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Clinical studies have shown that aldosterone and salt are independently related to hypertension, cardiovascular morbidity and mortality. More recently, studies in humans have demonstrated that, similarly to animals, endogenous aldosterone and dietary salt intake have not only separate, but also combined effects to accelerate target-organ deterioration. The aldosterone-salt interaction has important clinical implications, because combined effects of both can be minimized, if not avoided, by reducing salt intake. This interaction could also be interrupted by blocking the effects of aldosterone, with use of mineralocorticoid receptor antagonists, or by reducing aldosterone effects by adrenalectomy, in patients with aldosterone producing adenoma. Furthermore, aldosterone reduction or blockade may reduce salt appetite.

Although the aldosterone/renin ratio (ARR) is the most reliable screening test for primary aldo-steronism, false positives and negatives occur. Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy and treatment with diuretics (including spironolactone), dihydropyridine calcium blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. We recently reported selective serotonin reuptake inhibitors lower the ratio. Because potassium regulates aldosterone, uncorrected hypokalemia can lead to false negatives. Beta-blockers, alpha-methyldopa, clonidine, and nonsteroidal anti-inflammatory drugs suppress renin, raising the ARR with potential for false positives. False positives may occur in patients with renal dysfunction or advancing age. We recently showed that (1) females have higher ratios than males, and (2) false positive ratios can occur during the luteal menstrual phase and while taking an oral ethynylestradiol/drospirenone (but not implanted subdermal etonogestrel) contraceptive, but only if calculated using direct renin concentration and not plasma renin activity. Where feasible, diuretics should be ceased at least 6 weeks and other interfering medications at least 2 before ARR measurement, substituting noninterfering agents (e. g., verapamil slow-release±hydralazine and prazosin or doxazosin) were required. Hypokalemia should be corrected and a liberal salt diet encouraged. Collecting blood midmorning from seated patients following 2-4 h upright posture improves sensitivity. The ARR is a screening test only and should be repeated once or more before deciding whether to proceed to confirmatory suppression testing. Liquid chromatography-tandem mass spectrometry aldosterone assays represent a major advance towards addressing inaccuracies inherent in other available methods., (© Georg Thieme Verlag KG Stuttgart · New York.)

Experimental and human data suggest that adverse cardiovascular (CV) and renal effects of aldosterone excess are dependent on concomitant dietary salt intake. Increased urinary protein (Uprot) is an early sign of nephropathy independently associated with CV risk. We have previously reported a positive association between Uprot and urinary sodium (UNa) in patients with hyperaldosteronism, but not in patients with normal aldosterone levels. We aimed to determine whether Uprot is related to UNa in patients with aldosterone-producing adenoma (APA) and whether the degree of Uprot and strength of this relationship is reduced following correction of hyperaldosteronism. Subjects with APA (n=24) underwent measurement of 24 h Uprot and UNa before and after unilateral adrenalectomy (follow-up 15.0±11.9 months). Following surgery, mean clinic systolic blood pressure fell (150.4±18.2 vs 134.5±14.5 mm Hg, P=0.0008), despite a reduction in number of antihypertensive medications, and Uprot (211.2±101.6 vs 106.0±41.8 mg per day, P<0.0001) decreased. There was a positive correlation between Uprot and UNa both before (r=0.5477, P=0.0056) and after (r=0.5097, P=0.0109) adrenalectomy. Changes in UNa independently predicted Uprot reduction (P=0.0189). These findings suggest that both aldosterone levels and dietary salt contribute to renal damage, and that once glomerular damage occurs it is not completely resolved following correction of hyperaldosteronism. Our study suggests that treatment strategies based on reduction of aldosterone effects, by adrenalectomy or mineralocorticoid receptor blockade, in conjunction with low-salt diet would provide additional target-organ protection in patients with primary aldosteronism.

We examined in detail biochemical characteristics of 10 normotensive individuals (6 females; age range, 11-43 yr) with glucocorticoid-suppressible hyperaldosteronism (familial hyperaldosteronism type I) in an attempt to understand the development of hypertension in this disorder. All were normokalemic (median plasma potassium, 3.7 +/- 0.4 mmol/L SD), and upright plasma aldosterone levels (478 +/- 333 pmol/L) were within the normal range (140-1110 pmol/L) in nine subjects. However, upright PRA levels (3.3 +/- 30.5 pmol/L x min) were suppressed (<13 pmol/L x min), and the aldosterone to PRA ratio (169.0 +/- 308.3) was elevated (>65) in all but one subject. All subjects had elevated 24-h urinary levels of 18-oxo-cortisol (34.3 +/- 11.2 nmol/mmol creatinine; normal range, 0.8-6.5 nmol/mmol creatinine). Plasma aldosterone failed to rise by at least 50% during 2 h of upright posture in five of seven subjects, or during a 1-h infusion of angiotensin II (2 ng/kg x min) in each of six subjects so studied. Serial, second-hourly (day-curve) aldosterone levels correlated tightly with cortisol (r = 0.79-0.97, P < 0.01 to 0.001), but not with PRA (r = 0.13-0.40, not significant) levels in each of six subjects, and plasma aldosterone suppressed to less than 110 pmol/L during 4 days of dexamethasone administration (0.5 mg 6 hourly) in each of two studied, consistent with ACTH-regulated aldosterone production. In conclusion, biochemical evidence of excessive, abnormally regulated aldosterone production is present not only in hypertensive individuals with familial hyperaldosteronism type I, but also in those who are normotensive. The absence of hypertension in such individuals, therefore, cannot be attributed to lack of biochemical expression of the hybrid gene.

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.

We compared the aldosterone-producing potency of the angiotensin II-sensitive wild-type aldosterone synthase genes and the ACTH-sensitive hybrid 11 beta-hydroxylase/aldosterone synthase gene by examining aldosterone, PRA, and cortisol day-curves (2-hourly levels over 24 h) in patients with familial hyperaldosteronism type I, before and during long-term (0.8-13.5 yr) glucocorticoid treatment. In 8 untreated patients, PRA levels were usually suppressed, and aldosterone correlated strongly with cortisol (r = 0.69-0.99). Fourteen studies were performed on 10 patients receiving glucocorticoid treatment that corrected hypertension, hypokalemia, and PRA suppression in all. ACTH was markedly and continuously suppressed in 6 studies, 3 of which demonstrated strong correlations between aldosterone and PRA (r = 0.77-0.92). ACTH was only partially suppressed in the remaining 8 studies; aldosterone correlated strongly: 1) with cortisol alone in 5 (r = 0.71-0.98); 2) with cortisol (r = 0.90) and PRA (r = 0.74) in one; 3) with PRA only in one (r = 0.80); and 4) with neither PRA nor cortisol in one. Unless ACTH is markedly and continuously suppressed, aldosterone is more responsive to ACTH than to renin/angiotensin II, despite the latter being unsuppressed. This is consistent with the hybrid gene being more powerfully expressed than the wild-type aldosterone synthase genes in familial hyperaldosteronism type I.

1. Aldosterone-producing adenomas (APA) of the adrenal gland may be responsive or un-responsive to the renin-angiotensin system. 2. We have described increased expression of renin mRNA in angiotensin-responsive aldosterone-producing adenomas (AII-R-APA) compared with angiotensin-un-responsive aldosterone-producing adenomas (AII-U-APA) and significantly different allelic frequencies of the BglI, TaqI and HinfI restriction fragment length polymorphisms of the renin gene between the two groups. 3. An area including the 5' flanking region -500 bp from exon 1, exon 1 and intron A contained no gross insertions or deletions when studied by a long polymerase chain reaction technique. 4. In the present study, polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP) revealed no single base pair alteration in the proximal promoter region (-600 bp to transcription start) of the renin gene in patients with APA (either AII-U-APA or AII-R-APA) when compared with normal subjects. 5. Therefore, mutations in this regulatory region do not appear to explain the different levels of renin gene expression observed in these two subtypes of APA.

Aim: Since detection of familial hyperaldosteronism type I (glucocorticoid-suppressible hyperaldosteronism) allows specific treatment of hypertension with dexamethasone, we compared clinical, biochemical and genetic approaches to detection., Patients and Methods: We studied 22 affected patients, 21 from a single, large family and an additional adopted male. Plasma aldosterone, plasma renin activity and urinary 18-oxo-cortisol were measured by radioimmunoassay. The hybrid gene was demonstrated using either Southern blotting or a long polymerase chain reaction technique., Results: Thirteen out of 22 (59%) patients with familial hyperaldosteronism type I, but only four out of 12 (33%) under 20 years of age, were hypertensive. Plasma potassium and aldosterone were each normal in 20 out of 22 (91%), and unhelpful in diagnosis. Plasma renin activity, the aldosterone: plasma renin activity ratio and 18-oxo-cortisol were more sensitive, being abnormal in 20 out of 22 (91%), 19 out of 22 (86%) and 20 out of 20 (100%) patients, respectively. Aldosterone was unresponsive (<50% rise) to 2 h of upright posture following overnight recumbency in 15 out of 15 (100%) patients studied, and to angiotensin II infusion (2 ng/kg per min for 1 h) in 14 out of 14 patients (100%). Whereas all the abovementioned abnormalities are also characteristic of angiotensin II-unresponsive aldosterone-producing adenoma, marked aldosterone suppression following 4 days of dexamethasone (0.5 mg every 6 h) was sensitive and specific for familial hyperaldosteronism type I (n = 11). The hybrid gene was detectable in peripheral blood leucocyte DNA in all 22 affected patients by Southern blotting, and by a faster, long polymerase chain reaction method developed in our laboratory, both methods requiring only a single blood collection., Conclusions: Should studies in other families confirm its universal applicability, long polymerase chain reaction should prove to be the most practical means of detecting familial hyperaldosteronism type I in laboratories equipped with this technique.

Previous studies have shown a significant association between allelic frequencies at the ANP gene locus and aldosterone responsiveness to angiotensin in aldosterone-producing adenoma (APA). We searched for any gross insertions or deletions in the ANP gene in APA and any associations between allelic frequencies at the Hpa II and Sca I RFLP sites within the ANP gene and angiotensin-responsive and unresponsive APA and normal subjects. We also searched for possible point mutations in the promoter region of the ANP gene (-595 to transcription start site) in peripheral blood and tumor DNA from 59 patients with APA and in peripheral blood DNA from 39 normal subjects by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) analysis. No large alterations in the ANP gene were observed, and no difference in allelic frequencies at the RFLP sites were seen between the two tumor subtypes, angiotensin-responsive and angiotensin-unresponsive APA, or between the APA group and normal subjects. SSCP analysis, however, did reveal mutations in the promoter region of the ANP gene (-375 to -595) in both peripheral blood and tumor DNA from 8 of 59 (14%) patients with APA, compared with only one of 39 normal controls (2.6%). This study suggests that alterations in the proximal promoter region of the ANP gene in APA may be important in the regulation of ANP transcription and may be involved in the underlying pathophysiology of aldosterone-producing adenoma in at least some patients.

1. Angiotensin-responsive aldosterone-producing adenomas (AII-R-APA) have increased expression of renin mRNA compared with angiotensin-unresponsive aldosterone-producing adenomas (AII-U-APA) or normal adrenals. 2. Further, significant associations between the BglI, TaqI and HinfI RFLP and aldosterone responsiveness to the renin-angiotensin system of the two subgroups of patients have been reported. 3. Using the polymerase chain reaction based technique single stranded conformational polymorphism, we detected no alterations in exon 1 of the renin gene in peripheral blood leucocyte DNA from normal AII-U-APA and AII-R-APA subjects. 4. Using long-PCR, we amplified a fragment of the renin gene consisting of a region covering 500 bp upstream of exon 1, exon 1 and intron A. No gross changes in this area of the renin gene were found in the three groups of subjects studied. However this does not exclude small alterations in this area.

1. Aldosterone responsiveness to ACTH was compared in eleven patients with angiotensin-unresponsive (AII-U) aldosterone-producing adenomas (APA), 16 with AII-responsive (AII-R) APA and 19 with bilateral adrenal hyperplasia (BAH). 2. After overnight recumbency, aldosterone levels were highest in AII-U APA and lowest in BAH. Following 2 h of upright posture, however, levels were similar among the three groups. 3. During ACTH infusion, aldosterone levels in AII-U and AII-R APA were similar, and higher than those in BAH. Because of the higher basal level, the percentage rise in aldosterone was lower in AII-U APA compared with the other groups, as was the ratio of per cent aldosterone rise to per cent cortisol rise. 4. Slightly but significantly reduced plasma cortisol levels observed in the AII-R APA group may reflect secretion by AII-R APA of a cortisol-like substance that is capable of suppressing ACTH and thus adrenal cortisol production. 5. The tendency of aldosterone to follow the diurnal rhythm of ACTH in AII-U APA may thus represent an unmasking of the normal ability of ACTH to regulate aldosterone, secondary to the loss of AII responsiveness, rather than an enhancement of ACTH effect.

1. In patients with primary aldosteronism due to angiotensin-responsive and angiotensin-unresponsive aldosterone-producing adenomas, no differences in the coding region of the angiotensin II type 1 (AT1) receptor gene were observed compared to normal subjects in peripheral blood leucocyte DNA. 2. Furthermore, no differences in the AT1 receptor gene were observed in DNA extracted from tumour tissue of either subgroup. 3. Genotypic and allelic frequencies for an RFLP detected in the coding region of the AT1 receptor gene were not significantly different between normal subjects and patients with aldosterone-producing adenomas as a group, nor between normal subjects and patients of either subgroup when compared with each other. 4. In those patients heterozygous in peripheral blood at the RFLP site, tumour DNA showed the same allelic pattern. 5. In patients with aldosterone-producing adenomas either responsive or unresponsive to the renin-angiotensin system, no differences were detected using SSCP analysis in the coding region of the AT1 receptor gene in peripheral blood or tumour tissue.

Approximately one half of the aldosterone-producing adenomas (APA) removed from patients with primary aldosteronism in the Hypertension Unit at Greenslopes Hospital belong to a subgroup in which aldosterone levels are responsive to the renin-angiotensin system (angiotensin-responsive APA; AII-R-APA), unlike classical APAs in which aldosterone is unresponsive (AII-U-APA). Renin mRNA levels in AII-R-APA were elevated when compared with those in AII-U-APA or normal adrenal cortices. Renin mRNA levels in some adrenal cortices surrounding AII-R-APA (but never in AII-U-APA) were raised, suggesting that a genetic defect is not confined to the tumor. Renin gene RFLP analysis in peripheral blood DNA revealed a significant difference in allelic frequencies between patients with AII-R-APA and AII-U-APA, suggesting an association between an alteration in the renin gene and aldosterone responsiveness to the renin-angiotensin system in patients with APAs.

Primary aldosteronism is an important, potentially curable, form of hypertension. We examined the possible association between restriction fragment length polymorphisms in the atrial natriuretic peptide (ANP) gene and responsiveness of aldosterone to angiotensin II in 59 patients with primary aldosteronism due to aldosterone-producing adenoma (APA). Significant differences in the allelic frequencies of the BglI, TaqI and XhoI polymorphic sites at the ANP gene locus (chromosome 1; 1p36) between angiotensin II-unresponsive and angiotensin II-responsive tumors were observed. Variation in the ANP gene between the two groups may result in altered expression of ANP within the adrenal gland, and may contribute to the biochemical regulation of aldosterone production of these two subgroups of patients with APA.

1. Aldosterone levels in patients with unilateral aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia. 2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. 3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness. 4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.

Aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. We compared the frequency of two renin gene polymorphisms in peripheral blood DNA from the two subgroups and found a significant association (allele frequency X2 = 7.67, p < 0.006) between BglI polymorphism and aldosterone responsiveness. This may be a significant determinant of the biochemical behaviour of these tumours.

The responses of renin, aldosterone, and blood pressure to ACTH suppression with dexamethasone in a 61-yr-old man with glucocorticoid-suppressible hyperaldosteronism were modified by coexistent atheromatous renal artery stenosis (RAS). The apparent responsiveness of aldosterone to angiotensin-II resulting from RAS has implications for the regulation of steroidogenesis in this condition. After successful surgical correction of the RAS, the response changed and resembled that seen in two younger males (one his son) with uncomplicated glucocorticoid-suppressible hyperaldosteronism.

Because familial hyperaldosteronism type II (FH-II) includes tumor formation, we examined the karyotypes of benign adrenocortical aldosterone-producing adenomas (APAs), including those from patients with FH-II. Cell culture was successful in 12 of 14 tumors removed, two of which were from patients with FH-II. Five of the 12 tumors cultured (one from a patient with FH-II) had abnormal karyotypes. All were from male patients, and loss of the Y chromosome was observed in each. One showed loss of chromosome 19, and another showed an unbalanced t(6;7) producing partial trisomy 7q. Oncogenes are present at these breakpoints, and loss of the Y chromosome and monosomy 19 have previously been reported in neoplasia. This is the first report of cytogenetic abnormalities in benign adrenocortical tumors.

1. Infusion of increasing doses of angiotensin II (AII) in normal subjects sequentially increased blood pressure, aldosterone and atrial natriuretic peptide (ANP) levels. 2. The slope of ANP response to AII was positively correlated with basal ANP and with the slope of blood pressure response to AII (pressor slope) but not with age. 3. This is consistent with the response of ANP to AII being mediated partly by the rise in blood pressure, independent of ageing. 4. As expected in a selected normotensive population, there was no correlation between basal blood pressure and age, but pressor slope was positively correlated with age. 5. Thus, dose-response relationships may be an index of age-induced alterations in pressure regulatory mechanisms.

1. Nineteen out of 47 patients (40%) with confirmed unilateral aldosterone-producing adenoma (APA) were responsive to low-dose angiotensin II infusion (AII-R), as defined by an increase in plasma aldosterone concentration of > 50% over basal at 2 ng/kg per min for 60 min. 2. Seven to ten days after unilateral adrenalectomy, aldosterone was no longer responsive to angiotensin infusion in AII-R APA (100%, n = 17). Therefore, angiotensin responsiveness resides within the adenoma in AII-R APA. 3. The upright posture test for the differentiation of adenoma from hyperplasia was unreliable for the AII-R APA (26%), but generally reliable in the angiotensin-unresponsive subtype, (AII-U APA, 96%). 4. The reported predominance of females in APA was seen in AII-U APA (68%), but was reversed in AII-R APA (37%).

1. In vitro short-term production of cortisol by dispersed tumour and non-tumourous adrenal cortical cells was measured with and without added angiotensin II (AII) or adrenocorticotrophin (ACTH) in adrenals removed from five patients with primary aldosteronism. 2. Aldosterone-producing adenomas (APA) were classified as angiotensin responsive (AII-R) or angiotensin unresponsive (AII-U) based on pre-operative behaviour in vivo. 3. Cortisol was produced by both tumour and cortex in vitro without stimulation, and significantly more cortisol was generated by the cortex. 4. Addition of AII significantly increased cortisol production by both tumour and cortex to an equal extent. 5. Addition of ACTH also significantly increased cortisol production by both tumour and cortex, but tumours were more responsive than cortex. The response to ACTH exceeded the response to angiotensin in both tumour and cortex. 6. There was no obvious difference between AII-R and AII-U APA in terms of cortisol production.

1. Six (12%) out of 52 respondents to newspaper advertisements for antihypertensive drug trials had elevated aldosterone to renin ratio, confirmed by repeated measurement. 2. Failure to suppress aldosterone with fludrocortisone acetate administration and oral salt loading confirmed the presence of primary aldosteronism in all six patients. 3. Two of the six patients have already had aldosterone-producing adenomas removed, one has commenced spironolactone, and one has an adrenal mass on computerized tomography but investigation is incomplete. 4. None of the six patients with primary aldosteronism had unprovoked hypokalaemia. 5. Plasma aldosterone levels did not distinguish those patients with subsequently proven primary aldosteronism from the others. Plasma renin activity (PRA) was a better discriminator, but not as good as the aldosterone to renin ratio. 6. The incidence of primary aldosteronism is probably much higher than the 1% currently quoted in texts, with earlier, normokalaemic forms accounting for the majority of cases.

Exciting developments in knowledge of primary aldosteronism include description of new subtypes and elucidation of the genetic basis of one variety. Furthermore, relatively simple biochemical screening (aldosterone/renin ratio) has disclosed that primary aldosteronism is more common than previously thought, by diagnosing patients at an earlier, normokalaemic stage. The mutant gene discovered in the glucocorticoid-suppressible variety (FHI) codes for an aldosterone biosynythetic enzyme normally controlled by angiotensin II, and now controlled by corticotropin. The zona fasciculata is hyperplastic and makes aldosterone and "hybrid steroids" 18-oxocortisol and 18-hydroxycortisol in excess, in response to ACTH but not to angiotensin II. Adrenal tumours have not yet been described in this condition. Aldosterone-producing adenomas (Conn's syndrome) are also commonly composed of zona fasciculata-like cells, make "hybrid steroids" in excess and are very sensitive to ACTH but not to angiotensin II. We have described a new variety of aldosterone-producing adenoma which is responsive to angiotensin II (AII-responsive APA), consists of at least 20% zona glomerulosa-like cells, and does not make "hybrid steroids" in excess. We have also described a new familial variety of primary aldosteronism that includes tumours and is not glucocorticoid-suppressible (FHII). We propose that primary aldosteronism is a spectrum of genetic diseases expressed as either hyperplasia or neoplasia, and that morphological and genetic diversity explains biochemical and clinical behaviour.

1. Plasma atrial natriuretic peptide (ANP), renin activity, aldosterone, sodium, potassium and serum total protein and albumin during and after 14 normal pregnancies were compared with age-matched controls. 2. None developed toxaemia and all delivered healthy babies. 3. During pregnancy, plasma renin activity and aldosterone were significantly (P less than 0.01) higher and potassium, total protein and albumin significantly lowew (P less than 0.01) than in controls, while ANP was not different from the control level. 4. At 6-13 weeks postpartum, a significant (P less than 0.01) suppression of renin and aldosterone was accompanied by significant (P less than 0.01) elevation of atrial natriuretic peptide when compared with controls. 5. The hormonal changes are consistent with 'effective plasma volume' reduction during pregnancy and persistent volume expansion after pregnancy, perhaps due to a renal glomerular lesion sustained late in pregnancy. In contrast, levels of potassium, total protein and albumin are consistent with haemodilution during pregnancy and its correction postpartum. 6. Measurements available in seven women 40-120 weeks postpartum showed normal renin and aldosterone levels in most, but ANP was still elevated. 7. Pregnancy may have a protracted effect on volume regulation.

Fifteen patients with primary aldosteronism were classified as angiotensin II-unresponsive aldosterone-producing adenoma (AII-U APA, n = 9), or angiotensin II-responsive aldosterone-producing adenoma (AII-R APA, n = 6), based on the responsiveness of aldosterone to upright posture and to angiotensin II infusion. Lack of aldosterone response to angiotensin II infusion immediately postoperatively in the AII-R APA subtype was consistent with previous responsiveness residing solely within the adenoma. Cortisol levels in five of the six patients with AII-R APA failed to suppress normally with dexamethasone consistent with some autonomous production of cortisol by the adenoma. In contrast, cortisol levels suppressed normally during dexamethasone administration in all patients with AII-U APA. This biochemical distinction can be added to the previously described overproduction of 18-oxo cortisol in AII-U APA but not in AII-R APA. Histological examination of adenoma sections revealed predominantly (greater than or equal to 50%) zona fasciculata type cells in AII-U APA. In contrast, AII-R APA contained less than 20% zona fasciculata type. Thus, biochemical differences between AII-U APA and AII-R APA subtypes of primary aldosteronism may be due to underlying differences in cellular composition of the aldosterone-producing adenomas.

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.

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.

The ratio of aldosterone to renin in plasma was measured in samples collected from 79 hypertensive patients. Eighteen patients with primary aldosteronism had ratios ranging from 25 to 677 (mean 183) when measured on 34 occasions, while 16 normal subjects had ratios of 3.3-21 (mean 11.3). Of the remaining 61 patients with ratios ranging from 1.8 to 184, 15 patients have ratios greater than 25 and are under investigation for primary aldosteronism, which appears highly likely in five and has been excluded in two. The aldosterone/renin ratio appears promising as a screening test for primary aldosteronism. Consistency and the effects of sodium and potassium balance and of antihypertensive medications require further study.

1. Saline infusion was performed in normal subjects, in essential hypertensives and in patients with aldosterone-producing adenoma (APA), with serial measurements of plasma aldosterone, cortisol and atrial natriuretic peptide (ANP). The effect of recumbency alone was also observed in the normal subjects. 2. Plasma aldosterone after saline infusion was less than 7 ng per 100 ml in the essential hypertensives and normal subjects, but greater than 9 ng per 100 ml in the patients with APA. 3. The aldosterone/cortisol ratio in normal subjects and in essential hypertensives was unchanged or fell during saline infusion, but rose in five of eight patients with APA. 4. Thus, an increase in aldosterone/cortisol ratio after saline infusion appears to be diagnostic of APA, but its absence does not exclude it.

In order to define short-term ACTH/corticosteroid dose-respone characteristics, we infused ACTH for 1 h at each of five incremental rates into pedigreed male beagle dogs in four different states of sodium balance. Progressive sodium depletion was associated with progressive increased in basal (pre-ACTH) plasma levels of renin, angiotensin II, aldosterone, 18-hydroxycorticosterone (18-OH-B), and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC). Administration of dexamethasone significantly reduced the preinfusion levels of cortisol, aldosterone, 18-OH-B, and 18-OH-DOC. The threshold dose of ACTH required to elicit an aldosterone response during low-sodium intake was similar to that for cortisol, but was higher during normal or high-sodium intake. Steepest portions of the dose-response curves were at lower rates of ACTH infusion for cortisol than for aldosterone, and maximum increment was much greater for cortisol (60-fold) than for aldosterone (12-fold). Whereas the slopes of ACTH/aldosterone and ACTH/18-OH-B dose-response curves were steepened by lower sodium diets, the ACTH/cortisol response was significantly flattened by severe sodium depletion. We conclude that ACTH is a potent and direct-acting short-term regulator of aldosterone secretion, subject to modification by altered sodium balance.

In a prospective study of 37 patients who had unilateral adrenalectomy for an aldosterone-producing adenoma, five of 33 (15%) were symptomatically hypotensive after at least 1 year, and eight of 29 (28%) who were observed 3, 6, 12, 18 and 24 months after the operation showed 2-year blood pressures below the fifth percentile for age- and sex-matched controls. Postoperatively, plasma aldosterone was lower, and plasma renin activity higher than in controls, these differences being more marked in the hypotensive group. Pre-operatively elevated atrial natriuretic factor fell to levels lower than in controls. These serial changes in volume-regulatory hormones are consistent with chronic hypovolaemia, due to relative hypoaldosteronism. Plasma cortisol was lower 6 months after the operation and plasma adrenaline levels fell by half. A reduced adrenocortical (aldosterone and cortisol) and adrenomedullary (adrenaline) secretory mass may play a role in the hypotension observed after unilateral adrenalectomy.

Serial measurements of plasma renin activity, plasma progesterone and urinary aldosterone were made before, during and after pregnancy in a patient from whom an A-P-A was later removed with cure of hypertension and hypokalemia. Despite 16-fold increases in urinary aldosterone during pregnancy, plasma renin activity levels became unsuppressed, and hypertension and hypokalemia were reversed. Increases in plasma progesterone or other steroids, competitively inhibiting the effects of aldosterone on its receptor, may explain remission of A-P-A and reversal of renin suppression during pregnancy. In a second patient, the features of primary aldosteronism appeared immediately after a pregnancy, and removal of an A-P-A cured hypertension and hypokalemia. A-P-A is more common in females and may appear following pregnancy. Urinary aldosterone was 6-fold higher after pregnancy than before. Thus, sex steroids may not only protect from hyperaldosteronism but may also stimulate growth of A-P-A's.

In young males with essential hypertension, propranolol and pindolol in small doses caused significant expansion of plasma volume (PV) after one month which did not prevent a reduction in BP. With higher doses, changes in PV were inconsistent and reductions in plasma renin activity (PRA) and 24-hour aldosterone excretion (AE) not closely related to BP changes. The effects of beta-adrenoreceptor blocking drugs on PV, PRA, and AE do not appear to be important components of their anti-hypertensive action.

Two males with glucocorticoid-suppressible hyperaldosteronism had hyperaldosteronism, hypertension and hypokalaemia corrected by continuous administration of physiological doses of dexamethasone for more than a year. During long-term dexamethasone treatment: (a) Plasma renin activity increased from subnormal to high normal levels, with normal posture-mediated increases; (b) Plasma aldosterone became responsive to angiotensin infusion, a new observation; (c) A fall in plasma aldosterone between 0800 h (recumbent) and 1000 h (upright) was replaced by a rise; (d) Plasma aldosterone became suppressible with salt loading. These findings are consistent with a shift to more normal control of aldosterone by renin-angiotensin, once abnormal responsiveness to ACTH has been nullified.

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.

In 14 hypertensive patients aldosterone/cortisol ratio was always lower in a peripheral vein or low IVC than in either adrenal vein. In four patients with a right-sided aldosterone-producing adenoma (APA), the aldosterone/cortisol ratio in peripheral vein was always higher than in the left adrenal vein. If only the left adrenal vein is cannulated, right-sided APA can still be diagnosed with certainty. In three patients with glucocorticoid-suppressible hyperaldosteronism, urinary excretion of both 18-oxocortisol and 18-hydroxycortisol was elevated. In four patients with APA excretion of 18-oxocortisol was elevated. In two of three patients with bilateral adrenal hyperplasia (BH), excretion of both steroids was normal. 75Se-selenomethylcholesterol scanning correctly lateralized five APA, but falsely lateralized a patient with BH. Results with CT scans were often misleading.

Several lines of evidence have been developed indicating that the sympathetic nervous system may play a role in mediating the renal and adrenocortical secretory responses to upright posture and sodium deprivation. Despite concurrent increases in arterial blood pressure, the plasma renin activity of normal subjects increased both in response to the infusion of catecholamines (norepinephrine: epinephrine, 10:1) and in response to stimulation of the sympathetic nervous system by cold. Aldosterone excretion was also increased by catecholamine infusion. In normal subjects the stimuli of upright posture and of sodium depletion both resulted in increases in urinary catecholamines, plasma renin activity, and urinary aldosterone. A patient with severe autonomic insufficiency did not experience normal elevations of urinary catecholamines, plasma renin activity, or urinary aldosterone in response to upright posture or sodium deprivation, despite a substantial fall in arterial blood pressure. When orthostatic hypotension was prevented by infusion of catecholamines, however, increases in plasma renin activity and in aldosterone excretion were observed. We suggest that both upright posture and sodium depletion lead to decreases in effective plasma volume and increases in sympathetic nervous system activity. This increase in sympathetic activity is then responsible for an increase in renal afferent arteriolar constriction, leading to an increase in renin secretion and, ultimately, an increase in aldosterone secretion.

Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using high-density bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding ∼50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive. [ABSTRACT FROM AUTHOR]