Nongenomic Effects of Aldosterone in the Human Heart

Abstract

Abstract-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 34Ϯ3% and 15Ϯ4%, 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 17␤-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 mol/L aldosterone or 17␤-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 (PϽ0.01). 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 17␤-estradiol levels Ͻ1 mol/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.

Cardioprotective Effects of Eplerenone in the Rat Heart

“…7 Interestingly, spironolactone did not block aldosterone-induced vasoconstriction, which worsens cardiac contractile and metabolic function in the ischemic heart. 8,9 It also did not prevent the inotropic effects of aldosterone in the heart, 7,10 and, if anything, exerted inotropic effects of its own, independent of aldosterone.…”

Effects of Aldosterone on the Vasculature

“…Similar results have also been obtained recently in human coronary arteries obtained from heart valve donors. 61 In aldosterone-potentiated coronary artery Ang II responses in proportion to extracellular signal-regulated kinase 1/2 phosphorylation and PKC activation. These effects were not blocked by spironolactone or eplerenone, suggesting that they are nongenomic.…”

A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

“…These nongenomic, or rapid, effects occur within minutes at target tissues and organs, including the kidney, heart, and vasculature. 5 It is not yet fully defined which of the effects of aldosterone occur through genomic versus nongenomic mechanisms. Further, aldosterone may exert both genomic and nongenomic actions within the same tissue, as is seen in the vasculature.…”

“…6,7 Effects of aldosterone that have been proven to occur via a nongenomic mechanism include coronary vasoconstriction leading to worsening contractile and metabolic functions in the ischemic heart, increased systemic vascular resistance, negative inotropic response in human trabeculae, and potentiation of the vasoconstrictor effect of angiotensin II in coronary arteries. 5,6,8 That these nongenomic effects of aldosterone are sometimes mediated by MR is supported by the ability of MR blockers to inhibit many of these actions. Overall, eplerenone appears to produce more consistent inhibition of some of the nongenomic effects of aldosterone 7,9 than spironolactone.…”