A possible association between aldosterone response to vasopressin and circadian change of aldosterone in the patients with aldosterone-producing adenoma

Vasopressin was reported to stimulate secretion of both cortisol and aldosterone through eutopic V1a receptors in adrenal gland. Recently, adrenal hyper-responsiveness of plasma cortisol to vasopressin with eutopic overexpession of V1a receptors has been reported in Cushing's syndrome, such as a majority of cases of ACTH-independent macronodular adrenal hyperplasia and some cases of Cushing's adenomas. There were a few reports regarding the aldosterone response to vasopressin in aldosterone-producing adenoma. The aim of our study was to investigate the aldosterone response to vasopressin and its pathophysiological roles in the patients with aldosterone-producing adenoma. Vasopressin-loading test was performed in 10 patients with aldosterone-producing adenoma, and in 16 patients with non-functioning adrenal tumors. The roles of the aldosterone response to vasopressin were analyzed in terms of hormonal secretion and the expression of V1a receptor mRNA on the operated adrenal gland in aldosterone-producing adenoma. We found that (1) a varying aldosterone response to vasopressin was observed, (2) absolute response of plasma aldosterone in aldosterone-producing adenoma was significantly higher than that in non-functioning tumor, (3) aldosterone response rate to vasopressin was significantly and negatively correlated with the decline rate (%) in plasma aldosterone from morning to evening in aldosterone-producing adenoma, (4) V1a receptor mRNA was expressed at various values in aldosterone-producing adenoma, and (5) surgical removal of aldosterone-producing adenoma eliminated the aldosterone response to vasopressin observed in patients with aldosterone-producing adenoma. These findings indicated that vasopressin might be involved in the coordination of aldosterone secretion through eutopic expression of V1a receptor in aldosterone-producing adenoma.     

A case of glucocorticoid-suppressible hyperaldosteronism with aldosterone producing adenoma

A 34-yr-old woman with hypertension (142/102 mmHg), hypokalemia, high plasma and urinary aldosterone and low plasma renin activity was studied. A left adrenal tumor and enlarged right adrenal gland were demonstrated by adrenal venography. During administration of dexamethasone (2 mg daily, for 3 weeks), urinary aldosterone excretion decreased abruptly from 22.5 to 9-11 micrograms/day, serum potassium increased and blood pressure fell to 120-130/80-90 mmHg. After left adrenalectomy, all manifestations improved with no medication. The resected adrenal gland revealed clear cell adenoma and micronodular adrenocortical hyperplasia. The patient was considered to be a rare case of glucocorticoid-suppressible hyperaldosteronism with an aldosterone-producing adenoma.     

Hyper-responsiveness of adrenal gland to vasopressin resulting in enhanced plasma cortisol in patients with adrenal nodule(s)

Hyper-responsiveness of plasma cortisol to vasopressin has been demonstrated in ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) and some adrenal adenomas with Cushing's syndrome (CS). However, the clinical significance of hyper-responsiveness of plasma cortisol to vasopressin has not been investigated systematically in adrenal nodule(s). The aim of this study was to clarify the prevalence of hyper-responsiveness of plasma cortisol to vasopressin (vasopressin responder) and their clinical characteristics in terms of hormonal secretion using vasopressin-loading test in the patients with adrenal nodule(s) except pheochromocytomas. A vasopressin-loading test was performed on 61 consecutive patients with adrenal nodules (CS: 33, aldosterone-producing adenoma: 10, non-functional tumor: 18). Vasopressin responders were observed in 36.1% of adrenal nodule(s), 42.4% of CS and 28.5% of non-CS. In responders with CS, eight patients had bilateral nodules that were diagnosed as AIMAH, and the remaining six patients had a unilateral nodule. These patients had lower plasma cortisol than non-responders at both morning (P<0.01) and midnight (P<0.05), as well as the morning following overnight dexamethasone suppression at 1mg (P<0.05) and 8mg (P<0.05). Hyper-responsiveness of the adrenal gland to vasopressin resulting in enhanced plasma cortisol was frequently observed among patients with adrenal nodule(s). The vasopressin responders among the patients with adrenal nodule(s) frequently had CS with low autonomous cortisol secretion.     

Night-day variations of renin-activity in primary aldosteronism

To detect changes in previously unmeasurable low renin activity plasma specimens of 20 patients with primary aldosteronism (12 with an unilateral adenoma and 8 with idiopathic bilateral adrenal hyperplasia), obtained at short term intervals between 20.00 and 8.00, were incubated over a prolonged period of 18 hours. 6 of 12 patients with an aldosterone producing adenoma (APA) and 3 of 8 patients with idiopathic bilateral adrenal hyperplasia (IAH) showed typical night-day variations of PRA with lower values before and higher values after midnight. 7 of these 9 patients with night-day rhythmicity of PRA simultaneously showed secretory episodes. In 2 patients (1 with APA, 1 with IAH) PRA was constantly undetectable (less than 0.2 ng/ml . 18 h) and in 2 patients with APA a fixed secretion of renin was observed. We failed to demonstrate typical night-day variations of PRA in 3 patients with APA and in 4 with IAH, although in 5 of these 7 patients secretory episodes of PRA were found. Our results show that different patterns of PRA curves may be observed both in patients with APA and IAH. Thus, analysis of PRA curves is of no value to differentiate patients with APA from those with IAH.     

Steroids and hypertension

Primary aldosteronism is the principal disorder of zona glomerulosa and a number of subsets have been identified: unilateral adenoma; bilateral micro- or macro-nodular hyperplasia (idiopathic aldosteronism); primary hyperplasia and aldosterone-producing carcinoma either adrenal or ectopic. The diagnostic criteria for a correct differential diagnosis of these subsets are now quite reliable and our experience is presented in detail. Unfortunately the pathogenesis of most of these forms is still poorly recognized and requires further investigation. An extreme sensitivity to angiotensin II is present in patients with idiopathic aldosteronism, and a role for adrenal renin is now being advocated. A peculiar form of hyperaldosteronism is the glucocorticoid-remediable subtype. An unusual sensitivity of aldosterone to ACTH is present in this form. A qualitative biochemical abnormality in this disorder consists of marked over-production of products of the cortisol C18-oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, which are more abundant than aldosterone and 18-hydroxycorticosterone. A family with three affected sibs has been studied by our group. In other clinical situations, classical zona fasciculata mineralocorticoids [deoxycorticosterone (DOC), corticosterone and their 18-hydroxy compounds] are secreted in excess. The hypertensive diseases of this zone are rare DOC-secreting tumors and two forms of congenital adrenal hyperplasia (CAH), the 11 beta-hydroxylase (11-OHDS) and the 17 alpha-hydroxylase deficiency syndromes (17-OHDS), which are identified by the presence of hypokalemia and suppressed renin activity. DOC is the only mineralocorticoid hormone (MCH) oversecreted in the 11-OHDS, while all ACTH-dependent MCH are very high in the 17-OHDS. The molecular basis of gene abnormalities of this disorder are currently under investigation, and preliminary data obtained in some of our patients are presented. Finally a syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxy dehydrogenation of cortisol to cortisone. Studies on this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. The syndrome exists in two forms both characterized by a decreased turnover of a normal level of plasma cortisol, but in the type I variant an elevated cortisol/cortisone metabolite ratio is found, whereas in the type II variant this ratio is normal. Three patients of the latter form have recently been described by us and are shortly illustrated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adrenal sensitivity to angiotensin II and undiscovered aldosterone stimulating factors in hypertension

We have determined that the adrenal glands of patients with the syndromes of low-renin essential hypertension and idiopathic hyperaldosteronism are abnormally sensitive to the steroidogenic effect of angiotensin II. The mechanism of this heightened responsiveness to angiotensin II is unknown but may be due to the bilateral adrenal hyperplasia present in many patients with these low-renin hypertension syndromes. We have found that metoclopramide, a dopamine antagonist, causes three-fold increases in levels of plasma aldosterone in normal subjects. These increases could not be accounted for by changes in plasma renin activity, ACTH or potassium. Metoclopramide does not stimulate bovine adrenal glomerulosa cells to produce aldosterone in vitro, suggesting that it stimulates the secretion of aldosterone in vivo indirectly, by increasing the levels or the activity of an undefined aldosterone stimulating factor. We have also found that human urine, after partial purification, stimulates bovine adrenal glomerulosa cells to produce aldosterone in vitro. Urine samples from patients with low-renin essential hypertension or idiopathic hyperaldosteronism have more stimulating activity than urine samples from normal subjects. These preliminary findings support the hypothesis that excessive production of an undefined aldosterone stimulating factor may be the basic abnormality in some cases of idiopathic hyperaldosteronism and low-renin essential hypertension.     

Effects of corticotropin-releasing factor (CRF) on aldosterone and 18-hydroxycorticosterone in essential hypertension and primary aldosteronism

The effects of ovine corticotropin releasing factor (o-CRF) on plasma aldosterone, 18-OH-corticosterone (18-OHB), plasma adrenocorticotropin (ACTH) and cortisol were determined in eight patients with primary aldosteronism, six with aldosterone-producing adenoma (APA) and two with idiopathic hyperaldosteronism (IHA). The results were compared with those in six normal subjects and eleven patients with essential hypertension (EHT, 5 with low renin and 6 with normal renin). In patients with APA, the peak plasma aldosterone and 18-OHB responses to 100 micrograms iv of o-CRF (226% and 113% increase from baseline, respectively) were greater than those in EHT and normal subjects. The net integrated aldosterone and 18-OHB responses (840 +/- 156, and 419 +/- 121 ng/dl.hr, respectively) were also significantly greater (p less than 0.01) in APA than those in normals and EHT. In two patients with IHA, both the peak and net integrated aldosterone response were smaller than those in APA, in spite of nearly identical plasma ACTH and cortisol responses. These results suggest that augmented responses of mineralocorticoids to o-CRF may be characteristic of aldosteronism due to APA, mediated by CRF-induced ACTH, and possibly other proopiomelanocortin (POMC)-derived peptides.     

Hypertension,Increased Aldosterone Secretion and Low Plasma Renin Activity Relieved by Dexamethasone

A father and son are described with a condition characterized by benign hypertension, potassium deficiency, increased aldosterone secretion rate (ASR), raised plasma volume and suppressed plasma renin activity (PRA). There were intermittent elevations of urine 17-ketosteroids and 17-hydroxycorticoids (17-OHCS) but no increase in urine THS, normal circadian rhythm of plasma 17-OHCS, and normal urine 17-OHCS response to dexamethasone and intravenous ACTH. Plasma ACTH and corticosterone secretion were not elevated. Pregnanetriol excretion was normal but urine pregnanediol was increased. At operation on the father no adrenal tumour was found; the excised left adrenal weighed 7 g. and showed nodular cortical hyperplasia; juxtaglomerular cells showed only occasional granules. Following operation hypertension persisted and ASR was half the preoperative value. All abnormalities in father and son were relieved by dexamethasone (DM) 2 mg. daily. The condition recurred following cessation of DM but was relieved by a second course of treatment. No such response to DM was seen in a normal subject or in a patient with Conn''s syndrome. For a number of reasons it is suggested that patients with hypertension, increased ASR and low PRA be given a trial of dexamethasone treatment before undergoing adrenal surgery.     

Effect of prolonged ACTH stimulation on adrenal renin and aldosterone

Changes in adrenal renin, which have been regarded as mediator of aldosterone secretion in the adrenal gland, following prolonged ACTH treatment were investigated in male Wistar rats. After 2 days of daily sc injection of ACTH (Cortrosyn-Zinc, 50 micrograms/day), parallel increases in adrenal renin and aldosterone, and plasma aldosterone (PA) were induced. The plasma renin activity (PRA) was slightly but not significantly decreased. Prolonged treatment with ACTH for 8 days increased the adrenal renin, causing a marked reduction in the adrenal aldosterone concentration. The degree of decrease in the PRA was again not significant and similar to that after 2 days of ACTH treatment. Contrary to previout reports which have indicated participation of adrenal renin in the regulation of aldosterone secretion in the adrenal gland, the present results showed reciprocal changes in adrenal renin and aldosterone after prolonged treatment with ACTH. The present findings suggest a complicated relation between adrenal renin and aldosterone secretion in the adrenal gland.     

Plasma renin activity and urinary aldosterone in Cushing's syndrome.

The renin-angiotensin-aldosterone system has been evaluated in 19 patients with Cushing's syndrome due to bilateral adrenal hyperplasia and in 2 patients with unilateral adenoma. In the first group urinary aldosterone was within the normal limits with a mean of 8.3 +/- 1.86 microgram/24 h. Aldosterone excretion did not change significantly after furosemide administration, ACTH infusion or dexamethasone. Upright PRA was suppressed in 9/16 patients with a mean of 4.9 +/- 1.85 ng/ml/3 h and showed only a slight response to furosemide. Dexamethasone alone did not produce any change. Both aldosterone and PRA were to some extent stimulated by an association of dexamethasone and furosemide. In the 2 patients with adenoma, aldosterone excretion was also normal, but PRA was very elevated. From our data it is concluded that in Cushing's syndrome due to bilateral hyperplasia, PRA and aldosterone excretion are partially suppressed. From our results on plasma deoxycorticosterone and corticosterone concentration it seems unlikely that these mineralocorticoids are the major cause of this phenomenon. However, it may not be excluded that other yet unidentified hormones could play some role in the pathogenesis of hypertension and renin suppression in Cushing's syndrome.     

Effect of metoclopramide on adrenal secretion in sheep: influence of dexamethasone and sodium intake

Metoclopramide, a competitive dopamine antagonist, stimulates aldosterone in man and monkey without affecting cortisol secretion. In sheep, metoclopramide also stimulates aldosterone but ist action on adrenocortical secretion is more controversial. To clarify the action of metoclopramide in conscious sheep, the response of plasma aldosterone, cortisol, angiotensin II and potassium were studied after 0.16 and 0.64 mg/kg metoclopramide, with and without pretreatment with dexamethasone. The effect of sodium status on the response was also studied by repeating the experiments after 7 days of dietary sodium restriction. In the absence of dexamethasone, plasma aldosterone was significantly increased by metoclopramide in both sodium-replete and restricted sheep. In sodium-replete sheep, plasma cortisol was also increased by 0.64 mg/kg, and by both doses when salt-restricted. However all cortisol responses were completely suppressed by dexamethasone pretreatment. Dexamethasone also suppressed the aldosterone response to metoclopramide in sodium-replete but not in sodium-restricted sheep where significant responses of aldosterone to both doses of metoclopramide still occurred without changes in plasma angiotensin II or potassium. While a nonspecific stress effect of metoclopramide can contribute to the aldosterone response, these results show that the sheep's adrenal glomerulosa is capable of responding to metoclopramide without change in ACTH, angiotensin or potassium.     

Results of adrenal surgery in patients with hypertension,aldosterone excess,and low plasma renin concentration.

Fifty patients with hypertension, aldosterone excess, and low plasma renin concentration underwent adrenal surgery. There was a highly significant fall in mean systolic and diastolic pressures after the operation. The mean postoperative diastolic pressure fell to strictly normal levels, however, in only 19 out of 38 patients from whom an adrenocortical adenoma was removed and in only two out of 10 non-tumour patients. There was a significant correlation between the fall in blood pressure during spironolactone treatment and after adrenal surgery though levels were generally slightly lower during the former therapy. It is suggested that removal of an aldosterone-producing adenoma is the treatment of choice provided a good preoperative hypotensive response to spironolactone occurs, while the treatment of choice for non-tumour patients is often long-term spironolactone.     

Secretion of 6beta-hydroxycortisol by normal human adrenals and adrenocortical adenomas

Although 6beta-hydroxycortisol (6betaOHF) is usually considered a cortisol metabolite produced by the liver, a few reports suggest that it may also originate from extrahepatic sources. To examine whether human adrenal cells are capable of 6beta-hydroxylating cortisol, we measured 6betaOHF secretion with a radioimmunoassay method in isolated human adrenal cell systems obtained from three normal adrenals, four nonhyperfunctioning adrenocortical adenomas, two adrenal adenomas causing Cushing's syndrome, and five aldosterone (Aldo)-producing adenomas. Cells were examined both under basal conditions and after stimulation with adrenocorticotrophic hormone (ACTH). In addition, 6betaOHF concentrations were determined in inferior vena cava and suprarenal vein plasma samples obtained from the side of nonhyperfunctioning adrenal adenomas (five patients) and aldosterone-producing adenomas (five patients). Under basal incubation conditions, 6betaOHF secretion, expressed as a percent of cortisol secretion, was between 0.5 and 2.0% in normal adrenal cells, between 1.0 and 7% in cells from nonhyperfunctioning adenomas, 12 and 15% in cells from Cushing's syndrome patients, and between 2.6 and 3.9% in cells from aldosterone-producing adenomas. In these cells, increasing doses of ACTH produced a dose-dependent stimulation of both 6betaOHF and cortisol secretion. The 6betaOHF concentration in suprarenal vein samples obtained from the side of adenomas was markedly increased; the suprarenal vein/inferior vena cava 6betaOHF ratios were 13.1+/-2.1 (mean+/-S.E.) in the case of nonhyperfunctioning adenomas and 17.8+/-4.5 in the case of aldosterone-producing adenomas. These results firmly suggest that 6betaOHF is not only a hepatic metabolite, but also a secretory product of human adrenals and that similarly to cortisol, its secretion may be controlled by ACTH.     

Aldosterone synthase cytochrome P-450 expressed in the adrenals of patients with primary aldosteronism

A human cytochrome P-450 with aldosterone synthase activity was purified from the mitochondria of an aldosterone-producing adenoma. It was recognized by an anti-bovine cytochrome P-450(11 beta) IgG and by a specific antibody raised against a portion of the CYP11B2 gene product, one of the two putative proteins encoded by human cytochrome P-450(11 beta)-related genes (Mornet, E., Dupont, J., Vitek, A., and White, P. C. (1989) J. Biol. Chem. 264, 20961-20967). A similar and probably the same aldosterone synthase cytochrome P-450 was detected in the adrenal of a patient with idiopathic hyperaldosteronism. These aldosterone synthases were distinguishable from cytochrome P-450(11 beta), the product of another cytochrome P-450(11 beta)-related gene, i.e. CYP11B1, by their catalytic, molecular, and immunological properties and also by their localization. The latter enzyme was unable to produce aldosterone and did not react with the specific antibody against the CYP11B2 gene product. It was present both in tumor and non-tumor portions of the adrenals carrying the adenoma and in normal adrenal cortex. On the other hand, aldosterone synthase cytochrome P-450 localized in the tumor portions of the adrenals or in the adrenal of a patient with idiopathic hyperaldosteronism. Thus aldosterone synthase cytochrome P-450, a distinct species from cytochrome P-450(11 beta), is responsible for the biosynthesis of aldosterone in the human, at least in patients suffering from primary aldosteronism.     

Effect of nifedipine treatment on the renin-aldosterone system and secretion of cortisol and growth hormone in patients with essential hypertension]

The effect of treatment of hypertension with nifedipine on plasma renin activity, blood serum level of aldosterone in the course of renin test, and cortisol and growth hormone concentrations after stimulation with insulin hypoglycemia was followed during two weeks of treatment in 40 patients with essential hypertension. No significant differences in the secretion of the hormones studied, as compared to the patients with the normal arterial blood pressure, were found. After nifedipine treatment no significant changes in the secretion of aldosterone, cortisol and growth hormone were observed despite a significant fall in the arterial blood pressure while there was a moderate stimulatory effect on renin secretion. The results obtained indicate that nifedipine has only small effect on the hormonal system of patients with essential hypertension.     

Studies on lipoprotein and adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density lipoprotein-cholesterol for steroid production in functioning human adrenocortical adenoma cells in culture

We examined the utilization of human low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol for steroid production in primary monolayer culture cells from adenomas of primary aldosteronism and Cushing's syndrome and an adrenal of nodular hyperplasia of Cushing's syndrome. We compared the data obtained with findings in the case of cultured normal human adrenocortical cells. In the presence of 10(-7) M adrenocorticotropin (ACTH), the addition of either LDL or HDL to the culture medium at a cholesterol concentration of 100 micrograms/ml led to a significant increase in the daily secretion rates of cortisol, dehydroepiandrosterone sulfate (DHEA-S) and aldosterone in the adenoma and nodular hyperplasia cells, as in the normal cells. Although LDL greatly increased the secretion of steroid hormones, no significant difference in steroid secretion following the treatments with LDL and HDL were observed in these cultured cells. The contribution of endogenous cholesterol to steroid production was also high, thereby indicating that the neoplastic transformation did not have untoward effects. Cells from adenomas of primary aldosteronism secreted not only aldosterone, but also cortisol and DHEA-S. The daily secretion rates of these steroids were markedly increased when ACTH was added to the medium. With prolonged exposure to ACTH, however, the rate of aldosterone secretion showed a gradual decrease with the incubation time. This decrease might be due to the impaired conversion of corticosterone to 18-hydroxycorticosterone. In case of adenomas in patients with Cushing's syndrome, the secretion of steroid hormones varied in quantity and quality, depending on the type of plasma cortisol response to the rapid ACTH test in vivo, thereby suggesting that the adrenocortical adenoma of Cushing's syndrome might be divided into two subtypes. These results indicate that human functioning adrenocortical adenoma cells utilize plasma lipoproteins as a source of cholesterol for steroidogenesis during the prolonged stimulation of steroid secretion.     

Absent aldosterone response to metoclopramide in patients with high spinal cord transection: evidence that metoclopramide stimulates aldosterone secretion through central pathways

This study evaluates dopaminergic regulation of aldosterone secretion in 6 patients with high spinal cord transections. Administration of the dopamine antagonist metoclopramide resulted in a marked rise in plasma aldosterone and 18-hydroxycorticosterone levels in 12 normal individuals, but no change in plasma levels of these zona glomerulosa corticosteroid products in spinal cord patients. Spinal cord transected patients also did not have the rise in plasma renin activity that was observed in normals following metoclopramide administration. Basal levels of aldosterone, 18 hydroxycorticosterone, corticosterone and renin activity as well as the aldosterone responses to graded dose infusion of adrenocorticotropin were similar in the spinal cord patients and the normals. These data suggest that dopaminergic regulation of adrenal zona glomerulosa corticosteroid and renal renin secretion is absent in patients with high spinal cord transections, suggesting that intact neural pathways from the central nervous system are necessary for metoclopramide stimulation of aldosterone and renin secretion in men. Since basal plasma aldosterone levels were normal in spinal cord transected patients, it appears that the absence of dopaminergic control does not result in elevated secretion.     

Possible hyperaldosteronism and discrepancy in enzyme activity deficiency in adrenal and gonadal glands in Japanese patients with 17 alpha-hydroxylase deficiency

We reviewed the pathophysiology of our previously reported female patient who had glucocorticoid-responsive hyperaldosteronism and was treated successfully with daily dose of dexamethasone (Dex) for 21 years. In this present study, the possibility that the patient may have 17 alpha-hydroxylase deficiency (17-OH-D) mainly in the adrenal could not be ruled out. We therefore reviewed 31 Japanese patients diagnosed as having 17-OH-D with suppressed plasma renin activity reported in Japan. Among these patients, 9 were found to have a high plasma aldosterone (Ald) concentration (PAC) (group I). Twenty-one patients had either normal or low-normal PAC and the remaining patient had low urine Ald (group II). The slight cross-reactivity of the anti-Ald-antibodies used with 17-deoxy-steroids such as progesterone, 11-deoxycorticosterone and corticosterone which were increased in both groups did not explain the increased PAC in group I. In the patients in group I and group II with high-normal basal PAC, PAC further increased after ACTH and was suppressed by Dex. PAC in 2 group I patients, however, did not respond to angiotensin-II or angiotensin-III infusion. PAC in patients in group II with low or low-normal basal PAC responded equivocally to ACTH and Dex. The basal plasma cortisol in group I was lower than in group II, and plasma cortisol level after ACTH in group I appeared to remain at a lower level than that in group II patients. Among the study subjects, 28 showed a negative correlation between basal PAC and plasma cortisol. A possible discrepancy in the deficiency of 17 alpha-hydroxylase activity in adrenal and gonadal glands was also suggested in three 17-OH-D patients. The pathophysiology of Ald secretion and discrepancy in the deficiency of the enzyme activities in both glands in 17-OH-D patients was discussed.     

Hypertension, hypokalemia and hypoaldosteronism with suppressed renin: a clinical study of a patient with Liddle's syndrome

A 24-yr-old woman with hypertension, hypokalemic alkalosis, low plasma renin and hypoaldosteronism was studied. Plasma aldosterone, renin and potassium returned to normal and blood pressure fell after sodium restriction or the administration of triamterene. Thiazide therapy also normalized her blood pressure while dexamethasone, spironolactone and furosemide did not improve her symptoms. Plasma aldosterone levels were low and responded poorly to a short term ACTH injection, but responded well to the maximal adrenal stimulation by ACTH-Z. Plasma levels of cortisol, corticosterone and deoxycorticosterone were within the normal range. Adrenal scintigram with 131I-adosterol and abdominal computed axial tomography did not reveal the presence of a sizeable adrenal tumor. In addition, the urinary kallikrein excretion was low after sodium restriction and showed no response to saline infusion. These findings suggest that the excessive secretion of unusual mineralocorticoids may not exist in this case. From these observations and the results of the therapeutic responses to the diuretic agents, we conclude that the primary cause of the disorder of this patient seems to be a renal defect in the distal tubule in handling sodium and potassium which is similar to that in Liddle's syndrome.     

Serotoninergic stimulation of aldosterone secretion in vivo: role of the hypothalamo-pituitary adrenal axis.

The control of aldosterone secretion in vivo by serotonin was studied in conscious rats. Serial blood samples were taken from indwelling arterial cannulae before and after i.p. administration of 1 ml (4 g/l) 5-hydroxytryptophan (5-HTP), the precursor of serotonin (5-HT), or saline, and analysed for 5-HTP, serotonin, 5-hydroxyindoleacetic acid, plasma renin activity (PRA), corticosterone, aldosterone, sodium and potassium concentration. The relative contribution of the hypothalamo-pituitary adrenal axis was investigated in animals pretreated with the synthetic glucocorticoid dexamethasone. 5-HTP caused a significant increase in all parameters within 45 min except for plasma sodium and potassium. Saline administration showed no significant effect. Dexamethasone pretreatment significantly impaired the corticosterone and aldosterone response to 5-HTP, although the aldosterone response was merely attenuated. No other parameter was affected by dexamethasone pretreatment. The results show that administration of 5-HTP, which increases serum serotonin levels, stimulates PRA, corticosterone and aldosterone secretion. Dexamethasone pretreatment inhibits the aldosterone response, though not completely, suggesting that the stimulatory action of 5-HTP involves the release of ACTH, which stimulates corticosterone and aldosterone secretion by the adrenal cortex. The failure of dexamethasone to block the aldosterone response completely, suggests the involvement of other mechanisms such as the renin-angiotensin system or a direct action of serotonin on the adrenal zona glomerulosa.