Effect of bromocriptine treatment on the aldosterone response to angiotensin II and adrenocorticotropin in idiopathic hyperaldosteronism

Bromocriptine can prevent an increase in plasma aldosterone during the infusion of angiotensin II in normal subjects and during upright posture in some patients with idiopathic hyperaldosteronism. To determine if bromocriptine prevents the increase in plasma aldosterone concentration during angiotensin II infusion in idiopathic hyperaldosteronism, we infused angiotensin II in five patients with idiopathic hyperaldosteronism, before and after treatment with bromocriptine (2.5 mg, three times daily for 5 days), and measured the resulting plasma aldosterone and angiotensin II concentrations. We also determined the adrenal response to ACTH infusion before and after bromocriptine treatment in four of these patients. Bromocriptine treatment did not significantly change the plasma concentrations of aldosterone before or during the infusions of angiotensin II and ACTH. It did significantly decrease mean blood pressure and increase the plasma corticosteroid concentrations in the preinfusion periods, but it did not alter the response of blood pressure to angiotensin II or of plasma corticosteroid concentrations to the ACTH infusions.     

Effect of serotonin4 (5-HT4) receptor agonists on aldosterone secretion in idiopathic hyperaldosteronism

Serotonin (5-HT) stimulates aldosterone secretion in man through 5-HT4 receptors positively coupled to adenylyl cyclase. In particular, it has been shown that oral administration of a single dose of the 5-HT4 receptor agonist cisapride induces a significant increase in plasma aldosterone levels (PAL) in healthy volunteers. Idiopathic hyperaldosteronism (IH) is a rare disorder characterized by hypertension, hypokalemia and bilateral adrenal hypersecretion of aldosterone. In patients with IH, administration of the 5-HT precursor 5-hydroxytryptophan (5-HTP) is followed by a significant increase in PAL. 5-HTP-induced aldosterone secretion has been attributed to the activation of central serotonergic pathways. The aim of the present study was to evaluate the effect of the oral administration of a single dose of cisapride (10 mg) on aldosterone secretion in 15 patients with IH, in a simple blind fashion versus placebo. Cisapride induced a significant increase in PAL but did not affect renin, cortisol and potassium levels. The present study demonstrates that 5-HT4 receptor agonists are able to stimulate aldosterone secretion in patients with IH. These data also indicate that hyperplastic glomerulosa tissue, like normal glomerulosa cells, expresses a functional 5-HT4 receptor. Therefore, 5-HT4 receptor antagonists may represent a new approach in the treatment of primary hyperaldosteronism.     

Effect of standard oral glucose loading on aldosterone secretion in primary hyperaldosteronism

The effects of mild acute decreases in plasma potassium induced by standard oral glucose loading (100 g) on plasma aldosterone and renin levels were assessed in 10 patients with primary hyperaldosteronism as compared with 10 normal subjects. Following overnight fast, mean plasma glucose was identical in both groups; plasma insulin, potassium and renin levels were lower and plasma aldosterone higher in patients than in controls. Glucose loading significantly increased plasma glucose and insulin concentrations and decreased plasma potassium and aldosterone levels in both groups. The increases in plasma insulin and the decreases in plasma potassium or aldosterone tended to be blunted in primary hyperaldosteronism. glucose-induced changes in plasma aldosterone correlated significantly (P less than 0.025) with those in plasma potassium in the patients and with variations in plasma renin activity in the normal subjects. These findings suggest that the metabolic changes induced by glucose ingestion are capable of modifying aldosterone secretion in primary hyperaldosteronism. However, the glucose-induced decreases in plasma aldosterone are blunted in this disorder; this could be related to the impaired insulin response to glucose loading.     

Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism.

Idiopathic hyperaldosteronism (IHA) is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. We compared activity of aldosterone synthase and expression of CYP11B2 messenger RNA (mRNA) in mononuclear leukocytes (MNL) from patients with IHA to findings in leukocytes from patients with aldosterone-producing adenoma and normal controls. Aldosterone synthase activity was estimated from conversion of [14C]deoxycorticosterone to [14C]aldosterone. Levels of CYP11B2 mRNA were determined by competitive PCR. In the same subjects, we sought the chimeric CYP11B1/CYP11B2 that is candidate gene for glucocorticoid-remediable hyperaldosteronism. Southern blot analysis and a long PCR method were used to detect the chimeric gene. Direct sequencing of the CYP11B2 also was performed. No chimeric genes or mutations in the coding region of the CYP11B2 were found in genomic DNA from these patients. However, both aldosterone synthase activity and CYP11B2 mRNA expression were greater in mononuclear leukocytes of patients with IHA than those of patients with aldosterone-producing adenoma or controls. These results suggest that regulatory factors of the CYP11B2 gene, e.g. unidentified aldosterone-stimulating substances or abnormalities in the promoter region of the CYP11B2 gene in patients with IHA resulting in oversecretion, may cause overexpression of mRNA of CYP11B2.     

Increased adrenal sensitivity to angiotensin II in idiopathic hyperaldosteronism.

Plasma aldosterone increases briskly during upright posture in patients with idiopathic hyperaldosteronism, despite only small increases in PRA and presumably small increases in angiotensin II. To examine the postulate that small increments in angiotensin II mediate these brisk increases in aldosterone, we infused graded doses of angiotensin II into normal subjects and patients with idiopathic hyperaldosteronism and compared the changes in levels of plasma aldosterone in the two groups. Supplemental sodium and dexamethasone were given before the infusion to minimize the influence of endogenous angiotensin II and ACTH. In response to the infusion of angiotensin II, increases in the levels of plasma aldosterone of patients with idiopathic hyperaldosteronism were significantly greater than those of normal subjects. In addition, levels of plasma aldosterone increased at a lower rate of infusion of angiotensin II in patients than in normal subjects. It is concluded that patients with idiopathic hyperaldosteronism have increased adrenal sensitivity to angiotensin II. This increased sensitivity may explain the brisk increases in aldosterone that occur during upright posture in these patients.     

Concentration of adrenocorticotrophic hormone and aldosterone secretion in essential hypertension and hyperaldosteronism

The authors studied the effect of adrenocorticotropic hormone (ACTH), potassium and plasma renin activity on blood aldosterone in normal subjects as well as in patients with essential hypertension (of a labile and stable course) and hyperaldosteronism (primary and idiopathic). It was demonstrated that in normal subjects and patients with labile essential hypertension, the secretion of aldosterone was simultaneously stimulated by the renin-angiotensin system (RAS) and the hypothalamus-adenopituitary. The RAS dominated in normal conditions whereas in labile hypertension the hypothalamus-adenopituitary system was predominant. In stable hypertension, the RAS and hypothalamus-pituitary influenced aldosterone secretion in an equal degree. Hyperaldosteronism was associated with the most pronounced deviations in the relationship between stimulants and aldosterone. In addition to decreased plasma levels of renin activity and potassium, the corticotropic activity of the hypothalamus-adenopituitary was increased during the first 10 years of the disease, while later on the function of this system became inhibited. The highest ACTH levels were recorded in idiopathic hyperaldosteronism.     

Effect of a calcium inhibitor, nicardipine, on aldosterone secretion in primary hyperaldosteronism

The purpose of the study was to evaluate the effects of a dihydropyridine calcium antagonist, nicardipine (N), on blood pressure (BP) and aldosterone secretion in hypertensive patients (pt) with primary aldosteronism. The study concerned 8 pts, mean age 55.6 +/- 7.7 years, 1 pt with aldosterone-producing adenoma (APA) and 7 pts with idiopathic aldosteronism: plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were respectively 0.30 +/- 0.2 ng/ml/h) and 314 +/- 109 pg/ml. Acute administration of 12 mg of nicardipine during 90 mn (three periods of N infusion during 30 mn: 0.4 mg/mn-5 mn; then 0.08 mg/mn-25 mn) significantly decreased BP, with an increase in heart rate (HR); the levels of PAC were significantly reduced with a slight but not significant increase in PRA, 60 mn after N: (table; see text) N decreased also PAC in the pt with APA [600 to 410 pg/ml] but did not improve hypokalemia (3.1 vs 3.3 mmol/l, n = 8 N.S.). In contrast, PAC levels were not modified 2 hours after acute oral administration of captopril (1 mg/kg): 302 +/- 164 pg/ml vs 332 +/- 191 pg/ml (NS). This study demonstrated the antihypertensive efficacy of acute infusion of nicardipine in primary aldosteronism; the decrease of PAC under this calcium antagonist suggested its potential interest in the management of idiopathic aldosteronism.     

Adrenomedullin selectively inhibits angiotensin II-induced aldosterone secretion in humans

OBJECTIVE: Adrenomedullin inhibits angiotensin II stimulated aldosterone production in vitro and in vivo in experimental animals. The aim of this study was to investigate the effect of adrenomedullin on angiotensin II and adrenocorticotrophic hormone-stimulated aldosterone production in vivo in healthy humans. DESIGN AND METHODS: Seven volunteers were studied in a quiet, temperature-controlled laboratory. After 35 min of rest, an infusion of placebo or adrenomedullin (3 pmol/kg per min) was given over 60 min; 15 min after starting this first infusion, a second infusion of angiotensin II (0.96 fmol/kg per min) or adrenocorticotrophic hormone (0.1 mIU/kg per min) was co-infused and continued for 45 min. RESULTS: Adrenomedullin significantly inhibited angiotensin II stimulated aldosterone production: the increment in aldosterone on the placebo day was 691 pmol/l compared with 552 pmol/l on the adrenomedullin day (P< 0.004). Adrenomedullin did not inhibit adrenocorticotrophic hormone-stimulated aldosterone or cortisol release. CONCLUSION: Adrenomedullin selectively inhibits angiotensin II-stimulated aldosterone production.     

Effect of plasma sodium on aldosterone secretion during angiotensin II stimulation in normal humans

Studies were carried out in normal male subjects (n = 6, age 20-35 years) to determine the interaction of angiotensin II and plasma sodium on aldosterone secretion. These relations were quantified by elevation of plasma sodium with an infusion of 5% sodium chloride (4 ml/kg/30 min i.v.) with measurements of plasma aldosterone, atrial natriuretic factor (ANF), and arginine vasopressin (AVP) over 3 hours. Two hours before sodium chloride infusion, an intravenous infusion of angiotensin II was begun at 0.5 or 5.0 ng/kg/min and continued throughout the study. Plasma potassium was maintained constant by the addition of potassium to the infusate. NaCl/KCl infusion raised plasma sodium 4 meq/l with no decreases of plasma potassium. Plasma aldosterone averaged 7 +/- 1.8 ng/dl before NaCl infusion in subjects infused with 0.5 ng angiotensin II and was not significantly reduced with sodium chloride infusion. Angiotensin II infused at 5 ng/kg/min resulted in average plasma aldosterone levels of 31 +/- 3.6 ng/dl, which sodium chloride infusion decreased to 16.6 +/- 1.3 ng/dl (p less than 0.05) in 60 minutes. Plasma aldosterone remained depressed for the remaining period of study. Plasma ANF increased from 40 to 60 pg/ml with sodium chloride infusion. We conclude that small physiological elevations of plasma sodium concentrations can signal substantial decreases of plasma aldosterone in normal human subjects in situations where plasma angiotensin II is moderately elevated. The precise mechanisms of these responses remain to be determined.     

Differential effects of atrial natriuretic factor on angiotensin II- and adrenocorticotropin-stimulated aldosterone secretion

The possible role of atrial natriuretic factor (ANF) in the regulation of adrenal sensitivity to angiotensin II (AII) was investigated in vivo and in vitro by analyzing the characteristics of the inhibitory effect of ANF on aldosterone production stimulated by AII and other stimuli. In isolated adrenal glomerulosa cells, ANF caused a dose-dependent inhibition of basal and stimulated aldosterone production by submaximal concentrations of ACTH, AII, and potassium, with an ED50 of about 1 nM for ANF and complete inhibition with 10 nM ANF. ANF increased the ED50 for ACTH from 14.6 +/- 3.2 to 376 +/- 104 pM with no significant decrease in the maximum aldosterone response. In contrast, ANF inhibited the aldosterone responses to all doses of AII, decreasing maximal aldosterone production by 75%, with a small increase in the ED50 for AII. In conscious rats, ANF infusion (100 ng/min) markedly decreased the plasma aldosterone response to AII infusion (5-10 ng/min). With higher AII doses (50 and 100 ng/min), which increased plasma corticosterone (and presumably ACTH secretion), the inhibitory effect of ANF was less marked. When the rise in ACTH secretion was prevented by dexamethasone treatment, ANF decreased the aldosterone response to 100 ng/min AII by 85%. Similarly, ANF had a minor although significant inhibitory effect on the primary ACTH-mediated increases in plasma aldosterone after stress by immobilization for 15 min. The data demonstrate a prominent inhibitory effect of ANF on AII-stimulated aldosterone production in vivo and in vitro. Since plasma ANF levels are increased during atrial distension, these observations support a regulatory role of ANF in the control of the adrenal sensitivity to AII during alterations of extracellular volume.     

Direct modulation of basal and angiotensin II-stimulated aldosterone secretion by hydrogen ions

Disturbances in acid-base balance in vivo are associated with changes in plasma aldosterone concentration, and in vitro changes in extracellular pH (pH(o)) influence the secretion of aldosterone by adrenocortical tissue or glomerulosa cells. There is considerable disparity, however, as to the direction of the effect. Furthermore, the mechanisms by which pH(o) independently affects aldosterone secretion or interacts with other secretagogues are not defined. Thus, bovine glomerulosa cells maintained in primary monolayer culture were used to examine the direct effects of pH(o) on cytosolic free calcium concentration ([Ca(2+)](i))( )and aldosterone secretion under basal and angiotensin II (AngII)-stimulated conditions. pH(o) was varied from 7.0 to 7.8 (corresponding inversely to changes in extracellular H(+) concentration from 16 nM to 100 nM). Whereas an elevation of pH(o) from 7.4 to 7.8 had no consistent effect, reductions of pH(o) from 7.4 to 7.2 or 7.0 caused proportionate increases in aldosterone secretion that were accompanied by increases in transmembrane Ca(2+) fluxes and [Ca(2+)](i). These effects were abolished by removal of extracellular Ca(2+). A decrease in pH(o) from 7.4 to 7.0 also enhanced AngII-stimulated aldosterone secretion. This effect was more pronounced at low concentrations of AngII and was manifested as an increase in the magnitude of the secretory response with no effect on potency. In contrast to its effect on AngII-stimulated aldosterone secretion, a reduction of pH(o) from 7.4 to 7.0 inhibited the Ca(2+) signal elicited by low concentrations (相似文献   

Parathyroid hormone modulates angiotensin II-induced aldosterone secretion from the adrenal glomerulosa cell.

The effect of PTH on aldosterone secretion from isolated bovine adrenal glomerulosa cells was examined. PTH binding was autoradiographically localized to the adrenal cortex, suggesting a specific effect. This binding of PTH was displaceable by cold PTH, but not by ACTH. No binding was observed in the adrenal medulla. In addition, PTH was shown to stimulate aldosterone secretion in a dose-dependent manner and to potentiate aldosterone secretion in response to angiotensin-II, such that PTH (10(-9)M) elevated the secretory rate from 58.6 +/- 6.8 to 110.9 +/- 19 pg/min.million cells in the presence of 10 nM angiotensin-II. The magnitude of the synergism between the two hormones depended on the concentrations of PTH and angiotensin-II as well as the time during which aldosterone secretion was measured. Within the first 15 min of stimulation, PTH increased the sensitivity to angiotensin-II, shifting the Ka for activation from 1.0 to 0.3 nM. In contrast, between 30-45 min of angiotensin-II stimulation, PTH elevated the maximal secretory response to angiotensin-II from 109 +/- 3.4 to 219 +/- 13.3 pg/min.million cells. By itself PTH elicited only a small increase in the intracellular Ca2+ concentration, as measured by aequorin luminescence in glomerulosa cells. In cells pretreated with angiotensin-II or 15 mM potassium, the intracellular calcium response to PTH was markedly potentiated. PTH was also found to cause a small increase in the cellular cAMP content. Thus, PTH stimulates aldosterone secretion from adrenal glomerulosa cells, both alone and in combination with angiotensin-II.     

Differing effects of metoclopramide and adrenocorticotropin on plasma aldosterone levels in glucocorticoid-suppressible hyperaldosteronism and other forms of hyperaldosteronism

To investigate possible dopaminergic effects on aldosterone production, we administered the dopamine antagonist metoclopramide to 11 normal subjects, 8 patients with primary aldosteronism due to adenoma or hyperplasia, and 5 other patients with the glucocorticoid-suppressible form of hyperaldosteronism (GSH). All subjects except for those with GSH responded to metoclopramide with an increase in plasma aldosterone concentration even when endogenous ACTH was suppressed by dexamethasone pretreatment. This increase occurred without apparent mediation of other recognized stimuli for aldosterone secretion. In contrast, the patients with GSH failed to show any aldosterone response while receiving dexamethasone, but demonstrated a rise in plasma aldosterone concentration when dexamethasone was withheld. The responses in the patients with both forms of primary aldosteronism were greater in magnitude than in the normal subjects or in the subjects with GSH when not receiving dexamethasone. These studies, while demonstrating differences between the subtypes of hyperaldosteronism in their responsiveness to metoclopramide, indicate that ACTH or some other factor may exert a permissive effect in GSH for the aldosterone response to metoclopramide. A graded infusion of ACTH revealed a greater aldosterone response in GSH compared to that in the other groups, further suggesting the importance of ACTH in this disorder.     

特发性醛固酮增多症手术是否必要?

分析39例经手术和病理检查证实的特发性醛固酮增多症(IHA)的临床资料,提出了IHA手术指征:即药物治疗不能控制,或药物剂量过大、副作用严重者;临床上增生结节与腺瘤不能区别者。手术方法是一侧肾上腺全切除。     

Role of angiotensin II receptor subtypes on the regulation of aldosterone secretion in the adrenal glomerulosa zone in the rat.

The role of AII receptors subtypes, AT1 and AT2, in the regulation of aldosterone secretion was studied in adrenal glomerulosa cells and membranes from rats on normal and low sodium intake, using AII receptor subtype-specific antagonists. In adrenal glomerulosa cells, more than 90% of the receptors were AT1 and there was a good correlation between the potencies of the antagonists to inhibit ligand binding, and AII-stimulated aldosterone production and inositol phosphate formation. The inhibition of basal and ACTH-stimulated cAMP by AII was also abolished by the AT1, but not the AT2, antagonist. Sodium restriction for 6 days increased both receptor subtypes in the same proportion, but only the AT1 antagonist inhibited AII-stimulated aldosterone production. The data demonstrate that AT1 receptor mediates the regulatory actions of AII in the adrenal zona glomerulosa.