Reconsidering the Roles of the Mineralocorticoid Receptor
Reconsidering the Roles of the Mineralocorticoid Receptor
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DOI：
10.1161/hypertensionaha.108.119966
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发表时间：
2009-02-01
期刊：
影响因子：
8.3
通讯作者：
Funder, John W.
中科院分区：
文献类型：
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作者：
Funder, John W.
转化研究通常是指将实验室发现应用于临床实践。然而，就像语言或酶一样，翻译是一条双向路，在醛固酮和盐皮质激素受体 (MR) 领域，有许多临床研究促使人们重新考虑基础生物学的例子。例如，在原发性高血压受试者中，选择性 MR 拮抗剂依普利酮的抗高血压作用和电解质作用之间的区别已被解释为反对醛固酮/MR 激活在升高血压中的主要肾脏作用的证据。 1 同样，S810L MR 突变受体的发现导致青少年高血压因怀孕而加剧2，这促使人们重新考虑来自共同原始祖先蛋白的类固醇激素受体的 MR/糖皮质激素受体 (GR)/孕激素受体 (PR)/雄激素受体 (AR) 亚家族的分支顺序。 3这些研究及其对醛固酮作用的基础生物学的影响已在其他地方讨论过。 4 本综述重点关注近十年前促使重新审查过程的临床研究（随机 ALdactone 评估研究 [RALES] 5）。这项研究的基本原理是，针对纽约心脏病协会 III 级心力衰竭患者，之前的临床研究表明，血浆醛固酮水平可以突破长期血管紧张素转换酶抑制和血管紧张素 II 1 型阻断；此外，Brilla 和 Weber6 的早期实验室研究表明，外源性醛固酮加生理盐水作为饮用液会导致未切除肾的大鼠心脏肥大和纤维化。 RALES 的结果是显着的。由于两组之间的差异，该试验在预计招募期过半时停止：一组接受标准治疗（血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、利尿剂等）加安慰剂，另一组接受标准治疗加螺内酯。添加非常适度剂量的螺内酯（平均：26 毫克/天）可使生存率提高 30%，住院率减少 35%。 MR 阻断的功效被广泛地（如果可以理解的话，也许太容易了）归因于阻断醛固酮激活心脏 MR，从而归因于醛固酮在充血性心力衰竭中的病理生理作用。
Translational research is usually taken to mean the appli-cation of laboratory discovery to clinical practice. Like languages or enzymes, however, translation is a 2-way street, and in the field of aldosterone and mineralocorticoid receptors (MR), there are a number of examples where clinical studies have prompted reconsideration of the basic biology. For example, in essential hypertensive subjects the distinction between the antihypertensive and electrolyte effects of the selective MR antagonist eplerenone has been interpreted as evidence against a primary renal role for aldosterone/MR activation in raising blood pressure. 1 Similarly, the finding of an S810L MR mutant receptor causing juvenile hypertension exacerbated by pregnancy2 prompted a reconsideration of the order of branching of the MR/glucocorticoid receptor (GR)/progesterone receptor (PR)/androgen receptor (AR) subfamily of steroid hormone receptors from a common primordial ancestral protein. 3These studies and their implications for the basic biology of aldosterone action have been discussed elsewhere. 4 The present review focuses on the clinical study (Randomized ALdactone Evaluation Study [RALES] 5) that prompted this process of re-examination almost a decade ago. The rationale for this study, in patients with New York Heart Association class III heart failure, was that previous clinical studies had shown that plasma aldosterone levels could break through prolonged angiotensin-converting enzyme inhibition and angiotensin II type 1 blockade; in addition, early laboratory studies by Brilla and Weber6 had shown that exogenous aldosterone plus normal saline as drinking solution produced cardiac hypertrophy and fibrosis in uninephrectomized rats. The outcomes of RALES were remarkable. The trial was halted just more than half way through the projected period of recruitment on the basis of the divergence between the 2 groups: 1 treated with standard of care (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc) plus placebo and the other with standard of care plus spironolactone. Addition of a very modest dose of spironolactone (average: 26 mg/d) resulted in a 30% improvement in survival and a 35% reduction in hospitalization. The efficacy of MR blockade has widely (and perhaps too easily, if understandably) been attributed to the blockade of aldosterone from activating cardiac MR and thus for a pathophysiologic role for aldosterone in congestive heart failure.