Electrogenic Na+ transport in rat late distal colon by natural and synthetic glucocorticosteroids

Abstract

The potency of in vitro-added corticosteroids to stimulate electrogenic Na+ absorption (J(Na), the Na+ absorptive short-circuit current blockable by 10-4 M amiloride) was determined in rat late distal colon. J(Na) was determined 8 h after steroid addition from the drop in short-circuit current caused by 10-4 M amiloride. The concentration dependency of J(Na) was obtained for seven corticosteroids and compared with that established for aldosterone. Apparent mineralocorticoid potencies as determined from apparent Michaelis-Menten constant (K(m)) values were as follows: aldosterone 1.2 nM >> RU-28362 20 nM = deoxycorticosterone 20 nM > deoxycortisol 36 nM ≥ dexamethasone 37 nM >> corticosterone 170 nM > cortisol 210 nM. These steroids exhibited V(max) values of 9-13 μmol·h-1·cm-2 and similar concentration dependencies. Hill coefficients were between 1.6 and 2.1, suggesting cooperative effects between activated receptors. We conclude that corticosteroids exhibit graded mineralocorticoid potency instead of a sharp partition into exclusive groups of mineralocorticoid and nonmineralocorticoid hormones. The low apparent K(m) value of RU-28362 for mineralocorticoid action and the need for high concentrations of the mineralocorticoid antagonist mespirenone to block this response indicated that J(Na) in a native mammalian epithelium can be mediated by the glucocorticoid receptor. Glucocorticoid receptor-specific amounts of RU-28362 in combination with mineralocorticoid receptor-specific amounts of aldosterone or of the mineralocorticoid antagonist spironolactone showed cooperative action, suggesting a heterodimeric activation of J(Na) by the glucocorticoid receptor and mineralocorticoid receptor.