Rapid effects of mineralocorticoids on sodium-proton exchanger: genomic or nongenomic pathway?
High-affinity aldosterone binding sites have been described in human mononuclear leukocytes (HML), and in vitro effects of aldosterone on intracellular sodium, potassium, and calcium concentrations and cell volume have been shown in HML. In the present paper, the response of the sodium-proton exchanger of the cell membrane to agonists and antagonists was studied by determining the kinetics of HML swelling in isotonic sodium propionate. Within 1-2 min of incubation, aldosterone significantly stimulated propionate-induced swelling by an additional 30-50% at concentrations as low as 0.07 nM. This effect was not blocked by the classical aldosterone antagonists potassium canrenoate or canrenone at concentrations of 140 or 700 nM. Hydrocortisone and dexamethasone were effective agonists only at much higher concentrations (4,000 nM). These data are not well explained by a mechanism of steroid action involving the interaction of a steroid receptor complex with nuclear DNA, since the effect on the sodium-proton exchanger is too fast. The findings could indicate distinct membrane receptors with a high affinity for aldosterone, but not hydrocortisone, and rapid direct membrane effects of aldosterone. These putative novel receptors may in turn bind novel aldosterone antagonists with possible diuretic and vasodilator effects distinct from those of spironolactones.
Wehling
M
M
Medizinische Klinik Innenstadt, University of Munich, Federal Republic of Germany.
Käsmayr
J
J
Theisen
K
K
D000450:Aldosterone / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002191:Canrenoic Acid / Q000494:pharmacology; D002192:Canrenone / Q000494:pharmacology; D002352:Carrier Proteins / Q000097:blood*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D011188:Potassium / Q000097:blood; D011422:Propionates / Q000494:pharmacology; D012016:Reference Values; D012964:Sodium / Q000097:blood*; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D011422:Propionates; D017923:Sodium-Hydrogen Exchangers; D000450:Aldosterone; D002192:Canrenone; D003907:Dexamethasone; D002191:Canrenoic Acid; D004247:DNA; D012964:Sodium; D011188:Potassium; D002118:Calcium; D006854:Hydrocortisone