Markou Athina, Sertedaki Amalia, Kaltsas Gregory, Androulakis Ioannis I, Marakaki Chrisanthi, Pappa Theodora, Gouli Aggeliki, Papanastasiou Labrini, Fountoulakis Stelios, Zacharoulis Achilles, Karavidas Apostolos, Ragkou Despoina, Charmandari Evangelia, Chrousos George P, Piaditis George P
Department of Endocrinology and Diabetes Center (A.M., I.I.A., C.M. T.P., A.G., L.P., S.F., D.R., G.P.P.), G. Gennimatas General Hospital, Athens 11527, Greece; Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics (A.S., E.C., G.P.C.), University of Athens Medical School, Aghia Sophia Children's Hospital, Athens 11527, Greece; Department of Pathophysiology (G.K.), University of Athens Medical School, Laikon Hospital, Athens 11527, Greece; and Department of Cardiology (A.Z., A.K.), G. Gennimatas General Hospital, Athens 11527, Greece.
J Clin Endocrinol Metab. 2015 Aug;100(8):2857-64. doi: 10.1210/jc.2015-1268. Epub 2015 May 14.
Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA).
We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT).
One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs.
Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group.
A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.
醛固酮（ALD）分泌主要受血管紧张素II、钾离子（K⁺）和促肾上腺皮质激素（ACTH）调节。盐皮质激素受体拮抗剂（MRAs）已有效地用于治疗非原发性醛固酮增多症（PA）的高血压患者。
我们测试了慢性应激相关的ACTH介导的ALD分泌过多和/或球状带超敏反应是否可能与原发性高血压（ESHT）的发病机制有关。
113例无PA的高血压患者和61例血压正常的对照者接受了超小剂量（0.03μg）ACTH刺激和跑步机试验。根据从对照者获得的临界值，醛固酮反应过度的患者接受MRAs治疗，并进行基因组DNA检测，以确定是否存在CYP11B1/CYP11B2嵌合基因和KCNJ5基因突变。22例单纯ESHT患者的对照组接受MRAs治疗。
根据从对照者获得的ACTH刺激后醛固酮和醛固酮与肾素比值（ARR）的临界值，30例患者（27%）表现出醛固酮而非皮质醇（F）反应过度（反应过度组）。与对照者以及83例对ACTH刺激无醛固酮反应过度的高血压患者（73%）相比，该组基础ACTH/肾素（REN）浓度无差异。反应过度组患者在跑步机试验中醛固酮浓度、ARR和醛固酮/ACTH比值（AAR）显著更高。单独使用MRAs治疗可使这些患者的血压恢复正常，而作为对照组的既无PA也无对ACTH刺激醛固酮反应过度的高血压患者血压未能降低。此外，在反应过度组中检测到两个新的种系杂合KCNJ5突变。
许多无PA的高血压患者表现出ACTH依赖性醛固酮分泌过多，并从MRAs治疗中获益。这可能与通过ACTH分泌过多的慢性应激和/或增加球状带对兴奋性刺激反应性的基因突变有关。
