Corticosteroids and intestinal ion transport

GASTROENTEROLOGY

REVIEW

1987;93:188-96

ARTICLE

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Corticosteroids and Intestinal Ion Transport GEOFFREY

I. SANDLE and HENRY J. BINDER

Department of Medicine, Hope Hospital, University of Manchester School of Medicine, Salford, United Kingdom, and Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

In recent years the application of newer electrophysiologic and biochemical techniques has led to the rapid expansion of our knowledge about the effects of corticosteroid hormones on intestinal ion transport. It has become clear that endogenous corticosteroids are required for basal intestinal transport function, and pharmacologic doses of exogenous corticosteroids produce a variety of changes in ion transport at all levels of the intestinal tract. These changes are more complex than they appear at first because the small and large intestine exhibit different responses to glucocorticoid and mineralocorticoid hormones. In the small intestine, glucocorticoids have marked effects on several aspects of ion transport (l-5), whereas mineralocorticoids produce relatively few or only minor changes (l&8). In contrast, in the large intestine, both types of corticosteroid hormone stimulate sodium and potassium transport (1,9-20). It has proved difficult to establish whether the action of each type of corticosteroid (glucocorticoid and mineralocorticoid) is solely the result of their binding to specific cytosolic receptors (i.e., glucocorticoid or mineralocorticoid, respectively) or whether there is also crossover binding to the other corticosteroid receptor. Newer insights into this problem have come from recent studies in rat large intestine indicating that mineralocorticoid and glucocorticoid hormones probably produce distinctive changes in sodium and potassium transport processes (15,18,21-24)that result from activation of specific receptors (25,26)in addition to effects that Received August 25, 1986. Accepted January 12, 1987. Address requests for reprints to: Henry J. Binder, M.D., Department of Internal Medicine, 333 Cedar Street, New Haven, Connecticut 06510. This work was supported by U.S. Public Health Service Research grants AM 14669 and AM 18777 from the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases. Dr. Sandle holds a Medical Research Council Senior Clinical Fellowship. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50

are produced as a result of crossover receptor binding. Although the precise effects of corticosteroids on the biophysical properties of intestinal cell membranes have yet to be determined, substantial progress has been made in understanding the mechanisms of corticosteroid-induced ion transport and we highlight the more important experimental findings in this report.

Corticosteroids and the Small Intestine Role of Corticosteroids

in Basal Transport

Early studies with adrenalectomized animals focused on the role of endogenous corticosteroids in the control of small intestinal transport processes. Uncompensated adrenalectomy (animals maintained on tap water) resulted in loss of appetite and decreased intestinal weight (27-29), altered visceral blood flow (3O), and diminished brush-border enzyme activities that could be reversed by saline feeding or corticosteroid administration (29,3X,32). Both of these treatments also reversed the abnormalities of fluid and electrolyte transport seen in uncompensated animals (29,33-36). Some investigators, however, reported decreased electrolyte absorption even after compensated adrenalectomy (animals maintained on saline), which could be restored by the administration of cortical extract (37) or deoxycorticosterone (38).Recent studies suggest that both glucocorticoid and mineralocorticoid hormones play a role in the control of basal electrolyte transport in the small intestine. In isolated rabbit ileum, for example, endogenous glucocorticoid deficiency (produced by aminoglutethimide treatment in vivo) results in the inhibition of net sodium absorption and stimulation of net chloride secretion (2). Other studies suggest that corticosteroids influence several mucosal enzymes that may play a role in small intestinal electrolyte transport. Thus, in rat jejunum, carbonic anhydrase and mitochondrial magnesium,

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CORTICOSTEROIDS

HC03-stimulated adenosine triphosphatase (ATPase) activities fall after adrenalectomy but return to normal with aldosterone administration, although neither enzyme is altered by the glucocorticoid dexamethasone (39). Enzyme induction by aldosterone is inhibited by pretreatment with cycloheximide, suggesting that the mineralocorticoid stimulates the synthesis of new enzyme protein (39). Adrenalectomy also decreases the synthesis of trichloroacetatesoluble and trichloroacetate-insoluble proteins in rat small intestine, which are restored by aldosterone (but not by the natural glucocorticoid corticosterone) in a dose-dependent manner (40). The general conclusion to be drawn from these studies is that basal electrolyte transport and the activity of mucosal enzymes that may be involved in transport in the small intestine are at least partially dependent on adequate levels of corticosteroid hormone secretion. On the available evidence it is tempting to speculate that glucocorticoids and mineralocorticoids influence different aspects of electrolyte transport via specific glucocorticoid and mineralocorticoid receptors present in the cytoplasm of the small intestinal mucosa (41). Further work is required in this area, however, as the apparent dependency of certain transport parameters upon mineralocorticoids rather than glucocorticoids (and vice versa) may reflect species differences as well as variability between experimental techniques. Effects of Corticosteroid

Excess on Transport

Mineralocorticoids. Recently, more attention has been paid to the effects of exogenous corticosteroid (particularly glucocorticoid) hormones on small intestinal electrolyte transport in intact animals. Despite the presence of cytoplasmic receptors for both mineralocorticoid and glucocorticoid hormones throughout the small and large intestine (41) it has proved difficult to demonstrate that pharmacologic doses of mineralocorticoids exert even modest effects on small intestinal water and electrolyte transport (1,6-8). In recent studies in rat small intestine, however, secondary hyperaldosteronism induced by chronic dietary sodium depletion has been shown to increase sodium and water absorption and the short circuit current in the ileum but not in the jejunum (42). These changes in ileal transport were partially sensitive to micromolar concentrations of amiloride (which inhibits sodium movement across the apical membrane), and were not associated with changes in electrogenic sodium-coupled glucose transport or cyclic adenosine monophosphatedependent anion secretion (42). It should be noted, however, that aldosterone stimulates electrogenic sodium transport far more readily in the distal colon

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than in the ileum (42), and it seems unlikely that the ileum contributes significantly to sodium homeostasis during prolonged sodium restriction. Glucocorticoids. In contrast, pharmacologic doses of glucocorticoids produce a variety of clearcut changes in small intestinal transport. Parenteral treatment with methylprednisolone for 3 days increases net sodium and water absorption, net potassium secretion, and mucosal sodium-potassiumstimulated adenosine triphosphatase (Na,K-ATPase) activity in rat jejunum and ileum, whereas the mineralocorticoid deoxycorticosterone acetate has no effect (1). Glucocorticoid-induced changes in sodium and potassium transport are probably secondary to the rise in Na,K-ATPase activity, which mediates Na-K exchange at the basolateral membrane of villous cells. At present there is no evidence that the increase in small intestinal sodium absorption produced by parenterally administered methylprednisolone is associated with an increase in glucosewith coupled sodium transport (2,3). Pretreatment methylprednisolone also “reverses” the jejunal secretion of sodium and water induced by cholera enterotoxin, apparently by stimulating a sodium absorptive process that is cyclic adenosine monophosphate-independent (3). On the other hand, cyclic nucleotides other than cyclic AMP appear to play a positive role in the response of the small intestinal mucosa to glucocorticoids, as a single pharmacologic dose of methylprednisolone increases guanylate cyclase activity and cyclic guanosine monophosphate concentrations in rat jejunal and ileal mucosa by 6 h, at a time when Na,KATPase activity is unchanged (4). In the ileum, these biochemical changes are maximal in crypt cells and associated with increased active chloride secretion, and are not affected by pretreatment with the mineralocorticoid receptor inhibitor spironolactone (4). Methylprednisolone treatment for 3 days also stimulates a Na,K-ATPase-mediated sodium absorptive process in rat ileum which is superimposed on cyclic guanosine monophosphate-mediated chloride secretion (5). It is therefore quite likely that the overall changes in small intestinal electrolyte transport induced by glucocorticoids reflect different time-dependent effects on villous and crypt cells in the mucosa. Other studies in rabbit ileum have shown that methylprednisolone stimulates net sodium and chloride absorption (43). However, methylprednisolone does not change alanine-, glucose-, or epinephrine-stimulated sodium and chloride uptake at the apical membrane when these stimulators of absorption are present individually at maximal concentration, suggesting that the glucocorticoid does not have a specific effect on apical sodium and chloride

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entry mechanisms (43). In contrast, when present simultaneously these agents elicit significantly greater increases in net sodium and chloride absorption in methylprednisolone-treated ileum than in control ileum (43). These data indicate that methylprednisolone enhances the absorptive capacity of the ileum, probably by increasing the number or turnover of sodium pumps in the basolateral membrane. Not surprisingly, such detailed studies have not been performed in human small intestine, but Binder and Ptak (44) demonstrated that chronic prednisone treatment corrected the impaired jejunal absorption of sodium and water in patients with ulcerative colitis, and it seems more likely that the effect of prednisone reflected stimulation of fluid absorption rather than inhibition of a secretory process. Although chronic parenteral glucocorticoid treatment produces well-defined changes in small intestinal transport, the precise mechanisms of action at the cellular level have yet to be determined. Current concepts about the cellular effects of glucocorticoids have arisen from studies in the kidney (45-47). These indicate that glucocorticoids bind to cytosolic receptors and then activate a deoxyribonucleic acidchromatin binding site before stimulating the synthesis of new enzyme proteins that are involved in transepithelial ion movement, e.g., basolateral membrane Na,K-ATPase. As glucocorticoids stimulate mucosal Na,K-ATPase activity in the jejunum and ileum (l), and in the colon (vide infra), it is generally assumed that they trigger a similar sequence of receptor activation in intestinal epithelia. Glucocorticoids may also stimulate small intestinal absorptive function by inhibiting the mucosal synthesis of prostaglandins (48,49), as there is evidence that suggests that prostaglandins play a part in maintaining the secretory “tone” of the small intestine (50). In recent human studies, a pharmacologic concen(100 mg/L) administered tration of hydrocortisone intraluminally during jejunal perfusion with glucose-saline was found to stimulate net sodium and water absorption in normal subjects, and decrease net sodium and water secretion in patients with untreated celiac disease (51). Intraluminal hydrocortisone had similar effects in normal subjects when galactose or alanine was substituted for glucose (52), but there was no change in sodium and water absorption when hydrocortisone was infused in saline alone or in fructose- or bicarbonate-saline (53). Intraluminal hydrocortisone stimulated glucose, sodium, and water absorption within 20-30 min when peripheral plasma cortisol concentrations were in the normal range, whereas hydrocortisone infused intravenously to achieve similar plasma concentrations had no effect on jejunal transport (53). Intraluminal hydrocortisone therefore appears to ex-

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ert a local rather than a systemic effect on the jejunal mucosa, possibly by influencing the apical membrane carriers involved in the coupled transport of sodium and organic solutes, rather than by stimulating the synthesis of new transport proteins. These observations raise the possibility that short-term treatment with oral glucocorticoids may have beneficial effects on jejunal sodium and water transport and the maintenance of fluid and electrolyte homeostasis during acute diarrhea1 illnesses.

Corticosteroids and the Large Intestine In the past 5 yr we have made more progress in understanding the effects of corticosteroid hormones on transport function in the large intestine than in the small intestine, which may be due in part to the ability of corticosteroids to induce more dramatic effects in colonic epithelia. The application of in vitro techniques has enabled active transport processes to be investigated by measuring unidirectional ion fluxes under voltage-clamp conditions, and most recently the effects of corticosteroids on the membrane barriers and forces that control ion movements have been studied with intracellular microelectrodes. These studies have shown that mineralocorticoid and glucocorticoid hormones produce changes in large intestinal sodium and potassium transport that are both quantitatively and qual(15,18,21-24)and that are itatively different probably mediated via different types of corticosteroid receptors in the mucosa (25,26). The effects of glucocorticoid and mineralocorticoid hormones on active sodium absorption and active potassium secretion in the small and large intestine are compared in Table 1. Role of Corticosteroids

in Basal Transport

In adrenalectomized rats maintained on saline, colonic electrolyte movement, mucosal Na,KATPase activity, and transmucosal potential difference are lower than those found in normal animals (10,21). Colonic transport function returns to normal during the administration of physiologic doses of dexamethasone, but not with physiologic or higher doses of aldosterone (21). These results might at first be taken to indicate that colonic electrolyte transport is more dependent on adequate levels of glucocorticoid than of mineralocorticoid hormone. It should be noted, however, that aldosterone has a shorter halflife in plasma than dexamethasone, and one or two daily doses of the mineralocorticoid may not achieve the sustained plasma levels that are required to maintain basal colonic transport processes. In addition, about 80% of plasma corticosteroid (which is

July 1987

Table

CORTICOSTEROIDS

1. Comparison of the Effects of Glucocorticoid and Mineralocorticoid Hormones on Active Sodium Absorption and Active Potassium Secretion in the Small Intestine and Large Intestine Active Na absorption

Glucocorticoids Mineralocorticoids

Active K secretion

Small intestine

Large intestine

Small intestine

Large intestine

++ ‘-

+++ ++++

_ _

+ ++++

the naturally occurring glucocorticoid in the rat) is tightly bound to transcortin (54), whereas circulating dexamethasone is loosely bound to albumin (55) and is more readily available to receptor sites in the mucosa. More recent studies with an experimental model that allows the maintenance of constant predetermined levels of circulating corticosteroids indicate that physiologic amounts of both aldosterone and corticosterone may be required for basal electrolyte transport in rat colon (56). Because this study only measured transmural potential difference at one site (2.5 cm from with anus), additional studies that evaluate the effect of both acute and chronic replacement of glucocorticoids and aldosterone on colonic fluid and electrolyte movement in adrenalectomized animals will be required to establish whether glucocorticoids or aldosterone or both are required for the maintenance of basal electrolyte transport throughout the colon. Effects of Corticosteroid

Excess on Transport

Mineralocorticoids. Since the initial demonstration that aldosterone stimulated sodium and water absorption in human colon (9), the effects of mineralocorticoid hormones on colonic transport have been studied in depth. A variety of studies have shown that hyperaldosteronism (produced by the administration of exogenous aldosterone or secondary to dietary sodium depletion) increases colonic sodium and water absorption and potassium secretion, stimulates mucosal Na,K-ATPase activity, and increases transmucosal potential difference in vivo (10-16).

Several lines of investigation suggest that aldosterone alters sodium transport across colonic epithelia in a time-dependent manner. Incubation of rabbit descending colon with aldosterone (lo-” M) in vitro increases the apical membrane conductance to sodium and net sodium absorption after a 30-60-min delay (57). Infusion of pharmacologic amounts of aldosterone into adrenalectomized rats for 24 h increases the transmucosal potential difference, short circuit current, tissue conductance, and mucosal

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Na,K-ATPase activity in the distal colon, and 50% of the rise in short circuit current is achieved after 3.5 h (10). Other studies in rat distal colon have demonstrated an increase in short circuit current within 4 h of infusion of aldosterone, which becomes maximal after 48 h of continuous aldosterone administration [(58) and Halevy J, Boulpaep EL, Binder HJ, and Hayslett JP, unpublished observations]. The earliest effect of mineralocorticoid excess (probably within 1-4 h) is therefore an increase in the apical membrane conductance to sodium, reflected by the rise in amiloride-sensitive short circuit current. This timecourse is in keeping with the generally held view that mineralocorticoids stimulate the synthesis of transport proteins after binding to specific cytosolic receptors (41). These proteins are probably involved in the insertion of sodium conductive channels into the apical membrane or may activate “latent” proteins already present in the membrane. Studies with intracellular microelectrodes indicate that the characteristic transepithelial electrical effects induced by aldosterone in distal colon are due to depolarization of the apical membrane (reflecting an increase in the sodium conductance of the membrane which is amiloride-sensitive) and hyperpolarization of the basolateral membrane (reflecting an increase in electrogenic Na-K pump acitivity or the potassium selectivity of the membrane, or both) (59). Chronic hyperaldosteronism also increases the surface area and Na,K-ATPase activity (which constitutes the Na-K pump) of the basolateral membrane (60), the rise in enzyme activity mainly reflecting an increase in the number of pump sites (14). In contrast, incubation of isolated turtle colon with aldosterone for 9 h has no effect on the basolateral membrane Na-K pump despite a marked rise in amiloride-sensitive short circuit current (61). It would therefore appear that the initial change in sodium transport induced by mineralocorticoids is an increase in apical sodium entry via amiloride-sensitive sodium channels. Enhancement of basolateral Na,K-ATPase activity occurs later and may be secondary to the increase in apical sodium entry rather than a direct effect of mineralocorticoid hormone on the basolateral Na-K pump. This concept of a primary effect of aldosterone on apical membrane permeability is consistent with some (but not all) of the recent studies in rabbit kidney (62) and toad urinary bladder (63). Several recent studies have established that the mechanisms of electrolyte transport in the proximal and distal segments of the colon are dissimilar and also indicate that the effects of mineralocorticoid hormones on sodium transport may not be identical throughout the colon. In the rabbit, for example, sodium absorption in the distal colon is electrogenic and chloride-independent, whereas in the proximal

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colon, net sodium absorption is essentially zero and epinephrine stimulates chloride-dependent Na-H exchange (64).In rabbit distal colon, deoxycorticosterone acetate stimulates basal sodium absorption and potentiates the ability of SO, ions to stimulate the absorptive capacity for sodium, but the mineralocorticoid has no effect on basal sodium absorption in the proximal colon (65). Studies in rat colon also demonstrate a significant segmental variability with regard to sodium transport and its response to aldosterone. Thus, although aldosterone induces amiloride-sensitive, electrogenic sodium absorption and inhibits electroneutral sodium chloride absorption in the distal colon (15), aldosterone stimulates electroneutral sodium chloride absorption in the proximal colon (which most likely reflects parallel Na-H and Cl-HC03 exchanges) but does not induce amiloride-sensitive electrogenic sodium absorption (66).This observation indicates that aldosterone can augment sodium transport by more than one mechanism (that is, an electroneutral process, in addition to the traditionally accepted amiloridesenstive, electrogenic transport process). In the human colon, sodium transport is almost completely inhibited by amiloride in the distal (sigmoid) segment, but manifests only minimal amiloridesensitivity in the proximal (ascending) segment (67,683. Thus, it is evident that both basal and mineralocorticoid-induced sodium transport differ markedly in the proximal and distal segments of mammalian colon. Although the primary action of aldosterone on colonic sodium transport is stimulation (or induction) of electrogenic sodium absorption, aldosterone also significantly modifies electroneutral sodium chloride absorption. In the distal colon of the rat, aldosterone produces time-dependent changes of electroneutral sodium chloride absorption: aldosterone infused for 24 h increases electroneutral sodium chloride absorption (58),whereas more prolonged aldosterone infusions (7-10days) result in its In contrast, in the proximal colon inhibition (15,58). of the rat, sodium depletion or aldosterone administered for 7 days stimulates electroneutral sodium chloride absorption [(66), Budinger ME and Binder HJ, unpublished observations]. Additional studies are required to determine the mechanism of these disparate effects by aldosterone on colonic electroneutral sodium chloride absorption. It is now clear that aldosterone also induces profound changes in colonic potassium transport. In early human studies, Levitan and Ingelfinger (91 could not demonstrate an effect of aldosterone on potassium secretion during perfusion of the entire colon, but they used a potassium-free perfusate that may have resulted in passive potassium secretory

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fluxes that were sufficient to mask any effect of the mineralocorticoid. Aldosterone was also found to have no effect on active potassium transport in isolated rabbit descending colon (57). In contrast, however, there is strong evidence from in vivo studies that chronic hyperaldosteronism stimulates active (transcellular) as well as passive (paracellular) In addition, studpotassium secretion (11,12,69,70). ies involving the measurement of unidirectional 42K fluxes across isolated rat distal colon under voltageclamp conditions have shown that chronic hyperaldosteronism reverses net potassium absorption in control animals to net potassium secretion in experimental animals, as a result of both an increase in the serosa-to-mucosa (secretory) potassium flux and a decrease in the mucosa-to-serosa (absorptive) potassium flux (16).Similar experiments in rat proximal colon (normally characterized by net potassium secretion) indicate that hyperaldosteronism enhances net potassium secretion solely by increasing the serosa-to-mucosa potassium flux (16). It can be seen, therefore, that chronic hyperaldosteronism stimulates active potassium secretion along the entire colon, mainly by increasing the serosa-to-mucosa movement of potassium, and this probably reflects increased Na,K-ATPase-mediated potassium uptake at the basolateral membrane. Increased potassium uptake may lead to a rise in intracellular potassium activity and consequently to hyperpolarization of the basolateral membrane. Although this electrical change has been demonstrated in distal colon from chronically sodium-depleted animals (59), increased intracellular potassium activity has still to be confirmed by direct measurement with sodium-selective intracellular microelectrodes. In addition to the increase in potassium uptake at the basolateral membrane, in vivo (12,69)and in vitro (16)studies suggest that chronic hyperaldosteronism may increase the potassium conductance of the apical membrane. Addition of amiloride to the apical membrane of distal colon from sodiumdepleted rats completely inhibits electrogenic sodium transport and reverses the short circuit current, whereas unidirectional potassium fluxes and net potassium secretion are unchanged (16). Indeed, the reversed short circuit current can be completely explained by net potassium secretion (16),which suggests that the aldosterone-induced potassium secretory process is electrogenic and most likely involves a change in the apical membrane potassium conductance (an increase in the number of apical potassium channels would tend to hyperpolarize the apical membrane and be reflected by the reversed mucosal polarity in the presence of amiloride). Preliminary studies have shown that the addition of the potassium channel blocker tetraethylammonium

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chloride to the apical membrane inhibits aldosterone-stimulated potassium secretion (Swiery J, Hayslett JP, and Binder HJ, unpublished data) and produces electrical changes in distal colon from sodium-depleted animals that are consistent with the inhibition of an apical membrane potassium conductance (71). It is therefore clear that stimulation of colonic sodium absorption and potassium secretion by aldosterone reflects the combined effects of increased apical membrane conductance to both sodium and potassium, and enhanced activity of the basolateral membrane Na-K exchange pump. Glucocorticoids. Only recently has it become clear that glucocorticoid hormones alter colonic water and electrolyte transport. Pharmacologic doses of methylprednisolone acetate or dexamethasone administered for 3 days increase net sodium and water absorption, net potassium secretion, mucosal Na,KATPase activity, and transmucosal potential difference during in vivo perfusion of rat colon (1,17,18), and similar changes in potential difference and Na,K-ATPase activity are induced by lower “physiologic” doses of dexamethasone (17).Dexamethasone, like aldosterone, appears to alter transport in rat colon in a time-dependent manner, as a single dose of the glucocorticoid increases sodium absorption, potassium secretion, and potential difference in vivo after 5 h, whereas stimulation of mucosal Na,KATPase activity is delayed for a further 19 h (17). Recent in vitro studies have demonstrated that dexamethasone induces apical membrane sodium and potassium channels after 5 h, without a concomitant increase in basolateral membrane Na-K pump activity (72).In contrast, chronic dexamethasone treatment for 3 days results in hyperpolarization of the basolateral membrane (19,20) and a rise in basolateral Na,K-ATPase activity (17,60)as well as an increase in the sodium and potassium conductance of the apical membrane (20). Dexamethasone therefore acts initially to enhance sodium and potassium movement across the apical membrane. Whether the latter increase in basolateral membrane Na-K pump activity is secondary to increased apical sodium entry (as with aldosterone) or reflects direct stimulation of Na,K-ATPase activity by glucocorticoid hormone [as suggested in renal tubular epithelium (46,73)], remains unresolved. It is also of interest that segmental variability in the response of sodium transport to methylprednisolone has recently been demonstrated in rabbit colon; the glucocorticoid enhanced the absorptive capacity for sodium in both the proximal and distal colon even though basal sodium absorption increased only in the distal colon (65).

It should be noted that the ability of both mineralocorticoids and glucocorticoids to stimulate

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electrogenic sodium transport in rat distal colon within hours of administration may be due to binding of both types of hormone to mineralocorticoid receptors (26,74).Several recent observations, however, indicate that mineralocorticoids and glucocorticoids produce changes in sodium and potassium transport that are both qualitatively and quantitatively different, and therefore may reflect their binding to specific mineralocorticoid and glucocorticoid receptors, respectively; in addition there is probably crossover binding. For example, concurrent administration of spironolactone and deoxycorticosterone acetate to nonadrenalectomized animals for 3 days completely prevents the transport changes ordinarily induced by the mineralocorticoid, whereas spironolactone has no effect on the changes induced by methylprednisolone (18).In compensated adrenalectomized animals, colonic electrolyte transport and transmucosal potential difference are completely restored by physiologic doses of dexamethasone but not by physiologic or higher doses of aldosterone (21). More detailed studies have indicated that chronic hyperaldosteronism stimulates amiloride-sensitive electrogenic sodium transport at the expense of amiloride-insensitive neutral sodium chloride absorption, and reverses active potassium absorption to active potassium secretion. In contrast, chronic dexamethasone treatment stimulates amiloride-sensitive electrogenic sodium transport to a lesser degree, does not significantly alter neutral sodium chloride absorption, and only changes net potassium transport to zero (15). It should be emphasized that dexamethasone administered at these high doses (600 pg/lOO g body wt. day for 3 days) occupies mineralocorticoid as well as glucocorticoid receptors (74), and should therefore mimic the effects of aldosterone if both hormones act solely via the mineralocorticoid receptor. However, direct evidence that glucocorticoid hormones alter colonic cation transport via specific receptors has recently been obtained with the synthetic glucocorticoid RU 26988 (25).In a variety of tissues RU 26988 binds specifically to glucocorticoid receptors with no significant affinity for mineralocorticoid receptors. In adrenalectomized rats physiologic doses of RU 26988 stimulate colonic sodium absorption, potassium secretion, and transmural potential difference, particularly in the distal segment (25).The cytosolic receptor involved in these transport effects has been characterized as the corticosteroid binder IB (25), which appears to be the main glucocorticoid receptor in the colon and differs in its properties from the classical receptor (binder II) found in those tissues in which glucocorticoids stimulate metabolic processes (75,76). Other studies indicate specific high-affinity cytosolic receptors for aldosterone in rat colon (26).

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The results of these receptor binding studies substantiate the marked differences that have been observed between glucocorticoidand mineralocorticoid-induced changes in colonic sodium and potassium transport (15,18,21-24) and indicate that glucocorticoids and mineralocorticoids initiate changes in transport by activating specific types of corticosteroid receptor in the colonic cytosol. Figure 1 presents a model of sodium and potassium transport in rat distal colon, which summarizes the main transport mechanisms normally present in the epithelium, and the effects of chronic mineralocorticoid and glucocorticoid excess. Effects of Glucocorticoids Colon

Na

Cl

K

in the Inflamed

Glucocorticoid hormones play an important role in the management of patients with ulcerative colitis and Crohn’s disease (7i’-79), and their ability to decrease diarrhea is generally assumed to reflect their antiinflammatory effect on diseased colonic mucosa. Our improved understanding of the effects of glucocorticoid hormones on colonic electrolyte transport has recently been shown to have clinical relevance. Although glucocorticoids enhance coionic sodium and water absorption in experimental animals, it is only recently that studies have been performed in humans to determine whether the clinical efficacy of these agents is related to changes in fluid aqd electrolyte transport. Under in vitro conditions, transmucosal potential difference and short circuit current in human descending colon normally reflect electrogenic sodium transport (80,81), and the low potentials found in patients with active ulcerative colitis (82,83) suggest that either the disease impairs the sodium transport process or sodium is transported normally but leaks back into the lumen across the inflamed mucosa. In studies of isolated human descending colon, Hawker et al. (83) found that the mucosa-to-serosa and net fluxes of sodium were significantly lower in nonsteroid-treated inflamed colon than in normal colon, whereas sodium fluxes in steroid (prednisolone)treated inflamed colon and normal colon were similar, suggesting that prednisolone treatment had a direct effect on sodium transport. Recent rectal dialysis studies indicate that single intravenous doses of hydrocortisone hemisuccinate (100 mg) or methylprednisolone phosphate (40 mg) result 5 h later in significant increases in transmucosal potential difference and net sodium and water absorption in normal subjects, and similar changes occur in patients with active ulcerative colitis in whom basal potential difference and net sodium and water transport are severely impaired (84). Thus, whatever the

TEA

Figure

1. Models of sodium and potassium transport in rat distal colon under normal conditions (A), and after chronic administration of corticosteroid hormone (B). In normal animals (A), sodium absorption is an electroneutral chloride-dependent process, and probably reflects dual Na-H:Cl-HC03 exchanges (15); potassium absorption is an electroneutral sodium- and chloride-independent process, consistent with K-H exchange (16). Chronic mineralocorticoid (aldosterone) excess (B) induces amiloride-sensitive apical sodium conductive channels (59), inhibits neutral chloride-dependent sodium absorption (IS), induces amiloride-insensitive, tetiaethylammonium chloride (TEA)-inhibitable apical potassium conductive channels (16,71), and stimulates basolateral Na,K-ATPase activity (60). Chronic glucocorticoid (dexamethasone) excess induces apical and basolateral changes that are generally similar to those induced by aldosterone (17,19,20,60), except that electroneutral sodium absorption is not inhibited (15).

underlying transport defect in active ulcerative colitis, the inflamed mucosa responds normally to systemically administered glucocorticoids. If changes observed in the rectum reflect similar changes in the descending and more proximal sec-

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tions of the colon, it seems likely that glucocorticoids reduce diarrhea in both ulcerative colitis and Crohn’s colitis by exerting direct effects on sodium and water transport in addition to their ability to suppress mucosal inflammation.

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AN, Kinsey MD, Myers L, Giannella RA, Gots RE. Na+-K’ activated adenosine triphosphatase and intestinal electrolyte transport. Effects of adrenal steroids. J Clin Invest 1975;56:653-60. 2. Sellin JH, Field M. Physiologic and pharmacologic effects of glucocorticoids on ion transport across rabbit ileal mucosa in vitro. J Clin Invest 1961;67:770-8. 3. Charney AN, Donowitz M. Prevention and reversal of cholera enterotoxin-induced intestinal secretion by methylprednisolone induction of Na+-K+-ATPase. J Clin Invest 1976; 57:1590-g. 4. Marnane WG, Tai Y-H, Decker RA, Boedeker EC, Charney AN, Donowitz M. Methylprednisolone stimulation of guanylate cyclase activity in rat small intestinal mucosa: possible role in electrolyte transport. Gastroenterology 1981;81:90-100. 5. Tai Y-H, Decker RA, Marnane WC, Charney AN, Donowitz M. Effects of methylprednisolone on electrolyte transport by in vitro rat ileum. Am J Physiol 1981;240:G365-70. 6. 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) 1960;151:352-62. 7 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 1966;7:697-9. a Cracker A, Munday KA. Effect of aldosterone on sodium and water absorption from rat jejunum. J Endocrinology 1967; 3a:xxv. 9 Levitan R, Ingelfinger FJ. Effect of d-aldosterone on salt and water absorption from the intact human colon. J Clin Invest i965;44:aoi-a. IO. Will PC, DeLisle RC, Cortright RN, Hopfer U. Induction of amiloride-sensitive sodium transport in the intestines by adrenal steroids. Ann NY Acad Sci 1981;372:64-78. 11. Edmonds CJ. Transport of sodium and secretion of potassium and bicarbonate by the colon of normal and sodium depleted rats. J Physiol (Lond) 1967;193:589-602, 12. Edmonds CJ. Kinetics of potassium in colonic mucosa of normal and sodium-depleted rats. J Physiol (Lond) 1969; 203:533-54. 13. Will PC, Lebowitz

JL, Hopfer U. Induction of amiloride sensitive sodium transport in the rat colon by mineralocorticoids. Am J Physiol 1980;23a:F261-a, 14. Hayslett JP, Myketey N, Binder HJ, Aronson P.S. Mechanism of increased potassium secretion in potassium loading and sodium deprivation, Am J Physiol 1980;239:F378-62. 15. Foster ES, Zimmerman TW, Hayslett JP, Binder HJ. Corticosteroid alteration of active electrolyte transport in rat distal colon. Am J Physiol 1963;245:G668-75. 16. Foster ES, Hayslett JP, Binder HJ. Mechanism of active potassium absorption and secretion in the rat colon. Am J Physiol 1984;246:G611-7. 17. Binder HJ. Effect of dexamethasone on electrolyte transport in the large intestine of the rat. Gastreoenterology 1978; 75:212-7. 18. Charney AN, Wallach J, Ceccarelli S, Donowitz M, Costenbader CL. Effects of spironolactone and amiloride on

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