Cardioprotective effects of eplerenone in the rat heart: interaction with locally synthesized or blood-derived aldosterone?
Mineralocorticoid receptor antagonism with eplerenone reduces mortality in heart failure, possibly because of blockade of the deleterious effects of aldosterone. To investigate these effects, rat Langendorff hearts were exposed to aldosterone and/or eplerenone. Under normal conditions, aldosterone increased left ventricular pressure 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 left ventricular pressure 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 to 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), that is, 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 (half life, 9+/-1 minutes), and CE aldosterone disappeared biphasically (half life 1+/-0 and 8+/-1 minutes, respectively). During buffer perfusion, cardiac aldosterone was at or below the detection limit. In conclusion, eplerenone improves the condition of the heart after 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, mineralocorticoid receptor-independent kinetics of aldosterone suggest that its accumulation in the heart involves cell surface binding rather than internalization.
Chai
Wenxia
W
Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
Garrelds
Ingrid M
IM
de Vries
René
R
Danser
A H Jan
AH
D000450:Aldosterone / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology; D017202:Myocardial Ischemia / Q000150:complications; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D002316:Cardiotonic Agents; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone