Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells.
Genomic mechanisms of steroid action have been increasingly elucidated over the past four decades. In contrast, rapid steroid actions have been widely recognized only recently, and detailed analysis of the mechanisms involved are still lacking. The present article describes rapid effects of mineralocorticoid hormones on free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. These effects are almost immediate and reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The potent mineralocorticoids aldosterone and fludrocortisone are agonists with estimated apparent EC50 values of approximately 0.1 to 0.5 nmol/L; deoxycorticosterone acetate is an agonist with an EC50 of approximately 5 nmol/L; and progesterone, cortisol, corticosterone, and estradiol have much lower potency (EC50 values of approximately 0.5 to 5 mumol/L). The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca2+ effect appears to involve the release of intracellular Ca2+, as shown by the inhibitory effect of thapsigargin; intriguingly, a relatively small maximum effect (approximately 40 nmol/L increase) is consistently seen. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to be a likely candidate for rapid fine tuning of cardiovascular responsivity. It may also contribute to known clinical features of mineralocorticoid action that are difficult to explain by the traditional genomic mechanism alone.
Wehling
M
M
Baker Medical Research Institute, Victoria, Australia.
Neylon
C B
CB
Fullerton
M
M
Bobik
A
A
Funder
J W
JW
D000450:Aldosterone / Q000494:pharmacology*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008901:Mineralocorticoids / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009355:Neomycin / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D013050:Spectrometry, Fluorescence; D019311:Staurosporine; D013997:Time Factors
D000470:Alkaloids; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D010703:Phorbol Esters; D000450:Aldosterone; D011493:Protein Kinase C; D019311:Staurosporine; D009355:Neomycin; D002118:Calcium