Document Detail

Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II.
MedLine Citation:
PMID:  16144984     Owner:  NLM     Status:  MEDLINE    
Aldosterone exerts rapid "nongenomic" effects in various nonrenal tissues. Here, we investigated whether such effects occur in the human heart. Trabeculae and coronary arteries obtained from 57 heart valve donors (25 males; 32 females; 17 to 66 years of age) were mounted in organ baths. Aldosterone decreased contractility in atrial and ventricular trabeculae by maximally 34+/-3% and 15+/-4%, respectively, within 5 to 15 minutes after its application. The protein kinase C (PKC) inhibitor chelerythrine chloride, but not the mineralocorticoid receptor antagonists spironolactone and eplerenone, blocked this effect. Aldosterone also relaxed trabeculae that were prestimulated with angiotensin II (Ang II), and its negative inotropic effects were mimicked by hydrocortisone (at 10-fold lower potency) but not 17beta-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 micromol/L aldosterone or 17beta-estradiol (but not hydrocortisone) doubled the maximum contractile response (Emax) to Ang II. DeltaEmax correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (P<0.01). Spironolactone and eplerenone did not block the potentiating effect of aldosterone. Studies in porcine renal arteries showed that potentiation also occurred at pmol/L aldosterone levels but not at 17beta-estradiol levels <1 micromol/L. Aldosterone did not potentiate the alpha1-adrenoceptor agonist phenylephrine. In conclusion, aldosterone induces a negative inotropic response in human trabeculae (thereby antagonizing the positive inotropic actions of Ang II) and potentiates the vasoconstrictor effect of Ang II in coronary arteries. These effects are specific and involve PKC and ERK 1/2, respectively. Furthermore, they occur in a nongenomic manner, and require pathological aldosterone concentrations.
Wenxia Chai; Ingrid M Garrelds; René de Vries; Wendy W Batenburg; Jorge P van Kats; A H Jan Danser
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2005-09-06
Journal Detail:
Title:  Hypertension     Volume:  46     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-30     Completed Date:  2005-12-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  701-6     Citation Subset:  IM    
Department of Pharmacology, Erasmus MC, 3015 GE Rotterdam, The Netherlands.
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MeSH Terms
Aldosterone / administration & dosage,  metabolism,  pharmacology*
Angiotensin II / administration & dosage,  pharmacology*
Cardiac Output, Low / metabolism
Coronary Vessels / drug effects
Dose-Response Relationship, Drug
Drug Synergism
Estradiol / pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism
Heart / drug effects*,  physiology
Hydrocortisone / pharmacology
Middle Aged
Myocardial Contraction / drug effects
Myocardium / metabolism*
Protein Kinase C / metabolism
Renal Artery / drug effects
Vasoconstriction / drug effects
Vasoconstrictor Agents / administration & dosage,  pharmacology*
Reg. No./Substance:
0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 50-23-7/Hydrocortisone; 50-28-2/Estradiol; 52-39-1/Aldosterone; EC Kinase C; EC Signal-Regulated MAP Kinases

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