INTESTINAL TRANSPORT OF SODIUM, POTASSIUM, AND WATER IN THE DOG DURING SODIUM DEPLETION

Transcription

1 GASTROENTEROLOGY Copyright 1967 by The Williams & Wilkins Co. Vol. 52, No.5 Printed in U.S.A. INTESTINAL TRANSPORT OF SODIUM, POTASSIUM, AND WATER IN THE DOG DURING SODIUM DEPLETION A. M. CLARKE, M.B., F.R.A.C.S., MARLYN MILLER, AND ROBERT SHIELDS, M.D., F.R.C.S.E., F.R.C.S. University Department oj S1trgery, Western Infirmary, Glasgow, Scotland It has perhaps been too readily assumed that the gut plays a passive role in the regulation of body composition, by absorbing what is presented to it in an efficient but uncontrolled fashion, and by passing to other organs and tissues the responsibility of guarding against deficiences and excreting excesses. We should like to present evidence that the absorption of electrolytes may not be so indiscriminate and that a degree of control may be exercised by the intestine in response to the body's needs. An animal deprived of salt will attempt Received April 22, Accepted December 2,1966. A preliminary communication of this work was given to the Surgical Research Society, Edinburgh, in 1963." Address requests for reprints to: Dr. R. Shields, University Department of Surgery, Royal Infirmary, Cardiff, Wales, United Kingdom. Dr. Clarke's present address is: Department of Surgery, University of Otago Medical School, Dunedin, New Zealand. Dr. Clarke was, for part of the time, supported by a Xuffield Dominion Travelling Fellowship in Medicine. Part of this work was supported by a grant from the Medical Research Council. This work was undertaken in the W cllcome Research Laboratories, University of Glasgow, Bearsden, to whose staff, under the direction of Professor W. L. Weipers, we are indebted for the excellent care and attention given to the dogs. Weare grateful to Sir Charles Illingworth for advice and encouragement, and for facilities in his department. G. D. Searle and Company kindly supplied spirono (SC 942), and the London Rubber Industries, Ltd., donated the rubber balloons. The technical assistance of Miss Jeanette James is acknowledged. We thank Dr. G. F. Eglinton and Mrs. Lawry of the Department of Chemistry of the University of Glasgow for their advice and assistance with the estimations of deuterium oxide. 846 to restrict the loss of sodium from the kidney, sweat glands, and salivary glands. That the intestine may share in this conservation of sodium was suggested by the work of Field et al.,2 who observed that, in dogs, depleted of sodium, the concentration of sodium in the ileal lumen and in the feces was reduced while that of potassium was increased. The concentration of electrolytes in the intestinal lumen is largely governed by the ability of the bowel to absorb or secrete both electrolytes and water. However, these substances are simultaneously exchanged in both directions across the intestinal mucosa. 3,4 The purpose of the present study was therefore to define the changes in the unidirectional rates of transport of sodium, potassium, and water at different sites in the intestine of the dog before, during, and after sodium depletion. In some of the experiments, spirono was administered to the dogs while they were deprived of sodium. Sodium depletion provides a powerful stimulus to the secretion of adrenal mineralocorticoids which can influence the movement of electrolytes across the intestinal mucosa. 5,6 Because spironos have been shown to block the intestinal action of aldosterone,7 their influence upon any effect which sodium depletion might produce upon the intestine seemed worthy of additional study. Methods Experimental preparation. In 6 female mongrels, weighing 1 to 15 kg, Thiry-Vella fistulae were prepared from the jejunum (2 dogs), the ileum (2 dogs), and the colon (2 dogs). The fistulae of jejunum (both 16 em long) were fashioned from small intestine 1 cm distal to the duodenal-jejunal junction. The ileal fistulae, approximately 22 em long,

2 May 1967 ELECTROLYTES DURING SODIUM DEPLETION 847 'were constructed from bowel 1 em cranial to the ileocecal junction. The fistulae of colon were prepared from the cranial two-thirds of the large intestine. In each case these dimensions provided a serosal surface area of approximately 1 em'. The fistulae could accommodate 35 ml of fluid without any appreciable increase in the intraluminal hydrostatic pressure. The intestinal fistulae were irrigated daily with isotonic saline solutions. Experiments were begun 4 weeks after the preparation of the isolated intestinal segment. Production of sodium depletion. A state of sodium depletion was produced b y feeding the dogs with a low salt diet and by administering a cation-exchange resin (15 g of Katonium by mouth each day) to promote the loss of sodium in the feces. The daily diet, which consisted of thrice-boiled meat and salt-poor bread, contained 5 meq of sodium and provided approximately 1 calories. The dogs also r eceived each day 2 g of potassium chloride, 1 g of calcium gluconate, 1 mg of magnesium carbonate, and vitamins A, C, D, and B-complex. The total exchangeable sodium was measured in each dog by isotope dilutions using Na 2 ' before, and at the end of, the period of sodium depletion. In dogs C, D, E, and F the external losses of sodium were also measured by undertaking balance studies in a metabolic cage. The other parameters measured before and during sodium depletion included body weight and the concentrations of hemoglobin in the blood, of sodium in the serum, and of sodium' and potassium in the urine. The period of sodium depletion lasted 18 days in each dog. Measurement of intestinal tmnsport. Absorption experiments were performed before, during, and after the period of sodium depletion. Each experiment, which consisted of at least six 1-min tests with an interval of 3 min between each test, was begun at the same time of day to minimize a ny possible effect of circadian rhythm upon intestinal transport. For 24 hr preceding an experiment the animals were allowed only water ; during an experiment, dextrose solution (5% w Iv) was infused intravenously at a rate of 3 ml per hr to standardize the state o f hydration. Urine was collected at intervals by a catheter inserted into the bladder. While the tests were being performed, the dogs, which were not anesthetized, lay without restraint upon a specially constructed table. On several occasions spirono (SC 942) was given orally (1 mg), or by intramuscular injection (1 mg), 3 hr before the beginning of an experiment. Tests of absorption. Solutions were instilled into and withdrawn from the isolated intestinal segments through a multiperforated Foley catheter (French gauge, no. 16) modified by placing a b alloon 16 or 22 em from the tip.' A second Foley c atheter was inserted into the other end of the fistula and the balloons on both catheters were inflated to prevent leakage of the intraluminal solution. An experiment was begun by rinsing the lumen of the intestinal segment with modified Tyrode's solution'o at 37 C until the returning fluid was clear. The segment was emptied and left for 3 min. Exactly 25 ml of test solution were instilled into the segment. At 1 min as much as possible of the luminal solution was withdrawn. The volume of the test solution which could not be aspirated at the end of 1 min was calculated by measuring the radioactivity acquired by 1 ml of Tyrode's solution which, initially nonradioactive, was perfused through the bowe!." The bowel was allowed to drain freely for at least 3 min before the next test. Tests in which leakage occurred from the intestinal segments were abandoned. The test solution was modified Tyrode's solution containing the radioactive isotopes of sodium (N a 2., 2 fj.c per liter of solution) and of potassium (K", 4 fj.c per liter of solution) and the stable isotope of water, deuterium oxide (D2, 1 % v I v). The reaction of the test solution, measured by a glass electrode ph meter, was brought to ph 7 with.1 N hydrochloric acid. The test solution was kept in a stoppered flask in a water bath at 37 C. The radioactivities of the solutions were determined by simultaneous counting in a well type, thallium-activated, sodium iodide scintillation counter and in a liquid Geiger Muller counter (type M6 with a wall 1 mm thick). The technique of discrimination between Na 2 ' and K 42 was based on the method described by Veall and Vetter." Allowance was made for the "dead time" of the f1-counter and for radioactive decay during the course of the experiment. Deuterium oxide was determined by infrared spectrophotometry, using a modification" of the method described by Berglund-Larsson." The chemical concentrations of sodium and potassium in the test solution and in urine were measured by flame photometry. Terminology. The terminology used in this paper to describe the direction of movement of electrolytes and water is a modifica-

3 848 CLARKE ET AL. Vol. 52, No.5 TABLE 1. Changes in body weight and electrolytes, etc., during sodium depletion for 18 days Serum sodium Urinary Na:K ratio Hemoglobin Dog Site of fistnla Loss of weight a Loss of sodium b Before I During Before During Before I During depletion depletion depletion depletion depletion depletion % meq % meq/liter g/loo ml A Jejunum B Jejunum C Ileum D Ileum E Colon F Colon a Percentages given are the percentages of original weight. b Percentages given are the percentages of original exchangeable sodium. SODIUM FLUX ()JEq /1min.l 15 1 ~ c3>o I ;r- i I 1t 8 I = Insorption = Exsorption o ~ ~ ~------~ BEFORE DURING AFTER DEPLETION DEPLETION DEPLETION ( Control) (Controll FIG. 1. Rates of in sorption and of exsorption of sodium before, during, and after sodium depletion (data from dog D). Mean values are represented by the horizontal line in each group. 8 8 tion of that suggested by Code's and has been fully discussed elsewhere." Movement of a substance from the intestinal lumen into the body proper is referred to as insorption, while the movement of material in the opposite direction (from body into intestinal lumen) is termed exsorption. The difference between these unidirectional movements is called net movement. When the rate of insorption exceeds that of exsorption, absorption is said to occur, and, by convention, the rate of absorption is preceded by a plus sign. When the rate of exsorption is greater than that of insorption, the net movement is referred to as secretion; the rate of secretion is, by convention, preceded by a minus sign. Calculations of rates of movement. The rates of insorption of sodium, potassium, and water were calculated from the disappearance rates of the appropriate isotopes from the intestinal lumen by means of the formulas of Visscher et al. s., The net movements of sodium and potassium were derived from the differences between the total amounts (labeled and unlabeled) of the electrolytes in the test solution at the beginning and end of the lo-min test period. The net movement of water was calculated from the change in volume of the test solution. The rates of exsorption were then obtained by subtraction: 4 The assumptions and errors of the method have been discussed elsewhere." Results Clinical State The diet was palatable and throughout the period of depletion the animals remained in good health, although they lost some weight (table 1). Previous work has shown that dogs with Thiry -Vella fistulae of small bowel could be maintained in a state of sodium depletion for many weeks, but those in which two-thirds of the colon had been isolated as a fistula continued to lose sodium in the feces and within 3 or 4 weeks developed severe signs of salt depletion (A. M. Clarke et al., unpublished observations). Extent of Sodium Depletion All dogs suffered a loss of sodium (table 1). In 5 dogs the losses were similar in extent, within the range of 15 to 2% of

4 May 1967 ELECTROLYTES DURING SODIUM DEPLETION 849 the total exchangeable sodium. Although dog C did not apparently lose so much sodium, the low urinary Na:K ratio indicated avid conservation of sodium. The loss of body sodium and the reduction in body weight were closely correlated (r =.85; P <.5). During sodium depletion the concentration of sodium in the urine was invariably less than 1 meq per liter. Although alterations in the concentration of sodium in the serum were variable, hemoconcentration, as shown by elevated hemoglobin concentration, was observed in all dogs. Intestinal Transport of Sodium, Potassium, and Water In each dog the rates of transport of sodium, potassium, and water before and WATER FLUX (ml/1minj r e:.. o ):~ : 8 I = Insorption o = Exsorption c o o. POTASSIUM FLUX (f! Eq /1min ) d' I = Insorption = Exsorption o~-----'------' ' BEFORE DURING AFTER DEPLETION DEPLETION DEPLETION (Control) (Control) FIG. 2. Rates of insorption and exsorption of potassium before, during, and after sodium depletion (data from dog D). Mean values are represented by the horizontal line in each group. B o~----~----~---~ BEFORE DURING AFTER DEPLETION DEPLETION DEPLETION (Control) (Control) FIG. 3. Rates of insorption and exsorption of water before, during, and after sodium depletion (data from dog D). Mean values are represented by the horizontal line in each group. after the period of sodium depletion were similar (figs. 1 to 3). The results of the absorption tests performed before and after sodium depletion were therefore pooled to provide control data with which the rates during sodium depletion were compared. Because each dog served as its own control, errors arising from inaccuracies in measuring the surface area of the isolated intestine were avoided. Sodium transport (table 2). In all dogs there was evidence of increased intestinal absorption of sodium during salt depletion. In the jejunum the rates of absorption were significantly increased; in the ileum and colon, sodium, which under control conditions was secreted at low rates by the intestine, was absorbed when the dogs were deprived of salt. These alterations in net movement during sodium depletion were accompanied by a decrease in the rates at which sodium ions entered the intestinal lumen (fig. 1), exsorption being decreased

5 TABLE 2. Sodium transport under control conditions and during sodium, depletion with and without spirono a Direction of transport and type of experiment Jejunum Ileum Colon Dog A DogB Dog C Dog D DogE Dog F Insorption 1. Control 2649 ± ± ± ± ± ± 4 (15) (18) (17) (16 ) (7) (12) 2. Sodium depletion 2696 ± ± ± ± ± ± 46 without spirono- (12) (12) (17) (16) (16) (7) I Significance of differ- P >.8 P >.6 P <.5 P >.9 P >,1 P <.1 ence in mean rates between experiments 3. Sodium depletion - b 1168 ± ± ± ± 5 62 ± 84 with spirono- (1) (13) (1) (8) (6) Significance of differ- - P <.1 P>.8 P>,5 P >.1 P <.1 ence in mean rates between experiments Exsorption 1. Control 1878 ± ± ± ± ± ± 82 (15) (18) (17) (16) (7) (12) 2. Sodium depletion 1693 ± ± ± ± ± ± 79 without spirono- (12) (12) (17) (16) (16) (7) Significance of differ- P >.2 P <.5 P <.1 P <,1 P <,1 P <.1 ence in mean rates between experiments 3. Sodium depletion ± ± ± ± ± 55 with spironolac - (1) (13) (1) (8) (6) tone Significance of differ- - P >.9 P >,6 P >.4 P>.4 P >.8 ence in mean rates between experiments Net' 1. Control +771 ± ± ± ± 19-8 ± ± 42 (15) (18) (17) (16) (7) (12) 2. Sodium depletion +13 ± ± ± ± ± ± 19 without spirono- (12) (12) (17) (16) (16) (7 ) Significance of differ- P <,1 P <,5 P <,5 P <,1 P <.2 P <,1 ence in mean rates between experiments 3. Sodium depletion ± ± ± ± ± 34 with spironolac - (1) (13) (1) (8) (6) tone Significance of differ- - P <,5 P >,6 P>.8 P >,7 P <.1 ence in mean rates between experiments a Mean rates are expressed as microequivalents per 1 min ± SE of mean. Figures in parentheses indicate number of tests. b _, no experiment was performed., The plus signs and minus signs preceding the mean rates of net movement indicate absorption and secretion, respectively.

6 May 1967 ELEC'l'ROLYTES DURING SODIUM DEPLETION 851 by 21 % in the jejunum, 52% in the ileum, and 48% in the colon. The rates of insorption were less affected during salt depletion; only 2 dogs (C and F) showed a statistically significant increase in the rate at which sodium ions moved out of the intestinal lumen. Spirono did not uniformly affect the altered rates of sodium transport observed during salt depletion. In only 2 dogs (B and F) were the rates of insorption and net absorption of sodium reduced significantly. In control experiments the coefficients of variation of the rates of in sorption and exsorption were 2 to 3.5% in the small intestine and 15 to 3% in the colon. The variability in sodium transport was not altered during sodium depletion. Potassium transport (table 3). In all dogs (except dog A) the rate of intestinal secretion of potassium was greatly increased during sodium depletion. In the small intestine this increase in net movement of potassium was associated with an increase in the rate at which potassium ions entered the intestinal lumen (fig. 2). In the colon, the net secretion of potassium was increased with accompanying rises in the rates of both insorption and exsorption, the increase in the latter being more marked. In contrast, in dog A, potassium was more rapidly absorbed during sodium depletion. With the exception of the rate of insorption in dog B, these changes in potassium transport during sodium depletion were not affected by the administration of spirono. Water transport (table 4). The ileum and colon, which secreted water under control conditions, absorbed water during sodium depletion; on the other hand, water transport in the jejunum was not affected. The changes in net movement of water in the ileum were accompanied by a significant increase in the rates of insorption (fig. 3); in the jejunum and colon the unidirectional fluxes of water were not significantly or constantly affected during sodium depletion. Spirono had little or no constant effect on the transfer rates of water during sodium depletion. Relationship between the net transport rates of cation and water. A close correlation was observed between the net transport rates of sodium and water, both under control conditions and during sodium depletion (fig. 4). In the control group, on most occasions, when sodium was absorbed, water was absorbed, and when sodium was secreted, water was secreted. In only a few instances was water absorbed when sodium was secreted; the opposite situation was not encountered. Because the intercept of the regression line with the Y-axis did not differ significantly from zero (P >.5), it can be concluded that, in the absence of net transport of sodium, no net transport of water took place. During salt depletion, the net transport rates of sodium and water remained closely correlated. The regression lines drawn from the data obtained during sodium depletion and under control conditions had almost identical slope (P >.7), but the relationship between sodium and water net transport was altered to allow significantly (P <.1) more sodium than water to be absorbed during salt depletion. When the rates of net movement of total cation (the algebraic sum of the net transport rates of sodium and potassium) were plotted against the rates of net water movement (fig. 5), the regression lines during sodium depletion and under control conditions had a similar slope and intercept with the Y-axis. Thus, despite a relative and absolute increase in the rate of sodium absorption during salt depletion, the relationship between the net transport rates of cation and water was preserved mainly at the expense of an increased secretion of potassium. No correlation was observed between the rates of sodium and potassium transport. Concentrations of sodium and potassium in the intestinal lumen. Under control conditions the concentration of sodium in the luminal solution tended to increase slightly during the lo-min test period (fig. 6). In contrast, when the dogs were

7 TABLE 3. Potassium transport under control condi tions and during sodium depletion with and without spirono" Direction of transport and type of experiment Jejunum Ileum Colon Dog A DogB Dog C Dog D Dog E Dog F Insorption 1. Control 75.1 ± ± ± ± ± ± 1 (15) (18) (17) (18 ) (1) (12 ) 2. Sodium depletion 71.6 ± ± ± ± ± ± 3 without spirono- (12) (12) (17) (16) (16) (7) Significance of dif- P >.4 P >.4 P <.5 P >.8 P <.1 P <.1 ference In mean 3. Sodium depletion ± ± ± ± ± 4 with spironolac- (1) (13 ) (1) (8) (6) Significance of dif- - P <.1 P >.1 P >.9 P >.1 P >.2 Exsorption 1. Control 76. ± ± ± ± ± ± 5 ~ (15) (18 ) (17) (18) (1) (12) 2. Sodium depletion 63.2 ± ± ± ± ± ± 9 wit hout spirono- (12) (12) (17) (16) (16) (7) Significance of dif- P <.2 P <.1 P <.1 P <.1 P <.1 P <.1 ference In mean Sodium depletion ± ± ± ± ± 9 with spironolac- (1) (13) (1) (8) (6) tone Significance of dif- - P >.9 P >.1 P >.5 P>.2 P >.8 Net b 1. Control -.7 ± ±' ± ± 1-5. ± ± 5 (15) (18) (17) (18 ) (1) (12) 2. Sodium depletion +8.4 ± ± ± ± ± ± 1 without spirono- (12) (12) (17) (16) (16) (7) Significance of dif- P <.5 P <.1 P <.1 P <.1 P <.1 P <.1 3. Sodium depletion ± ± ± ± ± 1 with spironolac- (1) (13) (1) (8) (6) tone Significance of dif- - P >.2 P >.1 P <.5 P>.4 P>.7 ference III mean " Mean rates are expressed as microequivalents per 1 min ± SE of mean. Figures in parent heses indicate number of tests. b The plus signs and minus signs preceding the mean rates of net transport indicate absorption and secretion, respectively.

8 TABLE 4. Water transport under control conditions and during sodium de.pletion with and without spirono a Direction of transport and type of experiment Jejunum Ileum Colon Dog A DogB Dog C DogD DogE DogF Insorption 1. Control 35.5 ± ± ± ± ± ±.9 (15) (IS) (17) (IS) (1) (13) 2. Sodium depletion 34.6 ± ± 1.4 IS.3 ± ± ±.4 1.S ±.3 without spiro no- (U) (12) (11) (1) (16) (7) Significance of dif- P >.5 P >.1 P <.1 P <.1 P >.3 P >.1 erence In mean 3. Sodium depletion ± 1.6 IS.3 ± ±.4 U.5 ± 1.2 with spironolac- (1) (13) (1) (S) - tone Significance of dif- - P >.6 P >.9 P >.1 P >.3 - Exsorption 1. Control 29.7 ± ± ± ± ± ±.9 (15) (IS) (17) (IS) (1) (13) 2. Sodium depletion 2S.S ± ± ± ±.4 1. ± ±.5 without spirono- (U) (12) (11) (1) (16) (7) Significance of dif- P >.3 P <.2 P >.2 P <.1 P >.8 P <.5 3. Sodium depletion ± ± ±.5 1O.S ± 1.1 with spironolac- (1) (13) (1) (S) - Significance of dif- - P >.8 P >.9 P >.9 P >.3 - rates bet ween experiments Net b 1. Control +5.S ± ±.5-.4 ± ±.2-.6 ± ±.3 (15) (18) (17) (18) (1) (13) 2. Sodium depletion +5.S ± ± ± ± ± ±~.2 without spirono- (11) (12) (11) (1) (16) (7) Significance of dif- P >.9 P >.4 P <.1 P <.1 P <.1 P <.1 3. Sodium depletion ± ± ± ± ±.2 with spironolac- (1) (13) (1) (S) (6) tone Significance of dif- - P <.1 P >.1 P >.1 P>.9 P >.7 a Mean rates are expressed as milliliters per 1 min ± SE of mean. Figures in parentheses indicate number of tests. b The plus signs and minus signs preceding the mean rates of net transport indicate absorpt ion and secretion, respectively. 853

9 854 CLARKE ET AL. Vol. 52, No.5 No+ NET ABSORPTION ;UEqj 1min. 1, / 5 = CONTROL r = '93 P<'1 No = H 2 5 SECRETION 5 SECRETION 5 = Sodium Depletion r = ' 91 P<'1 No = H 2 1 H 2 NET ABSORPTION ml j 1min. FIG. 4. The relationship between the rates of net sodium and net water transport under eontrol conditions and during sodium depletion. No+ + K + NET ABSORPTION fj Eq/1min. 1 5 = CONTROL. r =' 93 P< ' 1 No+ + K+ = H 2 o = Sodium Depletion r='91 P< '1 No++ K+ = H 2 5 SECRETION 5 1 H 2 NET ABSORPTION ml /1min. 5 SECRETION FIG. 5. The relationship between the rates of net cation (Na + K) and net water movement under control conditions and during sodium depletion.

10 May 1967 ELECTROLYTES DURING SODIUM DEPLETION 855 Mean Change Luminal [Na+] meq/lilomin -1 F O ~--~~~ ~ E B D A r r C CONTROL Na Depletion FIG 6. Mean changes in the concentration of sodium in the test solution in 1 min under control conditions and during sodium depletion. The letters refer to the individual dogs. deprived of salt, the concentration of sodium in the intestinal content decreased. The concentration of potassium, which under control conditions tended to increase slightly during the test period, rose markedly in all sodium-depleted dogs, except in dog A. In dogs C and D the potassium concentration was increased almost 3-fold during the lo-min test period (fig. 7). Discussion These results demonstrate that deprivation of salt will profoundly influence the intestinal handling of sodium, potassium, and water. The absorption of sodium and the secretion of potassium were both increased. These changes in the net transport of sodium and potassium were accompanied by appropriate alteration in the rates at which these ions entered the intestinal lumen (exsorption). The rate of absorption of water was increased when the animal was depleted of sodium but there was no marked constant alteration in its unidirectional fluxes. The intestinal tract did not respond uniformly to sodium depletion. The absorption of water by the ileum and colon was increased during salt depletion, whereas in the jejunum no alteration in water absorption was detected. The effect of salt depletion upon the jejunal secretion of potassium was inconstant: in one dog potassium secretion was increased, but in another, reduced. In contrast, the secretion of potassium was invaribly increased in the ileum and colon. Although at all three sites the net absorption of sodium was augmented during sodium depletion, the magnitude of the increase was less in the jejunum than in the ileum and colon. Therefore, as far as the handling of water and electrolytes is concerned, the ileum and colon seemed more responsive to salt depletion than the jejunum. The jejunal segments absorbed sodium and water more rapidly than the more distal segments in the control experiments and during salt depletion. In addition, under Mean Change Luminal < +] meq/ L/1min +1 C D E A ~~----~ ~ -6 CONTROL B F Na Depletion FIG 7. Mean changes in the concentration of potassium in the test solution in 1 min under control conditions and during sodium depletion.

11 856 CLARKE ET AL. Vol. 52, No.5 both circumstances the rates of unidirectional movement of sodium and water were greatest in the jejunum. On the other hand, potassium was secreted more rapidly in the ileum and colon and the rate of its secretion increased more so during salt depletion. However, strict comparison of the absolute rates of intestinal transport between one site and another should be avoided because of the difficulty in constructing segments with identical mucosal surface areas. 14 In the present experiments the isolated segments were designed to have similar serosal dimensions. Therefore the mucosal surface area of the jejunal segment would be greater than the corresponding surface area in the ileum and colon. The intestinal response to salt depletion may be mediated by the adrenal cortex. Sodium depletion is a powerful stimulus to the secretion of aldosterone 15, 16 with consequent effects on the handling of sodium by the kidney, sweat glands, and salivary glands. In addition, adrenal mineralocorticoids are known to influence the intestinal handling of electrolytes.14 Thus, in dogs, ll-deoxycorticosterone increased the rates of sodium absorption and of potassium secretion by the colon but had no effect upon the small intestine. 5 When aldosterone was infused intravenously, the rate at which potassium ions entered the lumen of both small and large intestine was increased; no effect upon sodium movement was demonstratedy In the present study, it was not possible to measure directly the rates of secretion of aldosterone because of the low urinary volumes in these dogs, but the reduction in the urinary Na:K ratio provided adequate indirect evidence that a state of hyperaldosteronism existed. The effect of aldosterone upon the intestinal transport of electrolytes can be prevented by the previous administration of spirono. 7 In the present study, no blocking action could be demonstrated, perhaps owing to the large quantities of aldosterone being produced by the adrenal cortex, for we have observed that spirono did not block the intestinal action of aldosterone when the latter was given in high dose. 7 An alternative explanation is that the intestinal response to salt depletion may not be mediated by aldosterone and that other hormonal, vascular, and nervous factors are responsible for the changes which we have observed. There is very little evidence, however, to support an alternative mechanism. No other hormones have been shown to have such a clear-cut effect on the intestinal transport of electrolytes as the adrenal mineralocorticoids.14 It can be argued that reduction in the circulating blood volume in salt depletion may so alter splanchnic hemodynamics as to enhance the absorption of sodium and secretion of potassium. However, hypovolemia produced by experimental bleeding did not seem to affect the intestinal handling of electrolytes 17 until a state of hemorrhagic shock developed and became prolonged, when increased secretion of water and electrolytes was observed. 18 Intestinal absorption of electrolytes would not appear to be greatly affected by nervous factors.14 For these reasons, and because the intestinal response to salt depletion closely resembles the changes in electrolyte transport observed in the kidney and sweat glands, for which aldosterone is regarded as responsible, we consider it likely that the intestinal conservation of sodium and increased secretion of potassium during salt depletion are mediated by the adrenal cortex and aldosterone. Preliminary results with an in vitro preparation suggest that aldosterone acts directly upon the intestinal mucosa to promote the absorption of sodium and water (A. M. Clarke and O. L. Hill, unpublished observations). In the dogs with ileal and colonic fistulae, secretion of sodium and water was observed more frequently than absorption in the control experiments. Such behavior is not expected in bowel, the function of which is presumably to absorb rather than to secrete these substances. Secretion seemed to occur in a random fashion and could not be associated with any particular dog or type of experiment. Berger et al. 19 and Duthie (personal communication) have

12 May 1967 ELECTROLYTES DURING SODIUM DEPLETION 857 also observed this phenonemon. Code et a1. 9 have attributed secretion to the aging of the isolated segments. However, all the segments used in the present study were prepared in the preceding 6 months. We have confirmed Berger's observations 19 that, on light microscopy, there is no obvious histological change in intestinal mucosa (unpublished observations). It may be that such an artifact is caused by partial obstruction of the isolated bowel, for similar alterations in sodium and water transport are found in experimental intestinal obstruction. 2 However, although secretion rather than absorption of sodium and water occurred in the ileum and colon under control conditions, the intestine was not prevented from responding to salt depletion. Summary The intestinal transport of sodium, potassium, and water has been investigated in isolated segments of jejunum, ileum, and colon of dogs before, during, and after sodium depletion. During salt depletion, the rates of absorption of sodium and water, and of secretion of potassium, were increased, particularly in the ileum and colon. The rate of movement of sodium ions into the intestinal lumen was reduced whereas that of potassium ions was increased. Thus the intestinal response to salt depletion is one of sodium retention and conservation. Although the alterations in the intestinal handling of electrolytes during salt depletion closely resembled those following the administration of aldosterone, the effect of salt depletion upon the intestinal transport of electrolytes could not be prevented by spirono. REFERENCES 1. Clarke, A. M., and R. Shields The role of the intestine in fluid and electrolyte conservation during sodium depletion. Brit. J. Surg. 6: Field, H., L. Swell, R. E. Dailey, E. C. Trout, and R. S. Boyd Electrolyte changes in ileal contents and in feces during restriction of dietary sodium with and without the administration of cation-exchange resin. Circulation 12: Visscher, M. B., R. H. Varco, C. W. Carr, R. B. Dean, and D. Erickson Sodium ion movement between the intestinal lumen and the blood. Amer. J. Physio!. 141: Visscher, M. B., E. S. Fetcher, C. W. Carr, H. P. Gregor, M. S. Bushey, and D. E. Barker Isotopic tracer studies on the movement of water and ions between intestinal lumen and blood. Amer. J. Physio!. 142: Berger, E. Y., G. Kanzaki, and J. M. Steele The effect of desoxycorticosterone on the unidirectional transfers of sodium and potassium into and out of the dog intestine. J. Physio!. (London) 161: Shields, R., and R. G. Elmslie The effect of aldosterone on absorption of water and electrolytes from the ileum and colon of the dog. Brit. J. Surg. 6: Elmslie, R. G., A. T. Mulholland, and R. Shields Blocking by spirono (SC 942) of the action of aldosterone upon the intestinal transport of potassium, sodium and water. Gut 7: Veall, N., and H. Vetter Radioisotope techniques in clinical research and diagnosis. Butterworth and Company, Ltd., London, 417 p. 9. Code, C. F., P. Bass, G. B. McClary, R. L. Newnum, and A. L. Orvis Absorption of w ater, sodium and potassium in small intestine of dogs. Amer. J. Physioi. 199: Code, C. F., and F. C. McIntire Quantitative determination of histamine. Meth. Biochem. Ana!. 3: Shields, R., A. T. Mulholland, and R. G. Elmslie Action of aldosterone upon the intestinal transport of potassium, sodium and water. Gut 7: Berglund-Larsson, U Determination of small amounts of deuterium oxide in water by infra-red spectroscopy. Acta Chern. Scand. l: Code, C. F The semantics of the process of absorption. Perspect. BioI. Med. 3: Shields, R Surgical aspects of the absorption of water and electrolytes by the intestine. Monogr. Surg. Sci. 1: Crabbe, J., E. J. Ross, and G. W. Thorn The significance of the secretion of

13 8.58 CLARKE ET AL. Vol. 52, No.5 aldosterone during dietary sodium deprivation in normal subjects. J. Clin. Endocr. 18: Ross, E. J Biological properties of aldosterone. Brit. Med. Bull. 18: Goldberg, M., and J. Fine Traumatic shock. XI. Intestinal absorption in hemorrhagic shock. J. Clin. Invest. 24: Miles, J. B., M. W. Davies, and R. Shields The gastro-intestinal fluids in hemorrhagic shock. Brit. J. Surg. 52: Berger, E. Y., G. Kanzaki, M. A. Homer, and J. M. Steele Simultaneous flux of sodium into and out of the dog intestine. Amer. J. Physiol. 196: Shields, R The absorption and secretion of fluid and electrolytes by the obstructed bowel. Brit. J. Surg. 52: