ENZYME AND MINERALOCORTICOID RECEPTOR-CONTROLLED ELECTROGENIC NA-VITRO( ABSORPTION IN HUMAN RECTUM IN)

In vivo electrogenic Na+ absorption (J(Na)(e)) in the human rectum is controlled by acute variation of aldosterone in nanomolar concentratio n range. In this study we report both the induction of J(Na)(e), in hu man rectum epithelium by nanomolar aldosterone added in vitro and the enzymatic control of glucocorticoid action on J(Na)(e). J(Na)(e) was m easured as amiloride-sensitive short-circuit current 8 h after additio n of the respective steroid. Aldosterone (10 nM) caused J(Na)(e), of 5 .7 +/- 1.4 mu mol . h(-1). cm(-2). Cortisol in the same concentration did not induce significant J(Na)(e). Because cortisol is readily inact ivated by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the true mineralocorticoid activity of cortisol was evaluated after inhibition of 11 beta-HSD by carbenoxolone. Carbenoxolone alone did not exhibit mineralocorticoid activity. If cortisol (10 nM) was given together wit h carbenoxolone (1 mu M), the resulting J(Na)(e) (4.5 + 0.4 +/- mu mol . h(-1). cm(-2)) was not significantly different from that after 10 n M aldosterone, indicating equal intrinsic mineralocorticoid activity o f cortisol and aldosterone. The same mechanisms were found in rat late distal colon. Kinetic data of carbenoxolone at 10 nM cortisol resulte d in a Michaelis constant of 0.3 mu M, maximal absorption of 8.4 mu mo l . h(-1). cm(-2), and a Hill coefficient of 1.8. The effects of carbe noxolone and glycyrrhetinic acid did not differ. We conclude that J(Na )(e) is under complete control of mineralocorticoid action. ''Spontane ous'' J(Na)(e) in the beginning of the in vitro period can be explaine d by elevated steroid levels before tissue removal. The biological act ivity of 11 beta-HSD localized in rectum epithelium suffices to comple tely inactivate cortisol to cortisone in vitro for several hours, thus protecting the mineralocorticoid receptor from high glucocorticoid co ncentrations.