To test whether glucocorticoids act as the endogenous agonist of cardiac mineralocorticoid receptors, we evaluated the cardiac effects of aldosterone and corticosterone and cardiac steroidogenesis vs. steroid uptake from plasma.
Both corticosterone and aldosterone increased left ventricular pressure in the rat heart. Aldosterone decreased coronary flow, whereas corticosterone increased it. All corticosterone effects were blocked by the glucocorticoid receptor antagonist, RU486, and unaltered by the mineralocorticoid receptor antagonist, canrenoate, or the 11β-hydroxysteroid dehydrogenase (HSD11B)2 inhibitor, carbenoxolone. Unlike mineralocorticoid receptor blockade, RU486 did not ameliorate postischemia infarct size and arrhythmias. Corticosterone, when added to the perfusion buffer, rapidly accumulated at cardiac tissue sites, reaching steady-state levels that were identical to those in coronary effluent, independently of the presence of aldosterone, RU486 or canrenoate. After stopping the perfusion, cardiac corticosterone fully washed away with a half-life of less than 1 min. Measurements of steroid-synthesizing enzyme gene expression levels in human ventricular and atrial tissue pieces from heart-beating organ donors, patients with end-stage heart failure and hypertrophic cardiomyopathy patients revealed that under no condition, the human heart was capable of synthesizing aldosterone or cortisol de novo. Yet, expression of HSD11B1, HSD11B2, mineralocorticoid receptors and glucocorticoid receptors was found, and HSD11B2 and mineralocorticoid receptors were upregulated in pathological conditions. Moreover, aldosterone reduced cardiac inotropy in a Na+/K+/2Cl− cotransporter-dependent manner.
Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.
aDivision of Pharmacology, Vascular and Metabolic Diseases, The Netherlands
bDivision of Endocrinology, Department of Internal Medicine, The Netherlands
cDepartment of Thoracic Surgery and Heart Valve Bank, Erasmus Medical Center, Rotterdam, The Netherlands
1W.C. and J.H. contributed equally to the writing of this article.
Received 12 August, 2009
Revised 1 November, 2009
Accepted 24 November, 2009
Correspondence to Professor Dr A.H. Jan Danser, Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Room #EE1418b, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands Tel: +31 10 7043540; fax: +31 10 7044733; e-mail: firstname.lastname@example.org