University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
J Clin Endocrinol Metab. 2014 Mar;99(3):915-22. doi: 10.1210/jc.2013-2049. Epub 2013 Jan 1.
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.
This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart.
Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]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.
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.
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.
盐皮质激素受体（MR）拮抗剂在心力衰竭和心肌梗死患者中具有有益作用，这通常归因于阻断心肌中醛固酮的作用。然而，醛固酮与 MR 的结合需要酶 11β-羟类固醇脱氢酶 2（11β-HSD2）的局部活性，该酶将皮质醇失活为可的松，从而防止皮质醇占据受体。在人体心脏中，11β-HSD2 的体内活性和潜在的皮质醇与 MR 的结合尚未被量化。
本研究旨在测量 11β-HSD2 的体内活性，并确定皮质醇是否与人体心脏中的 MR 结合。
9 名无心力衰竭的患者在诊断性冠状动脉造影期间接受稳定同位素示踪剂 9、11、12、12-[(2)H]4-皮质醇和 1、2-[(2)H]2-可的松的恒稳态输注，以量化皮质醇和可的松的生成。在静脉注射 MR 拮抗剂钾可利农后，从股动脉和冠状窦取样本。冠状窦血流通过静脉造影和多普勒血流导丝测量。
在心肌中未检测到皮质醇或可的松的生成。钾可利农给药后，血浆醛固酮浓度显著升高，但醛固酮未从心肌中检测到释放。相比之下，皮质醇在全身循环中的浓度没有变化，但在给予钾可利农后，组织结合的皮质醇从心肌中短暂释放。
人体心脏中的 11β-HSD2 活性似乎太低，无法将皮质醇失活为可的松。MR 拮抗剂会使皮质醇从心肌中迅速被置换出来，这可能导致人体心脏中出现不良的 MR 激活。
