Effect of dexamethasone on electrolyte transport in the large intestine of the rat

00165085/78/7502-0212$02.00/0 GASTROENTEROL~GY 75:212-217, 1978 Copyright 0 1978 by the American Gastroenterological Association

ALIMENTARY

Vol. 75, No. 2 Printed in USA.

TRACT

EFFECT OF DEXAMETHASONE ON ELECTROLYTE THE LARGE INTESTINE OF THE RAT HENRY

J.

Department

BINDER, ofinternal

TRANSPORT IN

M.D. Medicine,

Yale University, New Haven, Connecticut

We examined the effect of glucocorticosteroids on fluid and electrolyte movement in the rat colon. Dexamethasone, 600 pg per 100 g of body weight daily for 3 days, significantly increased water and sodium absorption, potassium secretion, the electrical potentional difference (PD), and Na-K-ATPase activity. Significant increases in PD and Na-K-ATPase activity were also produced by doses of dexamethasone (10 and 25 pg per 100 g of body weight, respectively) that more closely approximate a physiological dose. Further, the increase in PD was observed as soon as 3 hr after dexamethasone administration and persisted for 24 to 48 hr. Five hours after the administration of dexamethasone, Na-K-ATPase activity was not increased despite significant increments in Na absorption, K secretion, and PD. Dexamethasone increased fluid and sodium absorption during both saline and deoxycholic acid perfusions. In contrast to the net water and sodium secretion in the control group during bile acid perfusions, net absorption was present in the dexamethasone-treated animals. These studies extend previous observations of the effect of glucocorticoids on water and electrolyte movement in the large intestine and provide data concerning the minimal dose and time course of the interaction of glucocorticoids with ion transport. These observations indicate that glucocorticoids may provide important regulatory control of colonic ion transport, and that the mechanism of these glucocorticoid effects is not mediated by Na-K-ATPase. Intestinal function is significantly altered by both glucocorticosteroids and mineralocorticosteroids.2-‘4 Mineralocorticoids primarily affect electrolyte movement in the colon; the absorption of sodium and water and the secretion of potassium are increased after the administration of pharmacological doses of aldosterone or during salt depletion. 2+ Although some alteration of ileal transport is noted, mineralocorticoids do not influence electrolyte movement in the proximal small intestine,and it has been suggested that mineralocorti-

Received August 23, 1977. Accepted March 6, 1978. This paper was presented at the plenary session of the American Gastroenterological Association on May 24, 1976, and appeared in abstract form. ’ Address requests for reprints to: Henry J. Binder, M.D., Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510. This study was supported in part by Research Grants AM 14669 and AM 18889 from the National Institute of Arthritis, Metabolism and Digestive Diseases, United States Public Health Service, and grants from the John A. Hartford Foundation, Inc., and the Connecticut Digestive Disease Society. The Na-K-ATPase determinations were performed in the laboratory of Dr. John P. Hayslett whose help and advise is acknowledged. Ms. Dianne Whiting provided expert technical assistance.

coids are solely responsible for the effect of the adrenal cortex on colonic ion transport. Glucocorticoids have several different actions on intestinal function,7-14 but, until recently, it has been generally concluded that the administration of glucocorticoids does not result in an alteration of intestinal water and sodium absorption. This general assumption has required revision by recent experiments in which methylprednisolone clearly resulted in an increase in water and sodium absorption and an increase in sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) activity in both the small and large intestine.13 Additional studies demonstrated that methylprednisolone “blocked” cholera enterotoxin-induced fluid secretion by increasing ileal absorption of water and Na without altering active electrolyte secretion.‘” These present studies were designed to examine in greater detail the relationship of dexamethasone, a glucocorticosteroid, to fluid and electrolyte absorption and secretion in the large intestine. These results indicate that dexamethasone is a potent stimulant of sodium absorption, potassium secretion, the electrical potential difference (PD), and Na-K-ATPase activity. Further, the administration of dexamethasone will also “inhibit” bile acid-induced fluid and electrolyte secretion in the colon. 212

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August 1978

AND

COLONIC

Materials and Methods Nonfasting male Sprague-Dawley rats weighing between 200 to 250 g were used in all experiments. Aqueous solutions of dexamethasone (Decadron, Merck Sharp & Dohme, West Point, Pa.) were administered intraperitoneally in several different dosage schedules; control animals received an equivalent volume of saline. The exact details of each experiment are provided in the legends to the figures, the footnotes to the tables, and the text. In certain experiments spironolactone (Searle Laboratories, Skokie, Ill.) was administered 1 hr before the injection of dexamethasone, 25 or 600 pg per 100 g of body weight. Spironolactone, 2.5 mg per 100 g of body weight, dissolved in corn oil was injected intraperitoneally. Control animals received an equivalent volume of corn oil, Initial studies demonstrated that neither corn oil alone nor spironolactone dissolved in corn oil affected colonic PD. Fluid and electrolyte movement was determined by an in vivo continuous perfusion technique as previously described.‘” The perfusion (or “saline”) solution contained (in millimolar concentration per liter): 115 NaCl, 25 NaHCO,, 5 KCl, and 5 g per liter of polyethyleneglycol and approximately 1.0 PCi per liter of [“C]polyethyleneglycol. Solutions were infused at a rate of 0.54 ml per min. The perfusion solution was infused for 80 min in order to establish equilibrium conditions. The mean of the next three 20-min collection periods was used to determine the rate of water, Na, and K movement in each experimental group. In certain experiments the effect of bile acids on fluid and electrolyte movement was also determined. In these studies 5 mM sodium deoxycholate were added to the perfusion solution. The bile acid solution was perfused in a fashion identical to the control solution. In order to determine changes in water movement, aliquots of the perfusion and effluent solutions were added to ReadySolve HP (Beckman Instruments, Inc., Fullerton, Calif.) scintillation fluid. Radioactivity was determined in a liquid scintillation spectrometer (Beckman Instruments, Inc.). Quench correction was made by the channel ratio method. Sodium and potassium were measured by a flame photometer with an internal lithium standard. Fluid and electrolyte movement was expressed as microliters per minute per gram of dry tissue weight and microequivalents per minute per gram of dry tissue weight, respectively. Positive values represent net absorption; negative ones represent net secretion. The electrical PD was recorded in two different experimental conditions. In one, measurement of the PD was made simultaneously with determination of fluid and electrolyte movement. In these studies PE 205 tubing containing 4% agar in the perfusion solution was placed in the rectum so that the tip of the salt agar bridge was 4 cm from the anal verge. A similar salt agar bridge was placed in the peritoneal cavity.

TABLE

1.Effect

of dexamethwone Water absorption ~llminlg

Control (21) Dexamethasone

(8)

dry wt

75.1 2 10.2 103.0 t 8.4b

Both bridges were connected to calomel cells, and the PD was then recorded with a high impedance potentiometer every 5 min. The asymmetry of the two bridges was always less than 2 mv. The PD readings made during the determination of fluid and electrolyte movement were averaged and a single value was then obtained for individual solutions in each animal. In other experimental situations, in which determination of fluid and electrolyte movement was not measured, the colon was cleansed, and 3 ml of perfusion solution were introduced into the colon. A salt agar bridge was then advanced from 2 to 10 cm from the anal verge and the PD was recorded at 2-cm intervals. Because analysis of these experiments revealed that qualitatively similar PD recordings were observed at all five locations, only the PD measurements at 4 cm are presented. The PD measurements obtained at 4 cm in these two experimental conditions were identical. Na-K-ATPase activity was determined on homogenates of colonic mucosa. After sacrifice, the colon was isolated, washed with warm saline, and then opened. The mucosa was scraped with a glass slide and then homogenized. Na-K-ATPase activity was determined as previously described.“’ Protein content was measured by the method of Lowry et al.” Na-K-ATPase activity was expressed as micromole Pi per hour per milligram of protein. Results are expressed as mean * SEM. Paired and unpaired Student’s t-test was employed as indicated.‘”

Results Water and electrolyte movement. The administration of dexamethasone, 600 pg per 100 g of body weight for 3 days, resulted in increases both in water and sodium absorption and in potassium secretion (table 1) when studied 24 hr after the last injection of dexamethasone. In the control animals Na absorption was 14.7 2 2.0 pEq per min per g of dry weight and increased to 30.7 2 2.5 (P < 0.01) in the dexamethasone-treated animals. Potassium secretion also increased from -1.8 * 0.2 to -2.9 * 0.4 FEq per min per g of dry weight in the steroid-treated rats. Transmural PD and Na-K-ATPase activity were also determined in these animals receiving dexamethasone, 600 pg per 100 g of body weight for 3 days. The PD increased from 15.6 ? 1.4 to 65.5 ? 3.3 mv (serosapositive). Concomitant with this increase in the PD, Na-K-ATPase activity also markedly increased from 14.7 * 1.5 to 25.3 2 1.0 pmoles Pi per hour mg of protein (P < 0.001). Dexamethasone did not change Mg-ATPase activity.

on water, Na, and K movement, potential difference Na movement $qlminlg

14.7 t 2.0 30.7 5 2.5’

213

ION TRANSPORT

K movement dry wt

-1.8 -2.9

PD mu

2 0.2 k 0.4d

15.6 + 1.5 65.5 2 3.3’

(PD), and ATPase activity Na-K-ATPase pm&

14.7 k 1.5 25.3 -+ 1.0

Mg-ATPase

P,/hrlmgprotein

29.0 2 1.4 32.4 f 1.4’

fl Mean 2 SEM. All studies were performed 24 hr after three daily injections of dexamethasone (600 pg per 100 g of body weight). Positive values represent net absorption; negative ones represent net secretion. Number in parentheses represents the number of animals studied, except for the enzyme determinations which were performed in eight pairs of rats. The PD was oriented with the serosa-positive relative to the mucosa. b P c 0.05, compared with control group. VP < 0.001, compared with control group. ” P <: 0.02, compared with control group. V Not significantly different from control group.

214

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BINDER

Time of onset of action. A series of experiments was performed in which the PD was monitored in order to ascertain both the time of onset and duration of the dexamethasone-induced increased in PD. Figure 1 demonstrates the PD after a single dose of dexamethasone (600 pg per ,100g of body weight). An increase in the PD did not occur during the initial 2 hr after the administration of dexamethasone. However, 3 hr after its administration there was a significant increase in the PD (34.9 ? 2.4 mv), and at 5 hr the PD was 56.0 f. 2.0 mv. The peak PD (75.2 ? 6.8 mv) was observed 24 hr after the single dose of dexamethasone. At 48 and 72 hr the PD was again similar to control values. Because the studies of fluid and electrolyte movement (table 1) were performed 24 hr after the last of three daily doses of dexamethasone, additional experiments evaluated the duration of the increased PD under these conditions.

60

0 HOURS

2 FOLLOWING

3

5

24

OEXAMETHASONE

40 (600

72

fig/100

g EW)

FIG. 1. Time course of increment in potential difference after administration of dexamethasone (600 Kg per 100 g of body weight). A significant increase (P < 0.01) in potential difference was observed at the times designated by an aster-i&. A minimum of 4 animals was present in each group.

TABLE 2. Effect of dexamethasone

on Na and K movement, potential difference

Na movement

K movement

15.5 -+ 1.3 21.0 -r- 2.ob 25.1 k 4.0’

-1.4 -2.0 -2.2

CPD), and ATPase PD

mu

flqlminlg dry wt Control (20) Dexamethasone-5 hr (8) Dexamethasone-24 hr (8)

Twenty-four hours after the final dexamethasone injection the PD was elevated (58.3 + 4.8 mv). The PD was still increased 48 hr after the last dose dexamethasone (42.9 + 7.8 mv), but not after 72 hr (21.6 ? 1.2 mv). The movement of sodium and potassium and Na-KATPase and Mg-ATPase activity were also determined 5 and 24 hr after the administration of a single dose of dexamethasone, 600 pg per 100 g of body weight. These results (table 2) indicate that, at both 5 and 24 hr after the administration of dexamethasone, sodium absorption and potassium secretion were modestly increased. The PD, as already noted, was significantly increased at both time periods. No increase in either Na-K-ATPase activity or Mg-ATPase activity was detectable 5 hr after the administration of dexamethasone, and a small increment in Na-K-ATPase activity was observed at 24 hr. Dose response. The initial experiments employed a pharmacological dose of dexamethasone. In additional studies several other amounts of dexamethasone were also given daily for 3 days, and the PD measured 24 hr after the last dose. Five micrograms per 100 grams of body weight did not alter the basal PD (table 3). However, significant increases were observed after the administration of 10, 25, and 50 ,ug per 100 g of body weight. The maximal increment in PD was produced by 100 pg per 100 g of body weight, and no higher increases in PD were observed when 6000 pg per 100 g of body weight were administered. Na-K-ATPase activity was also increased when measured after daily administration of a low dose of dexamethasone. In control animals Na-K-ATPase activity was 13.0 2 0.7 and was significantly increased to 15.5 -+ 0.4 pmoles Pi per hr per mg of protein (P < 0.01) in rats receiving 25 (ug per 100 g of body weight. Although adrenalectomy decreases the PD, administration of dexamethasone to adrenalectomized rats resulted in increases in PD comparable to sham-operated control animals. Mean increment in PD in adrenalectomized animals 5 hr after a single dose of dexamethasone (600 pg per 100 g of body weight) was 20.7 5 4.1 mv and was similar to that observed in the control group (21.6 f 4.6 mv). The effect of an aldosterone antagonist (spironolactone) on dexamethasone-stimulated increases in PD was also determined. In these studies spironolactone was administered 1 hr before the administration of

k 0.2 r 0.Y * 0.p

16.7 + 0.9 63.8 k 6.1’ 73.2 k 7.2

activity: response after 5 and 24 hP Na-K-ATPase

vole 12.5 f 0.5 12.5 + 0.8 15.0 + 0.8

Mg-ATPase

P,lhrlmg protein 28.3 k 2.3 24.3 r 0.86 25.0 k O.Sd

a All results represented as mean 2 SEM. All studies were performed 5 or 24 hr after a single dose of dexamethasone (600 pg per 100 g of body weight). Positive numbers represent net absorption; negative ones represent net secretion. Number in parentheses represents the number of animals in the group, except for the enzymes in which there were 8 animals in each group. b P < 0.05, compared with control group. c P < 0.001, compared with control group. d Not significantly different from control group. c P < 0.02, compared with control group.

August

GLUCOCORTICOIDS

1978

TABLE 3. Effect of dose of dexamethasone

AND

on potential difference

(PD)” Dexamethasond ~__

Potential difference 21.0 I? 1.1

Control 5 Irg

(34) 16.7 f 5.3’

10 pg

(10) 37.5 ? 6.1”

25 pg

( 8) 41.3 + 3.0”

50 CLg

( 4) 50.3 ‘- 2.3‘

100 Kg

( 4) 63.7 ? 8.2’

600 pg

( 3) 58.3 + 4.8

6000 cLg

(12) 61.8 f 12.9’ ( 4)

U Mean 2 SEM. PD expressed in millivolts (serosa-positive) was recorded 24 hr after three daily injections of dexamethasone. PD was measured at 2 to 10 cm from the anus. Qualitatively similar results were observed at all locations and only the results at 4 cm are presented. Number in parentheses represents number of animals studied in each group. D Dosage of dexamethasone is in micrograms per 100 grams of body weight. c Not significantly different from control group. ‘l P < 0.02, compared with control group. ” P < 0.001, compared with control group. f P <’0.005, compared with control group.

COLONIC

movement and the recent studies indicating that methylprednisolone will “reverse” cholera enterotoxin-induced secretion in the ileum,‘” additional experiments were designed to determine the effect of dexamethasone on bile acid-induced fluid and sodium secretion. During perfusion with 5 mM deoxycholic acid, water and sodium secretion occurred in the control group (fig. 2). In the dexamethasone-treated animals, however, net water absorption was observed during perfusion with 5 mM deoxycholic acid solution (fig. 2). During the bile acid perfusions, dexamethasone also reversed sodium secretion (-10.5 -+ 3.4 E*.Eqper min per g of dry weight) to sodium absorption (+3.8 + 3.0 PEq per min per g of dry weight; P < 0.02). As already noted, there was an increase in potassium secretion in the dexamethasone-treated animals during the saline perfusions (table 5). This increase was not present in the dexamethasone-treated animals during perfusion with deoxycholic acid (-1.4 t 0.4 PEq per min per g of dry weight), and potassium movement was similar during the bile acid periods in both the control and experimental animals. In both control and experimental animals deoxycholic acid perfusion resulted in a decrease in PD (table 51, and the PD was similar during the bile acid perfusions in the control group and in the dexamethasone-treated group. Discussion These present studies provide information concerning the effect of glucocorticoids on fluid and electrolyte

TABLE 4. Effect of spironolactone on dexamethasone-induced stimulation ofpotential difference (PD)” Spironolactone

Dexamethasone

2kipg

14.4 t 0.9

38.7 t 2.P

B. 600 pg

(6) 20.5 5 1.1

(10) 49.2 2 4.9

A.

Spironolactone + dexamethasone 20.8 ” 2.6,” (10) 27.7 + 2.7”,‘~

(5) ( 9) ( 8) (’All results expressed as mean ? SEM. PD expressed in millivolts (serosa-positive) was recorded 4 cm from anus. PD was determined 6 hr after the administration of spironolactone (25 mg per kg of body weight) and 5 hr after dexamethasone (25 gg per 100 g of body weight in group A and 600 yg in group B). Preliminary studies indicated that this dose of spironolactone did not affect the basal PD. b P <: 0.001, compared with spironolactone group. c P <: 0.001, compared with dexamethasone group. ” P c: 0.05, compared with spironolactone group. I’P <: 0.005, compared with dexamethasone group.

dexamethasone, and the PD was then measured 5 hr after the dose of dexamethasone. Table 4 demonstrates that spironolactone partially but significantly inhibited the increase in the PD produced by both 25 and 600 pg of dexamethasone per 100 g of body weight. The administration of spironolactone alone did not alter the PD when recorded 6 hr after its administration (20.5 % 3.4 mv in controls versus 17.7 -+ 2.5 mv in spironolactonetreated animals). Effect on bile acid-induced secretion. Because of the striking effects of dexamethasone on sodium and water

215

ION TRANSPORT

SALINE

PERFUSION

ABSORPTION ,oo

f ? = \” : 1 a.

PXO.05

-

BILE ACID PERFUSION

pco.01

75 -

50 -

0

Control

DOexomrthasonr 600 pg/lOO g BW x 3 days

FIG. 2. Effect of dexamethasone on water movement during saline and 5 mM deoxycholic acid perfusion. The number in each box represents the number of animals studied in each group. All perfusions were performed 24 hr after three daily injections of dexamethasone (600 pg per 100 g of body weight). Dexamethasone increased water absorption during both saline and bile acid perfusions, and there was diminished net water absorption in the dexamethasonetreated animals during perfusion with deoxycholic acid. The results of sodium movement during saline and bile acid perfusions in both control and dexamethasone-treated animals were similar.

216

BINDER

TABLE5. Effect of bile acids on dexamethasone-induced

changes in (BP

Vol. 75, No. 2

hr after the administration of specific corticosteroids and the onset of its physiological action. The time 5 rn~ deoxycholic acid course of the onset of action of the increase in PD after Saline perfusion perfusion the administration of dexamethasone (fig. 1) is consistA. Potassium secretion ent with this model of steroid-receptor interaction with @Eqlmin/g dry wt) subsequent stimulation of protein synthesis. In the -1.8 k 0.4 Control -1.8 + 0.2 kidney there are both glucocorticoid and mineralocortiDexamethasone -2.9 k 0.46 -1.4 + 0.4’ coid specific receptors in the cytoplasm.23, 24At pharmacological doses, glucocorticoids may interact with the B. Potential difference mineralocorticoid receptor and mineralocorticoids may (mv; serosa-positive) bind to the glucocorticoid receptor.“3* 24 Little informaControl 15.6 k 1.4 5.7 + 2.3” Dexamethasone 65.5 k 3.3’ 8.7 c 3.0’ tion is available concerning the presence of specific cytoplasmic steroid receptors in the adult intestinal N Mean -C SEM. Dexamethasone animals received 600 yg per 100 g mucosa,“” and it is uncertain whether the present reof body weight intraperitoneally for 3 days. The control group sults were caused by binding of the glucocorticoid to received an equivalent volume of saline. Perfusion studies were performed 24 hr after the last injection. The number of animals in mineralocorticoid receptors in the cytosol, to the preseach group is provided in figure 2. ence of minimal mineralocorticoid activity in dexamethb P < 0.02, compared with control group. asone, or to a direct interaction of the glucocorticoid c P < 0.02, compared with saline perfusion. with glucocorticoid specific receptors. d P < 0.005, compared with saline perfusion. The mechanism of action of spironolactone is generp P < 0.001, compared with control group. ally believed related to its competitive binding to min‘P < 0.001, compared with saline perfusion. eralocorticoid specific receptors.2” Table 4 demonstrates that the action of dexamethasone on PD was inhibited transport in the large intestine and confirm the recent by spironolactone and suggests that the effect of dexaobservations of Charney et a1.13 that pharmacological methasone in these present studies may be related to doses of methylprednisolone increase water and sodium its interaction with mineralocorticoid specific cytoplasabsorption in the colon similar to the effect of deoxycormic receptors. However, it is important to note that ticosterone. In these studies by Charney et a1.13only a high concentrations of spironolactone also bind to glusingle dose of methylprednisolone was administered cocorticoid specific receptors in the rat kidney.‘” Studies according to a single fixed schedule. An effect of methto assess the characteristics of specific cytoplasmic reylprednisolone was apparent when fluid and electrolyte ceptors for glucocorticoids and mineralocorticoids (and movement was measured 24 hr after the last of three for spironolactones) in both the small and large intesdaily dose of methylprednisolone (3 mg per 100 g of body tine are therefore required. There is considerable controversy regarding the weight). No other information is available regarding either the minimal dose or time course required for mechanism by which aldosterone increases Na transport in the kidney and other epithelia. Although an glucocorticoids to affect colonic ion transport or Na-Kincrease in Na-K-ATPase activity is frequently obATPase activity. served in the kidney after administration of aldosterOur present data suggest that the effect of dexamethone, a causal relationship between the observed inasone may not represent just a pharmacological phecreases in Na-K-ATPase activity and Na transport has nomenon. First, the stimulation of PD by dexamethanot been confirmed, there are differences in both the sone occurs at a dose as low as 10 pg per 100 g of body time course and dosage of aldosterone required to proweight. This dose may be equivalent to physiological duce the increases in enzyme activity and transport.2x replacement of glucocorticosteroids in the rat because the daily excretion of corticosterone, the naturally oc- In the colon Thompson and Edmonds2’ have also obcurring glucocorticoid in the rat, is approximately 750 served that aldosterone increases PD at a time when increased Na-K-ATPase activity was not detected. Tapg per 100 g of body weight.ls (The dexamethasone ble 2 and figure 1 indicate a similar phenomena after equivalent is 15 pg per 100 g of body weight.) Second, the administration of dexamethasone and suggest that Na-K-ATPase activity was also increased by the lowest dose of dexamethasone examined (25 pg per 100 g of the action of dexamethasone on colonic ion transport is Alternative explanabody weight). Other recent studies indicate that the not mediated by Na-K-ATPase. tions are that the sensitivity of the Na-K-ATPase assay administration of a similar low dose of dexamethasone, is less than that of the transport studies or that the but not of aldosterone, to adrenalectomized animals increase in Na-K-ATPase activity is secondary to the completely corrected all of the changes in colonic ion increase in Na absorption.28 transport produced by adrenalectomy.20 Thus, glucocorGlucocorticoids may be effective in the treatment of ticoids have significant biological effect on large intesseveral diarrhea1 illnesses such as ulcerative colitis, tinal electrolyte transport. Crohn’s disease, and celiac sprue.24-31 Although their The action of corticosteroids on cell function is initieffectiveness has usually been related to their ability to ated by the interaction of the steroid with specific decrease mucosal inflammation, it is now necessary to cytoplasmic receptors. 21*22 The “activated” cytoplasmic suggest that, in addition, glucocorticoids may have a receptor complex is then translocated to specific nuclear direct stimulator-y action on sodium and water absorpreceptors which initiate protein synthesis and gene action. There is usually a delay of approximately 2 to 5 tion. Charney and Donowitz14 demonstrated that the potassium

secretion

(A) and potential difference

August 1978

GLUCOCORTICOIDS

AND COLONIC ION TRANSPORT

“prevention” of cholera enterotoxin-induced fluid secretion in the rat ileum by methylprednisolone was related to stimulation of lumen to plasma absorptive processes without an effect on the active ion secretion stimulated by cholera enterotoxin. l4 Figure 2 provides parallel observations that dexamethasone also prevents bile salt-induced fluid secretion. The effect of dexamethasone on sodium and water movement during bile acid perfusion is probably related to an increase in sodium and water absorption (table 1) rather than any direct effect of dexamethasone on the secretory process. It is unlikely that dexamethasone directly prevents the effects of bile acids on the intestine because PD measurements were similar during the deoxycholic acid perfusions in the control and dexamethasone-treated animals (5.7 5 2.3 versus 8.7 t 3.0 mv). Binder and Ptak% in 1970 reported that the absorption of water and sodium from the jejunum of patients with ulcerative colitis not treated with glucocorticoids was diminished, but water and sodium absorption was normal in patients receiving prednisone. Because glucose-stimulated water and sodium absorption was intact in both groups of patients, this study concluded that prednisone might be inhibiting a secretory process. Although recent observations do not provide a ready explanation for the decrease in jejunal absorption in these patients with ulcerative colitis, they do permit the speculation that prednisone may have increased jejunal water and sodium absorption. Although direct evidence of glucocorticoid action on intestinal fluid and electrolyte movement in either normal subjects or patients with various diarrhea1 diseases is not available, the effect. of glucocorticoids in the treatment of diarrhea associated with inflammatory bowel disease may be related to a stimulation of intestinal water and sodium absorption in addition to its well known anti-inflammatory effects. REFERENCES 1. Binder HJ: Alteration of colonic electrolyte transport by glucocorticosteroids (abstr). Gastroenterology 70:864, 1976 2 Levitan R, Ingelfinger FJ: Effect of d-aldosterone on salt and water absorption from the intact human colon. J Clin Invest 44:801-808, 1965 3. Edmonds CJ, Marriott JC: The effect of aldosterone and adrenalectomy on the electrical potential difference of rat colon and on the transport of sodium, potassium, chloride and bicarbonate. J Endocrinol39:517-531, 1967 4. Shields R, Mulholland AT, Elmslie RG: Action of aldosterone upon the intestinal transport of potassium, sodium, and water. Gut 7:686-696, 1966 5. Berger EY, Kanzaki G, Steele JM: The effect of deoxycorticosterone on the unidirectional transfers of sodium and potassium into and out of the dog intestine. J Physiol (Land) 151:352-362, 1960 6. Elmslie RG, Mulholland AT, Shields R: Blocking by spironolactone (SC 9420) of the action of aldosterone upon the intestinal transport of potassium, sodium, and water. Gut 7:697-699, 1966 7. Clark SL: The ingestion of proteins and colloidal materials by columnar absorptive cells of the small intestine in suckling rats and mice. J Biophys Biochem Cytol5:41-50, 1959 8. Lebenthal E, Sunshine P, Kretchman N: Effect of carbohydrate and corticosteroids on activity of a-glucosidases in intestine of

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the infant rat. J Clin Invest 51:1244-1251, 1972 9 Lebenthal E: Induction of fetal rat enterokinase in utero by hydrocortisone and actinomycin D. Pediatr Res 11:282-285, 1977 10 Kimberg DV, Baerg RD, Gershon E, et al: Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest 50:1309-1321, 1971 11 Klein RG, Arnaud SB, Gallagher JC, et al: Intestinal calcium absorption in exogenous hypercortisonism. Role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest 60:253-259, 1977 12. Broder S, Muchmore AV, Stober W: Resolution of massive protein-losing enteropathy (PLE) following anti-inflammatory therapy (abstr). Clin Res 25:308, 1977 13. Charney AN, Kinsey MD, Myers L, et al: Na’ -K+-Activated adenosine triphosphatase and intestinal electrolyte transport. J Clin Invest 56:653-660, 1975 14. Charney AN, Donowitz M: Prevention and reversal of cholera enterotoxin-induced intestinal secretion by methylprednisolone induction of Na+-K+-ATPase. J Clin Invest 57:1590-1599, 1976 15. Bright-Asare P, Binder HJ: Stimulation of colonic secretion of water and electrolytes by hydroxy fatty acids. Gastroenterology 64:81-88, 1973 16. Silva P, Hayslett JP, Epstein FH: The role of Na-K-activated adenosine triphosphatase in potassium adaptation. Stimulation of enzymatic activity by potassium loading. J Clin Invest 52:2665-2671, 1973 17. Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275, 1951 18. Snedecor GW, Cochran WG: Statistical Methods. Sixth edition. Ames, Iowa, The Iowa State University Press, 1967, p 549 19. Palmore WP, Mulrow PJ: Control of aldosterone secretion by the pituitary gland. Science 158:1482-1484, 1967 20. Bastl CP, Hayslett JP, Binder HJ: Role of glucocorticoids on ion transport and transmural PD in colon (abstr). Clin Res 25:306. 1977 21. Feldman D, Funder JW, Edelman IS: Subcellular mechanisms in the action of adrenal steroids. Am J Med 53:545-560, 1972 22. Edelman IS, Fanestil DD: Mineralocorticoids. Biochemical Actions of Hormones. Edited by G Litwack. New York, Academic Press, 1970, p 324-364 23. Funder JW, Feldman D, Edelman IS: Glucocorticoid receptors in rat kidney: the binding of tritiated-dexamethasone. Endocrinology 92:1005-1013, 1973 24. Swaneck GE, Highland E, Edelman IS: Stereospecific nuclear and cytosol aldosterone-binding proteins of various tissues. Nephron 6:297-316, 1969 25. Pressley L, Funder JW: Glucocorticoid and mineralocorticoid receptors in gut mucosa. Endocrinology 97:588-596, 1975 26. Fanestil D: Mode of spironolactone action competitive inhibition of aldosterone binding to mineralocorticoid receptors. Biochem Pharmacol 17:2240-2242, 1968 27. Thompson BD, Edmonds CJ: Aldosterone, sodium depletion, and hyperthyroidism on the ATPase activity of rat colonic epithelium. J Endocrinol62:489-496, 1974 28. Hierholzer K, Lange S: The effects of adrenal steroids on renal function. In MTP International Review of Science, vol 6: Kidney and Urinary Tract Physiology. Edited by K Thurau. Baltimore, University Park Press, 1974, p 273-333 29. Truelove SC, Witts LJ: Cortisone and corticotrophin in ulcerative colitis. Br Med J 1:387-394, 1959 30. Singleton JW: National cooperative Crohn’s Disease Study (NCCDS): results of drug treatment. A cooperative study (abstr). Gastroenterology 72:110, 1977 31. Wall AJ, Douglas AP, Booth CC: Response of the jejunal mucosa in adult coeliac disease to oral prednisolone. Gut 11:7-14, 1970 32. Binder HJ, Ptak T: Jejunal absorption of water and electrolytes in inflammatory bowel disease. J Lab Clin Med 76:915-924, 1970