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(Hypertension. 2005;46:701.)
© 2005 American Heart Association, Inc.

Original Articles

Nongenomic Effects of Aldosterone in the Human Heart

Interaction With Angiotensin II

Wenxia Chai; Ingrid M. Garrelds; René de Vries; Wendy W. Batenburg; Jorge P. van Kats; A.H. Jan Danser

From the Departments of Pharmacology (W.C., I.M.G., R.d.V., W.W.B., A.H.J.D.) and Thoracic Surgery and Heart Valve Bank (J.P.v.K.), Erasmus MC, Rotterdam, The Netherlands.

Correspondence to Dr A.H Jan Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail a.danser{at}erasmusmc.nl

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 17ß-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 µmol/L aldosterone or 17ß-estradiol (but not hydrocortisone) doubled the maximum contractile response (E_max) to Ang II. E_max 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 17ß-estradiol levels <1 µmol/L. Aldosterone did not potentiate the ₁-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.

Key Words: aldosterone • mineralocorticoids • angiotensin • human

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