Document Detail

Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction.
MedLine Citation:
PMID:  19841288     Owner:  NLM     Status:  MEDLINE    
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.
Anastasia S Mihailidou; Thi Yen Loan Le; Mahidi Mardini; John W Funder
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-19
Journal Detail:
Title:  Hypertension     Volume:  54     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-20     Completed Date:  2009-12-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1306-12     Citation Subset:  IM    
Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, NSW 2065, Australia.
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MeSH Terms
Aldosterone / metabolism
Aldosterone Antagonists / pharmacology
Angina, Unstable / drug therapy,  metabolism,  pathology
Apoptosis / physiology
Dexamethasone / pharmacology*
Glucocorticoids / pharmacology*
Hormone Antagonists / pharmacology
Hydrocortisone / metabolism
Mifepristone / pharmacology
Myocardial Infarction / drug therapy*,  metabolism*,  pathology
Myocardial Reperfusion Injury / drug therapy,  metabolism,  pathology
Rats, Sprague-Dawley
Receptors, Mineralocorticoid / metabolism*
Spironolactone / pharmacology
Reg. No./Substance:
0/Aldosterone Antagonists; 0/Glucocorticoids; 0/Hormone Antagonists; 0/Receptors, Mineralocorticoid; 50-02-2/Dexamethasone; 50-23-7/Hydrocortisone; 52-01-7/Spironolactone; 52-39-1/Aldosterone; 84371-65-3/Mifepristone
Comment In:
Hypertension. 2009 Dec;54(6):1211-2   [PMID:  19841284 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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