary and faecal excretion of sodium and potassium when calculating balance status for either ion. Faecal excretion, as well as kidney function, shows important physiological adaptations. INTRODUCTION

In a series of papers published over 40 years ago, McCance described the alterations in the volume and composition of body fluids which follow dietary sodium restriction in man. It was also noted that compensatory changes occur in the output of sodium and potassium in urine and sweat (McCance & Widdowson, 1937; McCance, 1938). Subsequent studies using dogs (Field, Dailey, Boyd & Swell, 1954), demonstrated that dietary sodium restriction altered faecal excretion of sodium and potassium as well. Since the early studies, considerable attention has been directed towards the elucidation of the component physiological mechanisms involved. The dominant endocrine responses to sodium depletion are based on the reninangiotensin-aldosterone system. Renin secretion from the kidney is increased during *

Present Address: Department of Pathology, University of Bristol.

0022-3751/79/4410-0758 $01.50 © 1979 The Physiological Society

408 SHEILA A. GRACE, K. A. MUNDA Y AND A.R. NOBLE sodium depletion, both in experimental animals and in man (reviewed by Vander, 1967; Davis & Freeman, 1976). Aldosterone secretion is controlled by at least four variables, circulating levels of angiotensins II and III, ACTH, sodium and potassium. This, and other possible aspects such as a role for prostaglandins, has recently been reviewed by Peach (1977). The production of aldosterone and the angiotensins leads to altered sodium and potassium handling in both the kidney and the gut. In the past, interest in sodium and potassium excretion has centred mainly on kidney function. Work on the gut has primarily related to in vitro investigations of the mechanism of action of hormones on transporting epithelia. Faecal excretion of sodium and potassium has largely been ignored as an adaptive and variable entity. Another aspect of interaction between the functions of the two excretory organs has become apparent. Where intake of sodium is changing, it has been widely assumed that triggering of the appropriate endocrine responses to modify renal function occurs after ingested sodium has been absorbed. Such a series of events may be too slow to account for the time course involved and it has now been suggested, from studies on the rabbit and man, that sodium intake is monitored somewhere in the gut or portal circulation (Lennane, Peart, Carey & Shaw, 1975b; Lennane, Carey, Goodwin & Peart, 1975a). This mechanism appears to be independent of aldosterone secretion (Carey, Smith & Ortt, 1976). In addition to the broad relationships between gut and kidney function, it is now known that permissive interactions between the ions contribute to over-all sodium and potassium balance. Potassium, in addition to sodium, is important in the control of renin secretion (Brunner, Baer, Sealey, Ledingham & Laragh, 1970). Reduced intake of potassium attenuates the adrenal response to exogenous angiotensin and raised levels of potassium in the diet have been directly associated with increased aldosterone synthesis. The action of aldosterone on transporting epithelia involves a sodium-potassium linked pump mechanism although the stoichiometry of this is the subject of debate (Sharp & Leaf, 1973). It is now recognized that altered sodium permeability is also an important aspect of the action of aldosterone. Sodium and potassium cannot then be considered in isolation, but many existing studies of the effects of dietary sodium depletion have neglected to control potassium intake adequately. Some of the changes reported therefore may reflect alterations in potassium intake. A further problem in experimental design has been that authors have studied, what they assumed to be, steady-state conditions of sodium depletion. In the absence of a time-course study an interesting dynamic phase was missed, whilst, at the same time, it was not truly established whether a new steady-state had indeed been reached. Because of this, and other, published data it became important to reinvestigate fundamental aspects of sodium depletion taking cognizance of factors which have previously been overlooked. In the present study sodium and potassium excretion in both urine and faeces were monitored over a period of 54 days during sodium depletion and repletion with constant potassium intake. The changes in circulating levels of active and inactive forms of renin in these animals are described in the succeeding paper (Grace, Munday, Noble & Richards, 1979).

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METHODS

LoW sodium diet A diet was prepared as follows from crude cereals which had a low sodium content: maize meal (4-0 kg), wheat meal (2-6 kg), bran (1-0 kg), barley meal (3-6 kg), toasted soya bean meal (5*8 kg), corn oil (1.2 1.), dried yeast (1-0 kg), calcium phosphate (200 g), methionine (20 g), calcium carbonate (200 g), vitamin A (160,000 i.u.), vitamin D (320,000 i.u.). Dry constituents were thoroughly mixed before addition of the vegetable oil. The diet was moistened with distilled water, pelleted and dried at 35 'C. In this form the low sodium diet contained 6 mi-mole sodium/kg and 260 m-mole potassium/kg. Control diets were produced by adding 134 m-mole sodium/kg before pelleting, to give a final sodium content of 140 m-mole/kg. Stock laboratory diet for rabbits (RAG-Christopher Hill Ltd.) was found to contain 150 m-mole sodium/kg and 300 m-mole potassium/kg. Normal rabbit diets used by other authors have sodium contents in the range 123-680 m-mole/ kg and low sodium diets in the range 2-4-8 m-mole/kg (Braverman & Davis, 1973; Steele & Lowenstein, 1974; Johnson, Stubbs, Stanton, Payne, Ichikawa & Keitzer, 1977). The potassium content of normal diets used by these authors was in the range 355-467 m-mole/kg but in each case there was a drop of at least 50% in the potassium content comparing the low sodium diet to the normal diet. Potassium contents of these diets were in the range 85-230 m-mole/kg. Gavras, Brown, Lever & Robertson (1970) described a low sodium diet containing 5-6 m-mole sodium/kg and 15-2 m-mole potassium/kg. Although this had the advantage that sodium chloride could be added to give a normal or high sodium intake the potassium content of the diet was abnormally low.

Animals Nine New Zealand White rabbits (3-0-4-5 kg) of either sex were used. Animals were weaned onto the control diet described above and used for experimentation at 7 months old. Growth rate up to this time was not significantly different to a group of rabbits fed on routine laboratory diets. The animals were maintained in metabolism cages so that distilled water and food consumption could be monitored together with urine and faeces production. The experimental protocol was as follows: 18 days control diet (control period) followed by 18 days low sodium diet (depletion period) with a further 18 days on the control diet (repletion period). The following parameters were recorded every day: water and food consumption, urine volume, urinary sodium and potassium concentrations, faecal sodium and potassium content. At 3-day intervals blood pressure, packed cell volume and body weight were measured and a plasma sample retained for measurements of plasma renin activity. Plasma sodium and potassium concentrations were measured in a preliminary series of five rabbits subjected to the same dietary regime. No significant changes were observed in plasma sodium (141-5 ± 2-1 mM) or potassium (4-1 ± 0-2 mM) during either sodium depletion or repletion.

Sodium and potawsium estimations Sodium and potassium were measured using an integrating flame photometer (Evans Electroselenium). Food and faecal samples were refluxed for 24 hr in concentrated nitric acid. The resulting solution and urine samples were diluted as appropriate before estimation of sodium and potassium. Blood pressure measurement Systolic blood pressure was measured non-invasively using a Grant-Rothschild capsule (Grant & Rothschild, 1934).

Statiatioal analysis of results Results are shown as mean + s.E. of mean of data from nine rabbits. Statistical analysis was by paired Student's t test.

410

SHEILA A. GRACE, K. A. MUNDA Y AND A. R. NOBLE RESULTS

Food consumption and body weight Food consumption during the three phases of the experiment is shown in the lower histogram on Fig. 1. No significant changes were recorded. The mean food consumption of approximately 90 g per day provided the animals with an intake of 12-5 mi-mole sodium/day during the control and repletion periods and an intake of 0 55 m-mole sodium/day during sodium depletion. There was no evidence of increased consump-

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411 SODIUM, POTASSIUM AND WATER METABOLISM tion of food as a possible compensation for low dietary sodium content. Potassium intake was maintained at approximately 24 m-mole/day throughout the experiment. Sodium and potassium intakes have not been widely reported although Carey et al. (1976) found an intake of 9-11 m-mole sodium/day for normal diets and 0-3 m-mole sodium/day for low sodium diets. No potassium intake data was given. Body weight did not change during the course of the experiment, remaining at a mean of 3-9 kg (Fig. 1). This is in contrast to results reported by Lowenstein, Boyd, Rippon, James & Peart (1972) and Lennane, Peart, Carey & Shaw (1975b) who found that dietary sodium restriction caused a decrease in body weight.

Blood pressure and packed cell volume Indirect blood pressure recordings from the central ear artery are shown in the upper histogram of Fig. 1. Blood pressure did not change significantly from a mean of 67 mmHg throughout the experiment. This value, obtained using the GrantRothschild capsule method, is comparable to the value of 77 mmHg reported by Morris, Davis, Zatzman & Williams (1977) after cannulation of the same blood vessel. Gavras et al. (1970), using the Grant-Rothschild capsule method, reported a mean value of 94 mmHg for rabbits on a low sodium diet. No change in blood pressure from a mean of 68 mmHg was recorded during sodium depletion by Braverman & Davis (1973). Packed cell volume also did not change during the course of the experiment, remaining at a mean of 40 %. There was, therefore, no indication of the haemoconcentration reported by Gotshall, Davis, Shade, Spielman, Johnson & Braverman (1973) and by Brubacher & Vander (1968) in sodium depleted dogs. Urine volume and water consumption Results for measurements of urine volume and water consumption are shown in Fig. 2. Mean urine volume in the control period was 106-5 + 3-2 ml./day. This fell by 20% (P < 0O01) at the start of sodium depletion and then rose progressively back towards control values while the animal was still receiving the low sodium diet. A rise in urine flow of approximately 20 % (P < 0.01) was observed on return to the control diet. Again urine production fell towards control levels over the 18-day repletion period. Changes in water consumption paralleled the changes in urine volume. From the control value of 194 + 5-5 ml./day there was an initial fall of 12 % (P < 0-01) at the start of the depletion period. Water consumption returned to normal levels over the 18-day depletion period and then increased by 20 % (P < 0'001) when the animals entered the repletion phase. The elevated consumption fell back towards control levels during sodium repletion. Excretion of sodium in the urine andfaeces Urinary concentration of sodium is shown in the upper histogram on Fig. 3. From this, and the data for urine volume shown on Fig. 2, the urinary excretion rate for sodium was calculated. This is displayed on the middle histogram of Fig. 3. Total sodium excreted in the faeces is shown on the lower histogram of Fig. 3.

412 SHEILA A. GRACE, K. A. MUNDA Y AND A. R. NOBLE During sodium depletion there was a fall in sodium excreted in the urine from approximately 10 m-mole/day to only 5 % of this figure (P < 0001). As urine volume changes were relatively small, the decreased excretion reflected a drop from 90 to 5 mm in sodium concentration in the urine. In the second three day period of the repletion phase sodium excretion in the urine rose above control levels by 30 % 180 160 140

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(P < 0-01) and again fell progressively back towards control levels. The changes in urinary excretion of sodium were complete 5 days after both changes in diet. Reduced faecal excretion of sodium also contributed to sodium conservation during the low sodium diet phase. Under control conditions the faecal sodium excretion was 2-5 m-mole/day, equivalent to one quarter of the total sodium excreted in the urine.

413 SODIUM, POTASSIUM AND WATER METABOLISM The increase in retention of sodium in the gut was not as efficient as in the kidney but, nevertheless, faecal sodium excretion was reduced by 78 % during the depletion period. This important adaptation in gut function has been widely ignored by 120 E 100 C

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authors who have calculated sodium balance data purely on the basis of urinary excretion rates for sodium (Braverman & Davis, 1973; Lennane et al. 1975 b; Carey et al. 1976). Faecal excretion of sodium attained normal levels again during the second three day period of the repletion phase.

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SHEILA A. GRACE, K. A. MUNDA Y AND A. R. NOBLE

Excretion of potassium in the urine andfaeces Results for potassium excretion in the urine and faeces are shown on Fig. 4. The urinary concentration of potassium, which was approximately 210 mm, did not -i 240

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change significantly through the entire time course of the experiment. There were some relatively minor changes in urine volume, however (shown in Fig. 2), and these are reflected as the changes in urinary potassium excretion shown in the middle histogram of Fig. 4. Control potassium excretion was 20 m-mole/day and when

SODIUM, POTASSIUM AND WATER METABOLISM 415 urine volume fell at the start of sodium depletion there was, correspondingly, a 10 % drop in potassium excretion (P < 0.01). This returned to normal with the restoration of normal urine flow rates. The increased urine volume at the start of the repletion period also gave a 20% (P < 0001) increase in urine potassium excretion. Faecal excretion of potassium during sodium depletion is shown in the lower histogram on Fig. 4. There was a rise to 63 % above control levels (P < 0-001) from a +8 U

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control value of 3-9 + 0-2 to 6-3 + 0-4 m-mole/day. During the sodium repletion phase faecal potassium excretion returned towards control levels but, at a mean of 5-0 + 0.1 m-mole/day, was still above control levels 18 days after re-feeding the control diet. This represents a relative shift in potassium excretion from urine to faeces during sodium depletion as the percentage of total potassium excretion accounted for by faecal excretion rose from 17 to 25 %.

Sodium and potassium balance Sodium and potassium balances were calculated by subtracting the total excreted in the urine and faeces from the amount consumed in the diet (Fig. 5).

416

SHEILA A. GRACE, K. A. MUNDA Y AND A. R. NOBLE During the control and repletion periods, the rabbits had a small positive sodium balance and a negative potassium balance. In contrast. sodium depletion caused a negative sodium and a positive potassium balance. The largest changes in sodium balance were mirrored in the potassium balance. The negative sodium balance of 2-5 m-mole/day at the beginning of sodium depletion was accompanied by a positive potassium balance of 3 0 m-mole/day. At the beginning of sodium repletion, there was a large positive sodium balance of 7*5 m-mole/day and a corresponding negative potassium balance of 5-5 m-mole/day. DISCUSSION

The novel low sodium diet formulation reported in this paper allowed a reassessment of the effects of sodium depletion in the rabbit. A diet with a normal level of sodium was produced by adding sodium chloride to the low sodium diet before pelleting. Potassium content was therefore the same in both diets. As food intake did not change following transition from one diet to the other, the dietary potassium intake was constant, even though sodium intake was reduced by 95 % when feeding the low sodium diet. Body weight, packed cell volume and blood pressure were unchanged throughout the 54-day course of the experiment. As expected, there were striking changes in renal excretion of sodium which was reduced to 5 % of control values during depletion (Fig. 3). Increased aldosterone secretion under these circumstances has been reported by many authors, in several different species, and this probably constitutes the main basis for the increased sodium retention in the kidney (Blair-West, Coghlan, Cran, Denton, Funder & Scoggins, 1973; Braverman & Davis, 1973; Oelkers, Brown, Fraser, Lever, Morton & Robertson, 1974; Campbell, Schmitz & Itskovitz, 1977). Sodium depletion sensitizes the adrenal cortex to angiotensins II and III leading to increased aldosterone production. The proportion of the total sodium and water retained which is directly attributable to aldosterone secretion is debatable. In the longer term increased sodium retention following activation of the renin-angiotensin system may involve other mechanisms. An angiotensin-dependent change in intrarenal haemodynamics and glomerular filtration rate has been suggested (Hall, Guyton, Trippodo, Lohmeier, McCaa & Cowley, 1977; Hall, Guyton, Jackson, Coleman, Lohmeier & Trippodo, 1977). Another action of angiotensin II, studied by Harris & Young (1977), is a dosedependent effect on sodium reabsorption in the kidney tubule. Increased sodium retention occurs at physiological concentrations of angiotensin II. It may be seen in Fig. 5 that, excluding the first 3 days of depletion, the rabbits were close to neutral sodium balance. This reflects the ability of the nephron to increase sodium absorption. The other component of this new stable situation was an increase in intestinal sodium reabsorption leading to a 78 % reduction in sodium excreted in the faeces (Fig. 3). This aspect of sodium metabolism has been widely ignored in the past and many authors have calculated, from data for food consumption and urine output of sodium alone, that rabbits on low sodium diets are in negative sodium balance. This may still be true but it is not necessarily a valid conclusion on the basis of the measurements made. There are, of course, other components of sodium balance which cannot be easily assessed such as the sodium losses in sweat

417 SODIUM, POTASSIUM AND WATER METABOLISM and moulted fur. These are quantitatively small and can generally be ignored in gross balance calculations. Elevated levels of aldosterone also have a sodiumretaining effect on the salivary and sweat glands (Sharp & Leaf, 1973). Reduced faecal excretion of sodium in response to sodium depletion has been reported by other workers (Edmonds, 1967). The cellular mechanisms involved in this and other forms of mineralocorticoid excess have been studied (Edmonds & Marriott, 1970). In addition, direct effects of angiotensin on the gut may contribute to the enchanted absorption of sodium (Bolton, Munday, Parsons & York, 1975). The effects of sodium depletion on urinary potassium excretion have been less widely studied, especially in animals for which dietary potassium was maintained constant during sodium restriction. Conflicting observations have been reported. Malnic, Klose & Giebisch (1966) found reduced urinary potassium excretion in sodium depleted rats whereas Laragh & Capeci (1955) had shown no change in potassium excretion in sodium depleted dogs. A recent paper by Peterson & Wright (1977) suggests that reduced potassium excretion during sodium depletion occurs as a result of a change in collecting duct, rather than distal tubule, function. In the present paper no significant changes were observed in potassium concentration of the urine during sodium depletion but, at the beginning of depletion, urine volume fell by 10 % and there was a corresponding decrease in the total amount of potassium excreted. With the return of urine flow rate to normal levels in the latter part of the depletion period the potassium excretion also attained control levels. Potassium excretion in the faeces increased by 63% during sodium depletion. Increased faecal excretion of potassium has been reported by Field et al. (1954) in the sodium depleted dog and by Edmonds (1967) in sodium depleted rats. The observation that changes in faecal sodium and potassium occur in opposite directions could be taken to indicate an involvement of mineralocorticoids. But, the coupling of the excretory mechanisms for the two ions is by no means rigid and a dissociation in the time course of the changes was noted. Sodium excretion reached minimum levels after nine days whereas the maximum increase in potassium excretion was not achieved until twelve days into the repletion period. In addition, faecal excretion of sodium returned relatively quickly to control levels during the repletion period. Faecal potassium excretion was still above control levels eighteen days after the change in the diet. Other authors have also found a dissociation of the effects of aldosterone on sodium and potassium movements. Dolman & Edmonds (1975) showed that, in the proximal colon, aldosterone-stimulated sodium transport was accompanied by increased chloride absorption but, in the distal colon, it was principally a sodiumpotassium coupled exchange pump that was affected. It is also possible that angiotensin II contributes directly to the movement of sodium without affecting potassium excretion (Bolton et al. 1975). However, Dolman & Edmonds (1975) showed that the effect of sodium depletion in stimulating sodium uptake and potassium excretion was abolished by adrenalectomy but not affected by nephrectomy. The concurrent measurement of both faecal and urine potassium excretion in the present study allowed calculation of the relative amounts of potassium excreted in these two components. During sodium depletion the proportion accounted for by the faecal component increased from 17 to 25 %. Sodium depletion resulted in an initial 20 % fall in both water intake and urine 14

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volume. This subsequently returned to control volumes while the rabbits were still, receiving the low sodium diet. A polvdipsic response to dietary sodium restriction has been reported previously (Huang, 1935; Cizek, 1961). However, other dietary constituents, in addition to sodium chloride, were also changed in these studies. We can only speculate about the mechanisms involved. Water intake and excretion are clearly linked, but which, if either, of these variables is the primary event has not yet been ascertained. Angiotensin II is a very potent dipsogen and there are many reports of the effects of injecting this compound at various intracranial sites (Fitzsimons, 1976). Doubts have been expressed whether the components of the reninangiotensin system could cross the blood-brain barrier. Ganten, Minnich, Granger, Hayduck, Brecht, Barbeau, Boucher & Genest (1972) found an angiotensin-forming system in brain tissue. The co-identity of this enzyme with renal renin has recently been established (Hirose, Yokosawa & Inagami, 1978). It had previously been suggested that the angiotensin forming enzyme in the brain was a non-specific acidprotease. Although a renin-angiotensin system may exist in the brain, it has now been demonstrated that angiotensin administered systemically will also stimulate thirst. Infusions of angiotensin into dogs produced a dipsogenic response. The circulating levels generated in this way were within the range reported to occur in sodium depleted dogs (Fitzsimons, Kucharczyk & Richards, 1978). In the experiments reported in the present paper water consumption fell at the time of the initial rise in renin and aldosterone secretion. This change is in the opposite direction to those one would predict from the known effects of angiotensin on thirst mechanisms discussed above. It is likely that suppression of water consumption was secondary to changes in water reabsorption in the kidney. Again, there is no clear picture of the role played by the renin-angiotensin system. It is probable that water follows the sodium absorbed as a result of increased angiotensin and aldosterone levels. It has also been suggested that angiotensin II directly stimulates ADH release. Other workers have failed to confirm this however and the controversy has been discussed by McDonald, Miller, Anderson, Berl & Schrier (1976). This investigation weas carried out wh ile S. A. G. was in receipt of a Medical Research Council Studentship. We also wish to thank the National Kidney Research Fund for financial support. We are grateful to Professor T. G. Taylor for advice on the composition of the low sodium diet.

REFERENCES

BLAIR-WEST, J. R., COGHLAN, J. P., CRAN, E., DENTON, D. A., FUNDER, J. W. & ScoGGINs, B. A. (1973). Increased aldosterone secretion during sodium depletion with inhibition of renin release. Am. J. Physiol. 224, 1409-1414. BOLTON, J. E., MUNDAY, K. A., PARSONS, B. J. & YORK, B. G. (1975). Effects of angiotensin II on fluid transport, transmural potential difference and blood flow by rat jejunum in vivo. J. Phygiol. 253, 411-428. BRAVERMAN, B. & DAVIS, J. 0. (1973). Adrenal steroid secretion in the rabbit: sodium depletion, angiotensin II and ACTH. Am. J. Physiol. 225, 1306-1310. BRUBACHER, E. S. & VANDER, A. J. (1968). Sodium deprivation and renin secretion in unanaesthetised dogs. Am. J. Physiol. 214, 15- 2 1. BRUNNER, H. R., BAER, L., SEALEY, J. E., LEDINGHAM, J. G. G. & LARAGH, J. H. (1970). The influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects. J. din. Invest. 49, 2128-2138.

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Sodium, potassium and water metabolism in the rabbit: the effect of sodium depletion and repletion.

J. Physiol. (1979), 292, pp. 407-420 407 With 5 text-figure8 Printed in Great Britain SODIUM, POTASSIUM AND WATER METABOLISM IN THE RABBIT: THE EFF...
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