Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.
Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.
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DOI：
10.1210/jc.2013-2049
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Walker BR
中科院分区：
文献类型：
--
作者：
Iqbal J;Andrew R;Cruden NL;Kenyon CJ;Hughes KA;Newby DE;Hadoke PW;Walker BR
盐皮质激素受体(MR)拮抗剂对心力衰竭和心肌梗死患者有有益的作用，通常被归因于阻断心肌中的醛固酮作用。然而，醛固酮与MR的结合需要11β-羟基类固醇脱氢酶2(11β-HSD2)的局部活性，该酶可使皮质醇失活为皮质醇，从而阻止皮质醇占据受体。11β-HSD2的体内活性和皮质醇在人心脏中对MR的潜在占有率尚未被量化。本研究旨在检测11β-HSD2的体内活性，并确定皮质醇是否能与人心脏中的MR结合。对9例非心力衰竭患者行冠状动脉造影术，给予稳定同位素示踪剂9，11，12，12-[2H]-4-皮质醇和1，2-[2H]-2-皮质醇进入稳态，以定量皮质醇和皮质醇的生成。在静脉注射MR拮抗剂坎尼酸钾之前和之后40分钟，从股动脉和冠状静脉窦获取样本。用静脉造影和多普勒血流线测量冠状静脉窦血流量。在整个心肌中没有检测到皮质醇或皮质醇的产生。给药后，血浆中的醛固酮浓度显著增加，但从心肌中并未检测到醛固酮的释放。相比之下，血浆皮质醇浓度在体循环中没有变化，但组织结合的皮质醇在给药后从心肌中瞬时释放。人类心脏11β-hsd2活性似乎太低，不能使皮质醇失活为可的松。皮质醇被MR拮抗剂急剧地从心肌中置换出来，并可能导致人类心脏中不利的MR激活。
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-[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. 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.
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