Rapid effects of aldosterone on vascular cells: clinical implications.
Aldosterone has attracted considerable interest as an independent cardiovascular risk marker, which has been demonstrated in a number of studies. Furthermore, recent studies revealed the prevalence of hyperaldosteronism to be about tenfold higher than previously assumed, which underlines its clinical importance. Aldosterone affects virtually any part of the cardiovascular system, namely cardiac fibroblasts and myocytes, and vascular endothelial and smooth muscle cells. In the latter cells, our laboratory has demonstrated a variety of rapid effects of the steroid, e.g. on intracellular calcium, inositol trisphosphate, and cAMP. There is also evidence for a modulation of genomic events by rapid aldosterone effects that occur via phosphorylation of transcription factors such as CREB. Furthermore, rapid tyrosine phosphorylation has been observed in vascular cells. The majority of rapid responses reported to date are insensitive towards the classic mineralocorticoid receptor (MR) antagonist, spironolactone. The in vitro experiments are complemented by a series of clinical studies in healthy volunteers, which could demonstrate rapid modulation of cardiovascular parameters after aldosterone administration, e.g. of systemic vascular resistance. In addition, an interaction of aldosterone with the adrenergic system has been observed. Most recently, rapid aldosterone induced contraction of resistance arteries has been reported. In general, the rapid in vivo effects of aldosterone are likely to participate in the pathogenesis of cardiovascular disorders. As many rapid and thus nonclassic aldosterone responses cannot be blocked by spironolactone, further research is required in order to provide adequate inhibitors to interfere with these pathways.
Department of Clinical Pharmacology Mannheim, Institut für Klinische Pharmakologie, University of Heidelberg, Klinikum Mannheim, Theodor-Kutzer-Ufer, D-68167 Mannheim, Germany.
Ralf
R
Lösel
Armin
A
Schultz
Brigitte
B
Boldyreff
Martin
M
Wehling
D000450:Aldosterone / Q000494:pharmacology* / Q000502:physiology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D002319:Cardiovascular System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002986:Clinical Trials as Topic; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone