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Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist

Lookup NU author(s): Professor Brian Walker

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Abstract

Context: Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. Objective: This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. Participants and Interventions: Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[2H]4-cortisol and 1,2-[ 2H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. Results: There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. Conclusions: Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart. Copyright © 2014 by the Endocrine Society.


Publication metadata

Author(s): Iqbal J, Andrew R, Cruden NL, Kenyon CJ, Hughes KA, Newby DE, Hadoke PWF, Walker BR

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2014

Volume: 99

Issue: 3

Pages: 915-922

Print publication date: 01/03/2014

Online publication date: 01/03/2014

Acceptance date: 05/12/2013

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society

URL: https://doi.org/10.1210/jc.2013-2049

DOI: 10.1210/jc.2013-2049

PubMed id: 24423282


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