Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction

Anastasia S. Mihailidou, Thi Yen Loan Le, Mahidi Mardini, John W. Funder

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone. Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM). Spironolactone acts not merely by excluding corticosteroids from mineralocorticoid receptors but as a protective inverse agonist at low concentration. Mineralocorticoid receptor antagonists may, thus, provide an additional therapeutic advantage in unstable angina and acute myocardial infarction.

Original languageEnglish
Pages (from-to)1306-1312
Number of pages7
JournalHypertension
Volume54
Issue number6
DOIs
Publication statusPublished - Dec 2009
Externally publishedYes

Keywords

  • Cortisol
  • Inverse agonist
  • Mineralocorticoid receptor
  • Myocardial infarction
  • Spironolactone

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