The effects of metoclopramide and dopamine on aldosterone secretion in cultured adrenocortical adenoma cells and adjacent non-adenoma cells from patients with primary aldosteronism

Several authors have reported that metoclopramide (MCP), a dopaminergic antagonist, stimulates aldosterone secretion and that dopamine (DA) inhibits the MCP-mediated aldosterone secretion in man. However, many controversial results have been reported relating to the direct effect of MCP and DA on the secretion of aldosterone by adrenocortical cells in in vitro experiments. The present studies were designed to determine whether or not MCP and DA exerts its effect directly on the cultured human adrenocortical adenoma cells and adjacent non-adenoma cells obtained from patients with primary aldosteronism. A bolus intravenous injection of 10 mg MCP significantly increased the plasma aldosterone concentration (PAC) from 255 +/- 57 pg/ml (mean +/- SD) to 386 +/- 98 pg/ml after 15 min in patients with primary aldosteronism. But MCP (10(10)-10(-6) M) failed to increase aldosterone secretion from both adenoma cells and non-adenoma cells in culture. DA (10(-9) and 10(-6) M) did not suppress the basal secretion and the enhanced secretion of aldosterone by A II or ACTH in cells of either culture. The analysis by HPLC showed that 57% of dopamine hydrochloride added in the medium was preserved after 60 min incubation. These results suggest that MCP and DA do not act directly on the human adrenal glomerulosa cells in the regulation of aldosterone secretion.     

Effect of verapamil on aldosterone secretion in primary aldosteronism

Intracytoplasmic calcium seems to act as second messenger for aldosterone secretion. Both in vitro and in vivo studies demonstrate that drugs which block calcium entry cause a decreased responsiveness of glomerulosa cells to Angiotensin II and potassium. In order to evaluate the effect of a calcium channel blocking agent (Verapamil) in conditions of abnormal aldosterone secretion, we have studied 11 patients with primary aldosteronism, 5 with idiopathic hyperaldosteronism (IHA) and 6 with aldosterone producing adenoma (APA). In our study plasma aldosterone levels decreased after Verapamil infusion in IHA whereas no significant variations were observed in APA patients. These results suggest that calcium blockade can interfere with a possible regulatory system which plays a greater role in idiopathic aldosteronism.     

Effects of aldosterone on intralymphocytic sodium and potassium in patients with primary aldosteronism

In vitro effects of aldosterone have been described with regard to the intracellular sodium and potassium concentrations of human mononuclear leukocytes. In the present paper the in vitro effect of aldosterone on the intracellular sodium and potassium of human mononuclear leukocytes in 6 patients with primary aldosteronism was investigated. Except for one patient with elevated intracellular electrolytes, sodium and potassium in mononuclear leukocytes of patients with aldosteronism without incubation were within the range for normals. In the patients, no significant change of intracellular sodium or potassium was observed during incubation with or without aldosterone (1.4 nmol/l), whereas in normals, the loss of sodium and potassium during incubation without aldosterone was prevented by 1.4 nmol/l aldosterone. This insensitivity to aldosterone indicates that intracellular electrolytes in mononuclear leukocytes of patients with primary aldosteronism are kept in normal ranges by mechanism which are independent of mineralocorticoids and may represent the cellular correlate to the renal 'escape' phenomenon in aldosteronism.     

Plasma aldosterone response to ACTH in primary aldosteronism and in patients with low renin hypertension.

ACTH alpha 1-24 was infused at incremental rates of 12.5-200 mIU/30 min in dexamethasone-suppressed hypertensive patients on a regular sodium diet. The plasma aldosterone response to this stimulus in 8 patients with hyperaldosteronism due to an adrenal aldenoma and 11 with adrenal hyperplasia was significantly greater at all infusion rates (P less than 0.05) when compared with the response in 6 normal subjects on a similar diet. This responsiveness to ACTH in the patients with primary hyperaldosteronism was similar to that of the normal subjects on a low sodium diet. Twelve patients with low renin and 6 patients with normal renin essential hypertension were similarly studied. There was no significant difference in the median aldosterone response between these 2 groups and the normal subjects on a normal diet, but the response was significantly lower compared with that in patients with primary hyperaldosteronism. These data show that patients with hyperaldosteronism from an adrenal adenoma or hyperplasia have a consistent and exaggerated response to ACTH. The hyper-responsiveness is not apparently shared by the majority of patients with low renin essential hypertension and does not support the concept that this group is an intermediate form of primary aldosteronism. Individual patients within this group, however, may have such a response and might be identified by this type of testing.     

醛固酮/肾素比值在原发性醛固酮增多症筛查中的临床价值

目的 回顾分析瑞金医院内分泌科近5年怀疑原发性醛固酮增多症患者的资料,用受试者工作特征( receiver operating characteristic,ROC)曲线下面积评估醛固酮/肾素比值(aldosterone to renin ratio,ARR)在诊断原发性醛固酮增多症(原醛症)中的临床价值.方法 收集瑞金医院内分泌科2006年1月至2010年8月行卧位及立位ARR测定的590例怀疑原发性醛固酮增多症入院患者的临床资料,其中确诊为原醛症的患者357例,确诊为原发性高血压的患者233例.分析瑞金医院内分泌科2010年9月至2011年4月行随机及立位ARR测定的100例怀疑原醛症患者的临床资料,其中确诊为原醛症的患者29例,确诊为原发性高血压的患者71例.综合分析卧位、立位及随机ARR ROC曲线,以确定合适的切点用于诊断原发性醛固酮增多症.结果 2006年1月至2010年8月行卧位及立位ARR测定的590例患者卧位ARRROC曲线下面积为0.838(0.805～0.867),立位ARR ROC曲线下面积为0.873(0.843 ～0.899),两曲线下面积比较有显著差异(P＜0.01).2010年9月至2011年4月行立位及随机ARR测定的100例患者立位及随机ARR ROC曲线下面积分别为0.962(0.928 ～0.995)及0.944(0.893 ～0.994),两者比较无显著差异(P＞0.05).立位ARR切点为400(pg· ml-1)/(ng·ml-1·h-1)时,诊断原醛症患者的敏感性为91.9％,特异性为64.2％.结论 立位ARR比卧位ARR更适应作为原醛症的筛查指标,随机ARR与立位ARR在原醛症诊断中具有相似的临床价值.本研究认为,在严格控制患者药物、体位、检测时间条件下,ARR切点400( pg·ml-1)/(ng·ml-1·h-1)是原醛症筛查试验比较合适的切点.     

Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism

Primary aldosteronism is a specifically treatable and potentially curable form of secondary hypertension. The aldosterone/plasma renin activity ratio (ARR) is routinely used as a screening test. Antihypertensive therapy can interfere with the interpretation of this parameter, but a correct washout period can be potentially harmful. We have investigated the effects of therapy with atenolol, amlodipine, doxazosin, fosinopril, and irbesartan on the ARR in a group of 230 patients with suspected primary aldosteronism. The percent change from control of ARR in patients taking amlodipine was -17%+/-32; atenolol, 62%+/-82; doxazosin, -5%+/-26; fosinopril, -30%+/-24; and irbesartan, -43%+/-27. The ARR change induced by atenolol was significantly higher compared with that induced by all other drugs (P<0.0001), and the ARR change induced by irbesartan was significantly lower than that induced by doxazosin (P<0.0001). One of 55 patients from the group taking amlodipine (1.8%) and 4/17 of the patients taking irbesartan (23.5%) gave a false-negative ARR (<50). None of the patients of the groups taking fosinopril, doxazosin, and atenolol displayed a false-negative ARR. Doxazosin and fosinopril can be used in hypertensive patients who need to undergo aldosterone and PRA measurement for the diagnosis of primary aldosteronism; amlodipine gave a very small percentage of false-negative diagnoses. beta-Blockers also do not interfere with the diagnosis of primary aldosteronism, but they can be responsible for an increased rate of false-positive ARRs. The high rate of false-negative diagnoses in patients undergoing irbesartan treatment requires confirmation in a higher number of patients.     

Secretory regulation and episodic secretion of aldosterone in patients with primary aldosteronism (author's transl)]

In nine patients with primary aldosteronism (PA), plasma aldosterone was measured in order to evaluate a role of the renin-angiotensin system, ACTH and potassium in the secretion of aldosterone. The circadian rhythm and the episodic secretion were also studied in three patients. The results were as follows: 1) In seven out of nine patients, plasma aldosterone levels (PAL) decreased after the two-hours standing, and it run parallel with plasma cortisol levels (PCL), but not with plasma renin activity (PRA). 2) An intravenous infusion of saline of 2000 ml during four hours failed to suppress PAL in all of five patients and the change of PAL was parallel with that of PCL. 3) PAL decreased markedly after the oral administration of 1 mg of dexamethasone (Dexa), and there was a significantly positive correlation (r = 0.898, p less than 0.01) between basal PAL and the its decrement. 4) Following an intravenous infusion of angiotensin-II at a rate of 0.015 microgram/Kg/min after the pretreatment with Dexa, no significant increase of PAL was observed in any of the five patients. 5) Following a single injection of 0.25 mg of ACTH after the pretreatment with Dexa, PAL rose rapidly, and its peak level was found 60 minutes after the injection. In four out of eight patients this rise was greater than that in the normal subjects. 6) An intravenous infusion of 20 mEq of KCl after the pretreatment with Dexa, produced normal response i.e., an increase of PAL in all seven of the patients. 7) The circadian rhythm and the episodic secretion of PAL in the patients were synchronous with those of PCL throughout twenty four hours.     

The role of endogenous dopamine on mineralocorticoids secretion in normal subjects, patients with primary aldosteronism, and idiopathic hyperaldosteronism

The role of endogenous dopamine (DA) on the secretion of several mineralocorticoids was studied in six normal subjects, eight patients with primary aldosteronism (PA), two patients with non-familial idiopathic hyperaldosteronism (NF-IHA), and four patients with familial IHA (F-IHA). To these subjects 10 mg metoclopramide (MCP) was administered intravenously, and plasma aldosterone (Ald), 18-OH-corticosterone (18-OH-B), 18-OH-11-deoxycorticosterone (18-OH-DOC), and DOC were measured by RIA. Further, five normal subjects were studied with MCP test after pretreatment with DA infusion (5 micrograms/kg/min over 90 min). After the administration of MCP, normal subjects showed significant increases in their plasma Ald and 18-OH-B, and slight increases in plasma 18-OH-DOC and DOC. However, no significant changes were observed in plasma ACTH, cortisol, PRA, serum K, Na and Cl. In patients with PA and NF-IHA, plasma Ald and the three precursors were increased after the administration of MCP. Especially, marked increases in plasma 18-OH-DOC were seen in PA patients. In contrast, F-IHA patients showed increases in the above mineralocorticoids except 18-OH-B. Following DA infusion in normal subjects neither basal plasma Ald secretion nor the responsiveness to MCP were modified. These results suggest that endogenous DA plays an inhibitory role in the terminal stages of mineralocorticoids production in man. However, the degree of the dopaminergic inhibition might be different between normal subjects and the patients with mineralocorticoids excess, and among the three groups of aldosteronism mentioned above.     

评价卧立位醛固酮与肾素比值诊断原发性醛固酮增多症的价值

目的 探讨高血压患者卧立位检测血浆醛固酮浓度(plasma aldosterone concentration,PAC）与血浆肾素浓度(plasma renin concentration, PRC)比值（ratio of aldosterone/rennin,ARR）对原发性醛固酮增多症（primary aldosteronism,PA）的诊断价值与临床应用。 方法 回顾性分析2018~2019年240例高血压卧立位试验阳性或可疑阳性患者,通过卡托普利试验阳性联合盐水负荷试验阳性确诊114例PA患者及126例原发性高血压（essential hypertension,EH）患者。采用化学发光法检测卧立位PAC及PRC,基于受试者工作特征曲线分析诊断PA卧立位PAC、ARR截断点,评价不同指标诊断PA的敏感性及特异性。 结果 PA组与EH组间年龄、性别等基线资料差异无统计学意义,以卡托普利试验联合盐水负荷试验同时阳性为诊断标准,卧位ARR诊断PA最佳截断点6.73,敏感度=79.8%,特异度=90.5%,ROC曲线下面积为0.916(95% CI:0.873,0.948）;卧位PAC诊断PA的截断点18.15,敏感度83.3%,特异度64.3%,ROC曲线下面积为0.777 (95% CI:0.719,0.828）;立位ARR诊断PA的截断点4.08,敏感度58.8%,特异度87.3%,ROC曲线下面积为0.798 (95% CI:0.742,0.847）;立位PAC诊断PA截断点24.39,敏感度69.3%,特异度74.6%,ROC曲线下面积为0.744 (95% CI:0.687,0.801）。 结论 卧立位ARR较卧立位PAC诊断PA的特异度强而敏感度差,综合两种体位下的激素检查结果可提高诊断PA的准确性。     

血浆醛固酮/肾素活性比值——一个敏感的原发性醛固酮增多症的筛查指标

血浆醛固酮／肾素活性比值（ARR）是一个敏感的原发性醛固酮增多症（PA）的筛查指标，ARR的应用使高血压人群中PA的检出率明显增加。但目前ARR仍是一个非标准化的筛选方法，不同研究所采用的ARR切点差别很大，故应对ARR进行更深入和系统的研究，以提高ARR筛查方法的准确性。     

Detection of primary aldosteronism by the 6-hour integrated aldosterone/renin ratio

An outpatient diagnostic procedure measuring the 6-hour integrated plasma concentration of aldosterone and plasma renin activity was used to detect primary aldosteronism in 12 patients with low renin hypertension, including six with mild hypertension and normal urinary excretion and spot plasma levels of aldosterone. The ratio of integrated plasma concentration of aldosterone to plasma renin activity in the 12 patients (mean, 339; range, 116-700; p less than 0.0001) did not overlap with that measured in 105 normotensive controls (mean, 27.8; range, 5-97) or in 87 subjects with essential hypertension (mean, 29.2; range, 4-67). Eight patients had surgically proven adenomas (3 of which measured less than 5 mm) with normalization of blood pressure following adrenalectomy. The four remaining patients had bilateral hyperplasia. The 6-hour integrated plasma concentration of aldosterone to plasma renin activity ratio was found to be a useful new outpatient diagnostic tool for evaluation of primary hyperaldosteronism.