Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction
Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction
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DOI：
10.1161/hypertensionaha.109.136242
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发表时间：
2009-12-01
期刊：
影响因子：
8.3
通讯作者：
Funder, John W.
中科院分区：
文献类型：
--
作者：
Mihailidou, Anastasia S.;Le, Thi Yen Loan;Funder, John W.
心肌缺血再灌注导致氧化还原状态发生显著改变，缺血后功能恢复减慢，心肌细胞发生凋亡，从而导致心力衰竭的发生和发展。大鼠离体心缺血再灌流可作为心力衰竭的动物模型。在临床上，在心力衰竭中阻断盐皮质激素受体可降低发病率和死亡率，而不是单纯的标准治疗。在大鼠心脏缺血30min和再灌流2.5h后，观察皮质类固醇对心肌梗死面积和细胞凋亡的影响。醛固酮和皮质醇均增加梗塞面积和细胞凋亡指数，这种作用在1-10 nM之间达到一半，并被螺内酯逆转。地塞米松和米非司酮加重心肌梗死面积和细胞凋亡指数，螺内酯对其有类似逆转作用。在完整和肾上腺切除的大鼠的心脏中，单独使用螺内酯可以减少缺血再灌流下的心肌梗死面积和细胞凋亡指数。目前的研究表明，醛固酮或皮质醇激活盐皮质激素受体或地塞米松激活糖皮质激素受体可加重心脏损伤。米非司酮出人意料地作为糖皮质激素受体激动剂，这是有几个先例的。螺内酯通过盐皮质激素受体的反向激动剂活性来保护心肌细胞，这种作用在相对较低的剂量(10 NM)时接近最大。螺内酯的作用不仅是通过将皮质类固醇排除在盐皮质激素受体上，而且在低浓度时还作为一种保护性的反向激动剂。因此，盐皮质激素受体拮抗剂可能在不稳定心绞痛和急性心肌梗死中提供额外的治疗优势。(高血压。2009；54：1306-1312。)
Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone. Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM). Spironolactone acts not merely by excluding corticosteroids from mineralocorticoid receptors but as a protective inverse agonist at low concentration. Mineralocorticoid receptor antagonists may, thus, provide an additional therapeutic advantage in unstable angina and acute myocardial infarction. (Hypertension. 2009; 54: 1306-1312.)