Cardioprotective effects of eplerenone in the rat heart: interaction with locally synthesized or blood‐derived aldosterone?

Mineralocorticoid receptor (MR) antagonism with eplerenone reduces mortality in heart failure, possibly due to blockade of the deleterious effects of cardiac aldosterone. To investigate these effects, rat Langendorff hearts were exposed to aldosterone and/or eplerenone under normal and ischemic conditions. Under normal conditions, aldosterone increased left ventricular pressure (LVP) and decreased coronary flow. Eplerenone did not block these effects. Eplerenone reduced infarct size (from 68±2 to 53±4%, P<0.05) and increased LVP recovery (from 44±2% to 60±5%, P<0.05) after 45 minutes of coronary artery occlusion and 3 hours of reperfusion, whereas aldosterone did not affect these parameters. To verify the origin of cardiac aldosterone, hearts were perfused with 3–30 nmol/L aldosterone, and either frozen immediately or exposed to washout. Without washout, cardiac aldosterone was 1.5 times aldosterone in coronary effluent (CE), i.e. too high to be explained on the basis of its presence in extracellular fluid. The cardiac levels of aldosterone correlated with its CE levels (r=0.81, P<0.01), and both were unaffected by eplerenone. During washout, tissue aldosterone disappeared monophasically (t½ 9±1 min), and CE aldosterone disappeared biphasically (t½’s 1±0 and 8±1 min, respectively). During buffer perfusion, cardiac aldosterone was at or below the detection limit. In conclusion, eplerenone improves the condition of the heart following ischemia and reperfusion. This does not relate to interference with the inotropic and vasoconstrictor effects of aldosterone. The majority of cardiac aldosterone, if not all, is derived from the circulation. The rapid, MR‐independent, kinetics of aldosterone suggests that its accumulation in the heart involves cell surface binding rather than internalization.