Effects of spironolactone and amiloride on corticosteroid-induced changes in colonic function

Abstract

Mineralocorticoid and glucocorticoid effects on colonic electrolyte absorption were compared by examining the alterations caused by spironolactone and amiloride in corticosteroid-treated rats. Animals were treated for 3 days with deoxycorticosterone acetate (DOCA; 0.5 mg . 100 g-1 . day-1), methylprednisolone (MP; 3 or 0.5 mg . 100 g-1 . day), and spironolactone (14 mg . 100 g-1 . day-1 im) singly or in combination. On day 4, rats were anesthetized with pentobarbital sodium and perfused in vivo with Ringer-HCO3 solution. Both doses of MP and DOCA increased net colonic sodium and water absorption and mucosal Na-K-ATPase activity. Concurrent spironolactone treatment completely prevented these effects in DOCA-treated rats but had no effect in MP-treated rats. Untreated, MP-treated, and DOCA-treated animals were perfused with a Ringer-HCO3 solution containing 1 mM amiloride. Amiloride reduced net colonic sodium and water absorption, transmural potential difference, and potassium secretion in all rats by approximately 55%. These effects were almost immediate and completely reversible. These findings in the rat suggest that 1) different receptors mediate the colonic effects of mineralocorticoids and glucocorticoids and 2) these corticosteroids do not differ in their relative effects on amiloride-sensitive and amiloride-resistant colonic sodium transport processes.

Regulation of active sodium and potassium transport in the distal colon of the rat. Role of the aldosterone and glucocorticoid receptors.

“…It is now well accepted that aldosterone stimulates active amiloride-sensitive sodium absorption and active potassium secretion in the distal colon of rat and rabbit (3)(4)(5). Glucocor- ticosteroids have similar, but not identical effects on electrolyte transport in the mammalian colon (1,(7)(8)(9)(10)(11)(12), and considerable uncertainty exists regarding the exact role of aldosterone and glucocorticoids in the regulation of colonic ion transport. The demonstration that both specific mineralocorticoid and glucocorticoid cytosolic receptors are present in the rat and rabbit colon is consistent with the interpretation that each cytosolic steroid receptor mediates specific ion transport processes (13)(14)(15)(16).…”

“…However, dietary sodium depletion also affects electroneutral sodium and potassium absorption in the rat distal colon: electroneutral Na-Cl absorption is inhibited and electroneutral potassium absorption is stimulated (3,5). Recent studies with continuous infusion of aldosterone have confirmed that the changes in sodium and chloride transport observed in dietary sodium depletion are due to aldosterone (6); similar studies have not yet been performed for potassium transport. Synthetic glucocorticoids (e.g., dexamethasone, methylprednisolone) also produce substantial changes in both sodium and potassium movement in the mammalian distal colon (1,3,4,(7)(8)(9)(10)(11)(12). Although both glucocorticoid and aldosterone (i.e., mineralocorticoid) receptors have been identified in the cytosol of colonic epithelial cells (13)(14)(15)(16)(17), there has been considerable controversy whether separate and specific changes in ion transport are mediated by the activation of these glucocorticoid and mineralocorticoid receptors.…”

Regulation of cation transport by low doses of glucocorticoids in in vivo adrenalectomized rat colon.

“…In proximal colon, ileum, and jejunum, the major increase in sodium absorption and short-circuit current produced by glucocorticoids is amiloride resistant, a finding uncharacteristic for an aldosterone-induced response (2,8,36,49). In distal colon, amiloride-resistant transport may be induced with low doses or concentrations ofdexamethasone and amiloride-inhibitable transport induced at doses ofdexamethasone greater than the 10 nmol dose used in this study (2,3,5,7,8,17,18). Wills reported that the dose of dexamethasone required to produce 50% amiloride-sensitive short-circuit current in rat distal colon is 3 A/l00 g body wt per h (72 gg/I00 g body wt per d), a dose exceeding the highest dose (50 nmol) used in this study by 50% (8).…”

“…Subsequently, most of the in vivo and in vitro studies of glucocorticoid-induced colon transport have used amounts of glucocorticoids that could permit stimulation ofboth glucocorticoidand aldosterone-induced pathways (2)(3)(4)(5)(6)(7)(8)(9). Thus, the in vivo response of the colon to circulating physiologic levels of glucocorticoids has not been thoroughly investigated.…”

“…The colonic response to glucocorticoids has varied with the levels of glucocor-ticoids used. At levels that approach receptor saturation, glucocorticoid-induced distal colon sodium absorption is amiloride resistant, but at supersaturating levels sodium absorption is amiloride inhibitable (2,3,5,(7)(8)(9)(16)(17)(18). Although amiloridesensitive sodium absorption may be induced by crossover binding to aldosterone receptors, important differences have been found between glucocorticoid-and aldosterone-induced transport even with massive doses of glucocorticoids (2, 4-9, 13, 17, 18).…”