The effect of fludrocortisone on the uterine receptivity partially mediated by ERK1/2-mTOR pathway.

Implantation of embryos needs endometrial receptivity. Mineralocorticoids is one of the causes influencing the implantation window. This study targeted to evaluation fludrocortisone different properties on endometrial receptivity. The objective of this study was to assess whether treatment with fludrocortisone could impact the expression of diverse genes and proteins that are involved in uterine receptivity in mice. In this study, 40 female adult BALB/c mice were used. The samples were allocated to four groups of ten. Control group (C) received: vehicle; fludrocortisone group (FCA): received 1.5 mg/kg fludrocortisone; PP242 group (PP242): received 30 mg/kg PP242; fludrocortisone+PP242 group (FCA+PP242): received fludrocortisone and PP242. Mice were killed on window implantation day after mating and confirmed pregnancy. The endometrial epithelium of mouse was collected to assess mRNA expression of leukemia inhibitory factor (LIF), mucin-1 (MUC1), heparin-binding epidermal growth factor (HB-EGF), (Msx.1), miRNA Let-7a, and miRNA 223-3p as well as protein expression of extracellular signal-regulated kinase 1/2 (ERK1/2), mammalian target of rapamycin (mTOR), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the uterine using real-time PCR and western blot, respectively. In comparison with the control group, fludrocortisone administration upregulated the expression of LIF, HB-EGF, Msx.1, miRNA Let-7a, ERK1/2, and mTOR in the epithelial endometrium. The PP242-treated group demonstrated a significant rise in the expression of MUC1, miRNA 223-3p and a remarkable decline in ERK1/2 and p-4E-BP1 levels in comparison with the control group. Combination therapy of (FCA+PP242) resulted in a remarkable rise in LIF, Msx-1, HB-EGF, ERK1/2, and mTOR levels, in comparison with the PP242 group. Furthermore, combination therapy of (FCA+PP242) downregulated the expression of MUC1 in comparison with the PP242-treated group. According to the results, fludrocortisone affected uterine receptivity possibly by means of modulating the expression of genes involved in the uterine receptivity and activation of the ERK1/2-mTOR pathway.

Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium.

We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10-12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.

Evaluation of the oral fludrocortisone suppression test for diagnosing primary hyperaldosteronism in cats.

BACKGROUND: Primary hyperaldosteronism (PHA) in cats is suggested by clinical signs and an elevated plasma aldosterone-to-renin ratio (ARR), but a test to confirm the diagnosis is lacking. HYPOTHESIS: Fludrocortisone does not suppress urinary aldosterone excretion in cats with PHA, but does so in cats with arterial hypertension because of other causes. ANIMALS: Nineteen client-owned cats with arterial hypertension because of PHA (n = 9) or other causes (n = 10). METHODS: Prospective clinical study. The urinary aldosterone-to-creatinine ratio (UACR) was determined in morning urine before, during, and after 4 days of oral fludrocortisone administration in a dose of 0.05 mg/kg q12h. Arterial blood pressure and plasma potassium concentration were measured before and after fludrocortisone administration. RESULTS: A basal UACR above 46.5 × 10(-9), the upper limit of the reference range, was found in 3 cats with PHA. All PHA cats had basal UACRs >7.5 × 10(-9). In all non-PHA cats with a basal UACR >7.5 × 10(-9), fludrocortisone administration induced >50% suppression. In contrast, fludrocortisone administration resulted in <50% suppression in 6 of the 9 PHA cats. Neither basal UACR, nor UACR after suppression testing, correlated with the etiology of PHA (adenoma, adenocarcinoma, or suspected bilateral hyperplasia of the zona glomerulosa). Fludrocortisone induced hypokalemia in 7 cats, but did not induce or exacerbate arterial hypertension. CONCLUSIONS AND CLINICAL IMPORTANCE: Measuring the UACR before and after 4 days of administering fludrocortisone is a practical method of confirming most cases of PHA in cats, and of substantiating the absence of PHA in cats having an ARR within the reference range.

Aldosterone requires vasopressin V1a receptors on intercalated cells to mediate acid-base homeostasis.

Both aldosterone and luminal vasopressin may contribute to the maintenance of acid-base homeostasis, but the functional relationship between these hormones is not well understood. The effects of luminal vasopressin likely result from its interaction with V1a receptors on the luminal membranes of intercalated cells in the collecting duct. Here, we found that mice lacking the V1a receptor exhibit type 4 renal tubular acidosis. The administration of the mineralocorticoid agonist fludrocortisone ameliorated the acidosis by restoring excretion of urinary ammonium via increased expression of Rhcg and H-K-ATPase and decreased expression of H-ATPase. In a cell line of intercalated cells established from transgenic rats expressing the mineralocorticoid and V1a receptors, but not V2 receptors, knockdown of the V1a receptor gene abrogated the effects of aldosterone on H-K-ATPase, Rhcg, and H-ATPase expression. These data suggest that defects in the vasopressin V1a receptor in intercalated cells can cause type 4 renal tubular acidosis and that the tubular effects of aldosterone depend on a functional V1a receptor in the intercalated cells.

Steroid control of acute middle ear inflammation in a mouse model.

OBJECTIVE: To investigate steroids for their potential for therapeutic approaches to control otitis media. Glucocorticoids and mineralocorticoids have differential effects on inflammation and fluid absorption, but little is known of their control of middle and inner ear manifestations of acute otitis media. DESIGN: Both glucocorticoid (prednisolone and dexamethasone) and mineralocorticoid (aldosterone and fludrocortisone) steroids were investigated for their ability to reduce inflammatory symptoms in a mouse otitis media model. SETTING: Academic medical center. SUBJECTS: Acute inflammation was induced by transtympanic injection of heat killed Streptococcus pneumoniae to 100 BALB/c mice. INTERVENTIONS: Twenty mice in each experimental group (prednisolone, dexamethasone, aldosterone, and fludrocortisone) were given a steroid in their drinking water the day before inoculation, and these treatments were continued until the mice were killed for histologic examination. Twenty control mice were treated with water only. MAIN OUTCOME MEASURES: Histologic measure of inflammation: middle ear fluid, inflammatory cell number, and tympanic membrane thickness. RESULTS: Histologic middle ear morphometrics showed significant steroid effects at both 3 and 5 days in reduction of fluid area, cell number, and tympanic membrane thickness. CONCLUSIONS: Glucocorticoids were most effective in controlling inflammation. Interestingly, the mineralocorticoids were also effective in reducing the inflammatory response at 5 days, suggesting that their fluid transport function helped clear disease. Thus, steroid control of middle ear disease may be useful in alleviating symptoms faster and reducing the risk to the inner ear.

Urinary aldosterone to creatinine ratio in cats before and after suppression with salt or fludrocortisone acetate.

BACKGROUND: The endocrine diagnosis of primary hyperaldosteronism in cats currently is based on an increased plasma aldosterone to renin ratio, which has several disadvantages for use in veterinary practice. OBJECTIVES: To establish a reference range for the urinary aldosterone to creatinine ratio (UACR) and to determine whether oral administration of either sodium chloride or fludrocortisone acetate is effective for use in a suppression test. ANIMALS: Forty-two healthy cats from an animal shelter and 1 cat with primary hyperaldosteronism from a veterinary teaching hospital. METHODS: Morning urine samples for determination of the basal UACR were collected from 42 healthy cats. For the suppression tests, urine samples for the UACR were collected after twice daily oral administration for 4 consecutive days of either sodium chloride, 0.25 g/kg body weight (n = 22) or fludrocortisone acetate, 0.05 mg/kg body weight (n = 15). RESULTS: The median basal UACR was 7.2 x 10(-9) (range, 1.8-52.3 x 10(-9)), with a calculated reference range of < 46.5 x 10(-9). Administration of sodium chloride resulted in adequate salt loading in 10 of 22 cats, but without significant reduction in the UACR. Administration of fludrocortisone resulted in a significant decrease in the UACR (median, 78%; range, 44-97%; P < .001) in healthy cats. In the cat with an aldosterone-producing adrenocortical carcinoma, the basal UACR and the UACR after fludrocortisone administration were 32 x 10(-9) and 36 x 10(-9), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Using the UACR for an oral fludrocortisone suppression test may be useful for the diagnosis of primary hyperaldosteronism in cats.

Primary aldosteronism: diagnostic and treatment strategies.

Primary aldosteronism is caused by bilateral idiopathic hyperplasia in approximately two-thirds of cases and aldosterone-producing adenoma in one-third. Most patients with primary aldosteronism are normokalemic. In the clinical setting of normokalemic hypertension, patients who have resistant hypertension and hypertensive patients with a family history atypical for polygenic hypertension should be tested for primary aldosteronism. The ratio of plasma aldosterone concentration to plasma renin activity has been generally accepted as a first-line case-finding test. If a patient has an increased ratio, autonomous aldosterone production must be confirmed with an aldosterone suppression test. Once primary aldosteronism is confirmed, the subtype needs to be determined to guide treatment. The initial test in subtype evaluation is CT imaging of the adrenal glands. If surgical treatment is considered, adrenal vein sampling is the most accurate method for distinguishing between unilateral and bilateral adrenal aldosterone production. Optimal treatment for aldosterone-producing adenoma or unilateral hyperplasia is unilateral laparoscopic adrenalectomy. The idiopathic bilateral hyperplasia and glucocorticoid-remediable aldosteronism subtypes should be treated pharmacologically. All patients treated pharmacologically should receive a mineralocorticoid receptor antagonist, a drug type that has been shown to block the toxic effects of aldosterone on nonepithelial tissues.

A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer.

The cortisol/cortisone-responsive AR (AR(ccr)) has two mutations (L701H and T877A) that were found in the MDA PCa human prostate cancer cell lines established from a castrated patient whose metastatic tumor exhibited androgen-independent growth. Cortisol and cortisone bind to the AR(ccr) with high affinity. In the present study, we characterized the structural determinants for ligand binding to the AR(ccr). Our data revealed that many of the C17, C19, and C21 circulating steroids, at concentrations that are found in vivo, functioned as effective activators of the AR(ccr) but had little or no activity via the wild-type AR or GRalpha. Among the synthetic glucocorticoids tested, dexamethasone activated both GRalpha and AR(ccr), whereas triamcinolone was selective for GRalpha. In MDA PCa 2b cells, growth and prostate-specific antigen production were stimulated by potent AR(ccr) agonists such as cortisol or 9alpha-fluorocortisol but not by triamcinolone (which did not bind to or activate the AR(ccr)). Of the potential antagonists tested, bicalutamide (casodex) and GR antagonist RU38486 showed inhibitory activity. We postulate that corticosteroids provide a growth advantage to prostate cancer cells harboring the promiscuous AR(ccr) in androgen-ablated patients and contribute to their transition to androgen-independence. We predict that triamcinolone, a commonly prescribed glucocorticoid, would be a successful therapeutic agent for men with this form of cancer, perhaps in conjunction with the antagonist casodex. We hypothesize that triamcinolone administration would inhibit the hypothalamic-pituitary-adrenal axis, thus suppressing endogenous corticosteroids, which stimulate tumor growth. Triamcinolone, by itself, would not activate the AR(ccr) or promote tumor growth but would provide glucocorticoid activity essential for survival.

Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer.

The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the AR(ccr). Our studies provide the first structural explanation for the glucocorticoid activation of AR(ccr), which is important for the development of new therapeutic treatments for androgen-independent prostate cancer.

Close association of urinary excretion of aquaporin-2 with appropriate and inappropriate arginine vasopressin-dependent antidiuresis in hyponatremia in elderly subjects.

The present study was undertaken to determine whether urinary excretion of aquaporin-2 (AQP-2) participates in the involvement of arginine vasopressin (AVP) in hyponatremia less than 130 mmol/L in 33 elderly subjects (> or =65 yr old) during the last 5-yr period. Subjects were separated into euvolemic hyponatremia groups: 13 with hypopituitarism, 8 with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 8 with mineralocorticoid-responsive hyponatremia of the elderly, and 4 with miscellaneous diseases. Approximately 40% of those with hyponatremia was derived from hypopituitarism, but severe hyponatremia was found in the patients with SIADH and mineralocorticoid-responsive hyponatremia of the elderly. Plasma AVP levels remained relatively high despite hypoosmolality and were tightly linked with exaggerated urinary excretion of AQP-2 and antidiuresis in the 3 groups of patients, except for one miscellaneous one. An acute water load test verified the impairment in water excretion, because the percent excretion of the water load was less than 42% and the minimal urinary osmolality was not sufficiently diluted. Also, plasma AVP and urinary excretion of AQP-2 were not reduced after the water load. The inappropriate secretion of AVP was evident in the patients with SIADH and hypopituitarism, and hydrocortisone replacement normalized urinary excretion of AQP-2 and renal water excretion in those with hypopituitarism. In contrast, the appropriate antidiuresis seemed to compensate loss of body fluid in the patients with mineralocorticoid-responsive hyponatremia of the elderly, who lost circulatory blood volume by 7.3% (mean). Fludrocortisone acetate increased renal sodium handling and body fluid, resulting in the reduction in AVP release and urinary excretion of AQP-2 in mineralocorticoid-responsive hyponatremia of the elderly. These findings indicate that urinary excretion of AQP-2 may be a more sensitive measure of AVP effect on renal collecting duct cells than are plasma AVP levels, and that increased urinary excretion of AQP-2 shows exaggerated AVP-induced antidiuresis in hyponatremic subjects in the elderly. In addition, mineralocorticoid-responsive hyponatremia of the elderly has to be carefully differentiated from SIADH in elderly subjects.

Success of surgery for primary aldosteronism judged by residual autonomous aldosterone production.

Since February 1996 we have prospectively assessed residual adrenal autonomy by the fludrocortisone suppression test (FST) in 23 patients 3 months after unilateral adrenalectomy for Conn syndrome and in 45 patients after a longer interval. In regard to blood pressure, 36 (53%) patients were cured of hypertension and the remaining 32 (47%) patients had improved hypertension control at the time of their latest postoperative clinical assessment. In regard to the outcome of surgery, patients who achieved normal suppressibility of aldosterone were regarded as cured, and those who had greater suppressibility after surgery were considered improved. Time since surgery for the whole group averaged 26 months. By these biochemical criteria, 42 patients (62%) were cured by surgery, and the rest improved; 16 (76%) of 21 women were cured, and 26 (55%) of 47 men. The women (mean +/- SD age 47 +/- 11 years) were significantly (p < 0.05) younger than the men (52 +/- 9 years). Preoperative aldosterone levels before and after FST were similar in the cured and improved groups and fell significantly (p < 0.01) in both groups following surgery. After surgical reduction of autonomous aldosterone production, mean plasma renin activity levels increased sixfold in the cured group and threefold in the improved group. Surgical mortality in this group of 68 patients with Conn syndrome was zero.

Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia.

An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis. Recent studies showed that a 30-kDa mitochondrial phosphoprotein, designated steroidogenic acute regulatory protein (StAR), is essential for this translocation. To allow us to explore the roles of StAR in a system amenable to experimental manipulation and to develop an animal model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce StAR knockout mice. These StAR knockout mice were indistinguishable initially from wild-type littermates, except that males and females had female external genitalia. After birth, they failed to grow normally and died from adrenocortical insufficiency. Hormone assays confirmed severe defects in adrenal steroids-with loss of negative feedback regulation at hypothalamic-pituitary levels-whereas hormones constituting the gonadal axis did not differ significantly from levels in wild-type littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, with lesser deposits in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement support a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation inducing progressive accumulation of lipids within the steroidogenic cells and ultimately causing their death. These StAR knockout mice provide a useful model system in which to determine the mechanisms of StAR's essential roles in adrenocortical and gonadal steroidogenesis.

Análise da massa óssea em crianças com hiperplasia adrenal congênita em uso de glicocorticóides / Bone mass analysis in children with congenital adrenal hyperplasia in use of glucocorticoids

Um grupo de 15 crianças com a forma clássica de hiperplasia adrenal congênita (HAC) por deficiência de 21-hidroxilase foi investigado para avaliar a possível ocorrência de alterações na sua massa óssea e na composição corporal durante tratamento com glicocorticóides, através do estudo de densitometria de dupla emissão com fonte de raios-X (DEXA). Foram realizadas 54 avaliações de corpo inteiro, com intervalo entre elas de 3 a 21 meses. Estas avaliações foram realizadas durante um estudo terapêutico cruzado ("crossover") com intervalo (HC) nas doses de 15 ou 25 mg/m2 VO (seis meses cada) associada à fludrocortisona (FC) na dose de 0,1 mg VO ao dia. Foram estudados: a densidade e o centeúdo mineral ósseos, a densidade óssea segmentar da coluna vertebral, a quantidade de tecido gorduroso e a quantidade de tecido relacionado à massa muscular (massa magra). À avaliação da densidade óssea, não foram encontradas evidências de redução da massa mineral óssea das crianças, em relação à população de referência. Observou-se, ao contrário, um aumento da densidade óssea do segmento relacionado à coluna vertebral, que poderia estar relacionado aos níveis elevados de androgênios observados nessas crianças, mesmo durante tratamento com glicocorticóides, na dose de 15 mg/m2/dia. Observamos também uma tendência para índices mais baixos da relação massa magra/gordura nos exames realizados durante o uso de 25 mg/m2/dia de HC em relação à dose de 15 mg/m2/dia.

[Effect of 9-alpha-fluorhydrocortisone (Florinef) in extrarenal regulation of potassium]. / Efeito da 9-alfa-fluoridrocortisona (Florinef) na regulação extra-renal do potássio.

There are evidences that adrenal hormones regulate extrarenal potassium homeostasis. The present study evaluated the effect of Florinef modulation on extrarenal mechanisms in potassium adaptation of adrenalectomized rats. The results demonstrated that the rats treated with Florinef had serum potassium levels at normal range probably due to an increase in cellular potassium uptake consequently to en enhanced activity of Na-K-ATPase.

Modulation of the secretion of potassium by accompanying anions in humans.

In animals, secretion of potassium (K) in the cortical collecting duct (CCD) is modulated by the properties of the accompanying anion. In humans, results are inconclusive as previous studies have not differentiated between a kaliuresis due to a rise in the concentration of K from one due to an increase in the volume of urine. Our purpose was to study the effects of chloride (Cl) and bicarbonate on the secretion of K in the CCD in humans using the transtubular K concentration gradient (TTKG), a semi-quantitative index of secretion of K in the terminal CCD. After control blood and urine samples were obtained, all subjects ingested 0.2 mg fludrocortisone to ensure that mineralocorticoids were not limiting the secretion of K. The anionic composition of the urine was varied using three protocols: Normal subjects (N = 11) ingested cystine and methionine to induce sulfaturia; nine subjects with a contracted ECF volume (to lower the concentration of Cl in the urine) were also studied during sulfaturia following the ingestion of cystine and methionine; 13 normovolemic subjects were studied during bicarbonaturia following the ingestion of acetazolamide. When the concentration of Cl in the urine was greater than 15 mmol/liter, sulfate had no effect on the TTKG. With lower concentrations of Cl in the urine, the TTKG rose 1.5-fold. The TTKG rose 1.8-fold in the presence of bicarbonaturia despite concentrations of Cl in the urine that were greater than 15 mmol/liter, suggesting that bicarbonate has additional effects on this K secretory process. At comparable concentrations of sulfate and bicarbonate in the urine, the TTKG was increased only with bicarbonaturia.(ABSTRACT TRUNCATED AT 250 WORDS)

Some aldosterone-producing adrenal tumours also secrete cortisol, but present clinically as primary aldosteronism.

1. Two patients with angiotensin-responsive aldosterone-producing adenoma (APA) and one with adrenal cortical carcinoma demonstrated autonomous secretion of cortisol as well as of aldosterone. 2. The response of cortisol and of aldosterone to ACTH did not differentiate between the two APA which secreted cortisol and the eight which demonstrated normal suppression with dexamethasone. 3. Concurrent autonomous secretion of cortisol as well as aldosterone may occur in patients who present clinically with primary aldosteronism. 4. Biochemical distinctions between adenomas may reflect differences in their cellular composition.

Antialdosterones: incidence and prevention of sexual side effects.

The use of spironolactone in the treatment of hypertension has been limited by the occurrence of sexual side effects, mainly menstrual disturbances in women and gynaecomastia in men. In order to minimize this limitation on the use of an effective potassium-sparing antihypertensive agent, two strategies can be proposed: (1) A decrease in the daily dose of spironolactone. In 182 patients with essential hypertension treated with spironolactone alone for a mean follow-up period of 23 months, daily doses of 75-100 mg were as effective on blood pressure as doses of 150-300 mg. In contrast, the development of gynaecomastia--91 cases among 699 men--was dose-related in 6.9% (50 mg/day) to 52.2% (150 mg or more/day) of the cases. (2) An improvement in the receptor-binding specificity of spironolactone. Three 9 alpha, 11 alpha-epoxy derivatives have been characterized in vitro in rats and in rabbits. They exhibited a 3- to 10-fold decrease of the antiandrogenic and progestagenic effect, compared with spironolactone. In humans, one of these derivatives counteracted the fall in urinary Na/K ratio induced by 9 alpha-fluorohydrocortisone at a 25 mg dose.

Primary role of hyperkalemia in the acidosis of hyporeninemic hypoaldosteronism.

A 65-year-old woman with mild renal insufficiency had persistent hyperkalemia and hyperchloremic acidosis. Her plasma aldosterone level was relatively low for her hyperkalemia, and her urine pH was low. Fludrocortisone acetate administration corrected both hyperkalemia and acidosis by increasing urinary excretion of potassium and net acid, implicating deficient mineralocorticoid activity in the distal renal tubule in this patient. During this medication urinary ammonium excretion increased, but urine pH remained low, so that urinary titratable acid excretion did not decrease. On the other hand, correction of hyperkalemia by administration of a potassium-calcium exchange resin alone also resolved the acidosis by increasing urinary ammonium excretion. This increment exceeded the decrement of urinary titratable acid excretion, which was caused by raised urine pH secondary to increased urinary ammonium excretion, and resulted in increase of net acid excretion. Thus, in this patient, hyperkalemia appears to be a decisive causative factor in the acidosis, with deficient mineralocorticoid effect only contributing in part to the reduction of net acid excretion and the acidosis.

Human atrial natriuretic polypeptide during escape from mineralocorticoid excess in man.

1. Plasma concentrations of human alpha-atrial natriuretic polypeptide (h-alpha ANP) during escape from the effects of mineralocorticoid excess were determined in six healthy volunteers. 2. Escape, as indicated by an abrupt increase in sodium excretion on the third to sixth day of 9 alpha-fludrocortisone acetate administration (0.6 mg/day), was observed in all subjects. 3. The mean plasma h-alpha ANP level was 30.9 +/- SEM 8.8 pmol/l on the control day; it increased exponentially in response to 9 alpha-fludrocortisone acetate administration, reached a significant level (114.0 +/- 22.4 pmol/l, P less than 0.05) on the day before escape and remained elevated during escape. 4. The 24 h creatinine clearance and blood pressure did not change significantly before the escape. Plasma h-alpha ANP increased markedly when the cumulative sodium balance exceeded 220 mmol. 5. These results suggest that h-alpha ANP may play a contributory role in natriuresis and diuresis after mineralocorticoid excess.

Aldosterone-producing adenomas responsive to angiotensin pose problems in diagnosis.

1. A subgroup of patients with aldosterone-producing adenoma (APA) have been identified who lack many of the biochemical features regarded as characteristic of APA and used to distinguish APA from bilateral adrenal hyperplasia. 2. In these patients, aldosterone is responsive to infused angiotensin II (angiotensin-responsive APA), which explains their uncharacteristic responses to upright posture, saline infusion and fludrocortisone acetate administration. 3. The angiotensin-responsiveness of these patients may derive from the contralateral adrenal gland, since renin levels are less completely suppressed in angiotensin-responsive APA than in angiotensin-unresponsive APA. 4. However, while the excretion of 18-oxo-cortisol was consistently increased in angiotensin-unresponsive APA, it was normal in angiotensin-responsive APA, consistent with biochemical and biosynthetic distinctiveness residing in the tumours. 5. Angiotensin-responsive APA should always be considered as an alternative diagnosis to bilateral hyperplasia causing primary aldosteronism.