Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II.
Hypertension , Volume 46 - Issue 4 p. 701- 706
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.
|Adolescent, Adult, Aged, Aldosterone/administration & dosage/metabolism/*pharmacology, Angiotensin II/administration & dosage/*pharmacology, Animals, Cardiac Output, Low/metabolism, Coronary Vessels/drug effects, Dose-Response Relationship, Drug, Drug Synergism, Estradiol/pharmacology, Extracellular Signal-Regulated MAP Kinases/metabolism, Female, Heart/*drug effects/physiology, Humans, Hydrocortisone/pharmacology, Male, Middle Aged, Myocardial Contraction/drug effects, Myocardium/*metabolism, Protein Kinase C/metabolism, Renal Artery/drug effects, Swine, Vasoconstriction/drug effects, Vasoconstrictor Agents/administration & dosage/*pharmacology|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Chai, W, Garrelds, I.M, de Vries, R, Batenburg, W.W, van Kats, J.P, & Danser, A.H.J. (2005). Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II. Hypertension, 46(4), 701–706. doi:10.1161/01.HYP.0000182661.98259.4f