title: Steroid metabolism determines mineralocorticoid specificity in the toad bladder.
abstract: Edwards et al. (C. R. W. Edwards, P. M. Stewart, D. Burt, L. Brett, M. A. McIntyre, W. S. Sutanto, E. R. de Kloet, and C. Monder, Lancet 2: 986-989, 1988) proposed that 11 beta-hydroxysteroid-dehydrogenase (11 beta-OHSD) plays a key role in the kidney by converting glucocorticoids (cortisol or corticosterone), which display a high affinity for type 1 mineralocorticoid receptors, into their inactive metabolites (cortisone or 11-dehydroxy-corticosterone), thus preventing their illicit occupation of the receptor in the target cell for aldosterone. We have tested this hypothesis in the urinary bladder of Bufo marinus by measuring the sodium transport responses to aldosterone and corticosterone. Aldosterone (10 nM) on the serosal side elicited a quarter of the maximal increase in sodium transport. At the same concentration, corticosterone (10 nM, serosal side) was ineffective. Adding corticosterone (10 nM) on the mucosal side elicited a response equivalent to that of aldosterone, suggesting that corticosterone was inactivated in the serosal or underlying tissue of the toad bladder. Carbenoxolone (10 microM, serosal side), a potent inhibitor of 11 beta-OHSD, did not modify the base-line sodium transport. However, in the presence of carbenoxolone (10 microM, serosal side, 2 h pretreatment) corticosterone (10 nM, serosal side) became as potent as aldosterone in eliciting the mineralocorticoid response. Our data are consistent with the idea that corticosterone is converted into an inactive metabolite in the mucosal and/or submucosal tissue of the toad bladder. These studies are consistent with our concept that 11 beta-OHSD is crucial in protecting the nonspecific mineralocorticoid receptor from glucocorticoid.
authors.affiliation: Institut de Pharmacologie de l'Université de Lausanne, Switzerland.
authors.forename: H P
authors.initials: HP
authors.lastname: Gaeggeler
authors.forename: C R
authors.initials: CR
authors.lastname: Edwards
authors.forename: B C
authors.initials: BC
authors.lastname: Rossier
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D005075:Biological Evolution; D001693:Biological Transport, Active / Q000187:drug effects; D002024:Bufo marinus; D002229:Carbenoxolone / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology*; D004553:Electric Conductivity; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D066298:In Vitro Techniques; D009092:Mucous Membrane / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D000450:Aldosterone; D012964:Sodium; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D003345:Corticosterone