Abstract 14332: Mineralocorticoid Receptor Antagonists Displace Cortisol, not Aldosterone, from the Human Heart
Introduction: Beneficial effects of mineralocorticoid receptor (MR) antagonists in heart failure and adverse associations with elevated plasma aldosterone have been attributed to MR activation by aldosterone. MR has similar affinity for cortisol and aldosterone; since physiological concentrations of cortisol are 2-3 times more than aldosterone, MR are preferentially occupied by cortisol except in cells expressing the cortisol-inactivating enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). We aimed to measure cortisol-cortisone interconversion in human heart in vivo, and to test whether aldosterone or cortisol is displaced from myocardium by an MR antagonist, potassium canrenoate (KC).
Methods: Nine patients 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 femoral artery and coronary sinus before and for 40 min after intravenous bolus of KC. Myocardial blood flow was measured by coronary sinus venography and Doppler velocitometry.
Results: Four men and 5 women were studied, aged 61±4 years with body mass index 29.9±1.8 kg/m2 and BP 141±13/74±4 mmHg. Coronary sinus blood flow was 0.21±0.02 L/min at baseline and was unaffected by KC. There was no detectable production of cortisol or cortisone in myocardium either at baseline or post KC. Plasma aldosterone increased substantially after KC (Fig 1A) but was not released across myocardium (Fig 1B). In contrast, cortisol was released transiently from the myocardium after MR antagonism with KC (Fig 1C).
Conclusion: Aldosterone was displaced into the systemic circulation by KC, most likely from MR in kidney. However, 11β-HSD2 activity in human heart is too low to inactivate cortisol to cortisone. As a result, it is cortisol rather than aldosterone which occupies MR and is displaced from the myocardium by MR antagonism.
- © 2012 by American Heart Association, Inc.