Pathogenesis of essential hypertension with low renin: responses of plasma renin activity to various stimulation tests in essential hypertension.

Plasma renin activity (PRA) was measured in 14 control subjects and 27 patients with essential hypertension (EH) (low renin group: 9, normal renin group: 11, and high renin group: 7) before and after the following stimulation tests. Test procedures: 1) Circadian rhythm (0600, 1600 and 2400h). 2) Adrenal stimulation test (ACTH: 12.5 I.U.). 3) Adrenal suppression test (Dexamethasone: 1.0 mg). 4) Metopirone test (1.5 g). 5) Angiotensin II infusion test (8 ng/kg/min). 6) Saline infusion test (1000 ml/hr). Patients with low PRA showed significantly lower levels of PRA than those of other two groups in circadian rhythm, after 2 hours of ACTH infusion and after angiotensin II infusion. Furthermore, these patients showed significantly higher responses of PRA than other two groups after furosemide test under dexamethasone and after metopirone test. In case of saline infusion test, patients with low and normal PRA did not show significantly decreased levels of PRA after the infusion, though all patients with high PRA and all control subjects showed significantly decreased levels of PRA. From the present studies, it might be concluded that patients with low PRA has an unknown mineralocorticoid excess which is ACTH dependent and 11 hydroxylated and some of hypertensive patients have an abnormality in their renin-angiotensin-aldosterone volume feed back loop as a factor for hypertension.     

Renin and aldosterone secretion under converting enzyme inhibition

The converting enzyme inhibitor (CEI) is known to inhibit the conversion of angiotensin I to angiotensin II. In order to analyse the regulatory mechanisms involved in aldosterone secretion independent of renin-angiotensin system, one of the CEIs, SQ 14,225 was infused to the dogs in association with several pharmacological agents. To the mongrel dogs under pentobarbital anesthesia, SQ 14,225 was administered intravenously as a bolus injection (0.5 mg/kg), followed by two hour infusion (0.5 mg/kg/hr). The effects of several pharmacological agents on plasma renin activity (PRA) and aldosterone concentration (PA) were examined in the condition in which endogenous angiotensin II production was blocked by CEI. PRA was increased significantly from the basal level (6.4 +/- 1.2; mean +/- SEM) to 14.1 +/- 2.6 ng/ml/hr 60 min after the administration of SQ 14,225. PA, on the other hand, was decreased from 12.2 +/- 3.6 to 7.6 +/- 2.2 ng/dl. The CEI-induced increase in PRA was completely blocked by infusion of angiotensin II (40 ng/kg/min), physiological saline (0.25 approximately 0.44 ml/kg/min), pretreatment of propranolol (0.5 mg/kg) or norepinephrine (200 ng/kg/min). Both pindolol and indomethacin had no significant effect on the CEI-induced increase in PRA. Increase in PRA was also observed by the infusion of furosemide, prostaglandin 1 or E1. PA was increased by KCl infusion (1.0 mEq/kg/hr), but was not affected significantly by the administration of furosemide, pindolol, prostaglandin A1 or E1, during the SQ 14,225 infusion. An elevation of PRA observed under the converting enzyme inhibition, was considered to be due to decreased feedback inhibition as a result of reduction of angiotensin II formation. It was suggested from the present results, that the CEI-induced increase in PRA might be mediated by beta-receptor and baroreceptor in addition to the direct negative feedback by angiotensin II. The present data also suggested that both furosemide and prostaglandins stimulated aldosterone secretion via the renin-angiotensin system, rather than by acting directly on the adrenal cortex.     

The Effects of Acth on the Renin-Aldosterone System in Normotensive Man

The present study examined the effects of low dose ACTH administration (0.1 mg/day for 2 days) on plasma renin concentration, (PRC), activity (PRA) and substrate (PRS), cortisol and aldosterone in man. Six healthy male volunteers on a diet calculated to contain 150 mmol Na/day received an infusion of 5% dextrose (6 ml/h) for 24 hours, then ACTH (Synacthen, Ciba-Geigy) was added to the infusion at the rate of 100 μg per day, for 48 h. Blood samples were taken four hourly for determination of plasma cortisol aldosterone, PRC, PRA and PRS. There was a highly significant increase in plasma cortisol and aldosterone concentrations during ACTH infusion compared with dextrose infusion, but no significant increase in active or inactive PRC, PRA or PRS. In a separate study of 15 healthy male volunteers, dexamethasone (1 mg at 2300 h) suppressed plasm a cortisol but had noeffecton PRC. These results do not support the view that stimulation of aldosterone by ACTH ismediated through the renin angiotensin system.     

Adrenocortical dysfunction in paracoccidioidomycosis: comparison between plasma β-lipotrophin/adrenocorticotrophin levels and adrenocortical tests

OBJECTIVE: Paracoccidioidomycosis is an important cause of Addison's disease in South America. We have carried out an extensive and prospective study on paracoccidioidomycosis comparing glucocorticoid, mineralocorticoid and androgen function with adrenal regulators, ACTH/beta-LPH and plasma renin activity (PRA). PATIENTS AND METHODS: Forty-seven male patients with active paracoccidioidomycosis were studied consecutively together with 20 healthy controls. On day 1, plasma aldosterone and PRA levels were measured in blood samples obtained from patients in the supine and erect position. On day 2 at 0900 h, baseline plasma samples were taken for ACTH, beta-lipotrophin (beta-LPH), cortisol, corticosterone, aldosterone, androstenedione (delta 4-A) and dehydroepiandrosterone sulphate (DHEA-S). ACTH 1-24 (250 micrograms) was given i.v. and blood samples for these steroid assays were taken at 1 and 2 hours. RESULTS: Five patients (10%) had Addison's disease with high basal plasma ACTH and beta-LPH, and low cortisol levels after the ACTH test. In the remaining 42 patients, baseline ACTH and beta-LPH levels and plasma cortisol after ACTH were within the normal range. A high percentage of patients presented with reduced corticosterone (21% of patients) and aldosterone (23%) secretion and increased PRA (31%). Plasma delta 4-A (19%) and DHEA-S (50%) levels were also reduced. CONCLUSIONS: The frequency of Addison's disease among our patients with paracoccidioidomycosis was 10%. In addition, a subset of patients presented with adrenal dysfunction detected by mineralocorticoid or androgen tests. In parallel to pathological lesions a functional adaptation may occur during adrenal involvement in paracoccidioidomycosis.     

Response of plasma ACTH and adrenocortical hormones to potassium loading in essential hypertension

The effect of potassium loading on plasma adrenocortical hormones concentrations in 9 patients with essential hypertension (EH) was investigated. The plasma renin activity (PRA), plasma concentrations of growth hormone (GH), ACTH, cortisol, deoxycorticosterone (DOC), 18-hydroxy-deoxycorticosterone (18-OH-DOC) and aldosterone, and serum electrolytes were measured before and after potassium chloride (KC1) infusion (0.33 mEq/kg/h, for one hour). The KC1 infusion caused significant increases in serum potassium levels and plasma levels of GH, ACTH, cortisol, DOC, 18-OH-DOC and aldosterone, while PRA remained unchanged. Regression analysis at 30 min revealed significant positive correlations between delta ACTH and delta cortisol, between delta ACTH and delta DOC, between delta ACTH and delta 18-OH-DOC. However, the relationship between delta ACTH and delta aldosterone was not statistically significant. These results suggest that (1) acute potassium loading causes a significant increase in the plasma ACTH level and increased levels of adrenocortical hormones may be produced by increased ACTH secretion, and (2) it may be considered that a part of the increased level of plasma aldosterone following acute potassium loading may arise from increased ACTH secretion in EH.     

Simplified Screening Procedures for Primary Aldosteronism. Studies on the Mechanism of the Hyper-Responsiveness to Furosemide and Standing

Screening tests for primary aldosteronism were compared in 22 patients with this disorder and 140 hypertensive controls.

Adequate (93–100%) sensitivity and specificity were not provided by single tests ((1) serum K, (2) furosemide-stimulated PRA, or (3) plasma aldosterone concentration (PAC) after furosemide, or (4) after 2 liters 0.9% NaCl)), but were provided by combinations: (2) + (1) or (3); (2) + (1) or (4); and by a pressor response to saralasin + (3) or (4). Mechanism of the observed excessive rise in PAC “stimulated” by furosemide and standing for 2 h was studied in the same patients. The rise in “stimulated” PAC was (a) associated with a low PRA and not reproducible by angiotensin II infusions; (b) associated with a slight but significant rise in plasma cortisol and was reproducible by ACTH infusions. It is, therefore, attributed to the effects of slight ACTH release acting on adrenal tissue with super-sensitivity of aldosterone response to ACTH.     

PITUITARY—ADRENOCORTICAL FUNCTION IN PATIENTS DURING TREATMENT WITH THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR CAPTOPRIL

To study effects on pituitary-adrenocortical activity of a sustained block of angiotensin II formation, six 'drug-resistant' patients with essential hypertension were studied before and during treatment with an inhibitor of the angiotensin-converting enzyme (Captopril, SQ 14,225). The drug was given in increasing doses (100-400 mg/day) for 2 weeks whilst patients received a moderately restricted sodium intake (60-80 mmol/day). Immunoreactive ACTH, cortisol, aldosterone, plasma renin activity (PRA) and the activity of the angiotensin-converting enzyme (ACE) were measured in blood samples drawn at 0800-0900 h. Urinary excretion of cortisol and aldosterone were measured in 24-h urine collections. Further information on pituitary-adreno-cortical function was obtained by measuring serial plasma corticosteroid levels after submaximal stimulation with a synthetic ACTH preparation. ACTH and cortisol did not change an observation which does not support the hypothesis that glucocorticoid activity is influenced by a decrease in plasma angiotensin II concentrations.     

EFFECTS OF NALOXONE ON THE PITUITARY-ADRENAL AXIS IN PATIENTS WITH DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM

Endogenous opioids may normally modulate the function of the hypothalamo-pituitary-adrenal axis. We investigated whether opioid peptides play any role on aldosterone secretion in dexamethasone-suppressible hyperaldosteronism (DSH). Clinical and hormonal effects of i.v. administration of naloxone (10 mg as a bolus) in two siblings affected by this disease and in eight normal volunteers were studied. In normals, naloxone caused a significant increase in plasma cortisol compared with placebo, an insignificant increase in ACTH and no change in plasma renin activity (PRA) and aldosterone level. In DSH patients there was a slight increase in plasma cortisol, no change in PRA and a marked rise of aldosterone level. In five normals retested after dexamethasone 2 mg, baseline ACTH and cortisol were reduced and no response to naloxone was observed compared to naloxone alone. After dexamethasone, aldosterone levels were suppressed in DSH patients and unchanged in normals, and did not respond to naloxone in any case. In conclusion, naloxone may increase the responsiveness of adrenal zona fasciculata to physiological levels of ACTH in normals, since the slight increase in ACTH seems inadequate to explain per se the marked cortisol elevation. The marked aldosterone rise after naloxone indicates an underlying adrenal rather than pituitary abnormality in patients with DSH, and possibly implicates endogenous opioids.     

Effect of combined administration of dexamethasone and captopril on plasma aldosterone response to angiotensin II in normal man

Aldosterone responses to angiotensin II were evaluated in normal subjects in 3 conditions, (1) with suppression of neither ACTH secretion nor angiotensin II, (2) with suppression of ACTH by dexamethasone, and (3) with suppression of both ACTH and angiotensin II by combined administration of dexamethasone and captopril. Baseline levels of plasma aldosterone were significantly lowered by administration of either dexamethasone or both dexamethasone and captopril. Aldosterone responsiveness to angiotensin-II was not altered by suppression of ACTH secretion. However, the responsiveness was significantly enhanced during suppression of both ACTH and angiotensin II. These results suggest that aldosterone response to angiotensin II in normal man is not dependent upon endogenous ACTH secretion, but to an action of angiotensin II on the pituitary gland to release ACTH. The combined administration of dexamethasone and captopril may be a useful maneuver to assess more precisely the reactivity of the adrenal cortex to angiotensin II in man.     

Role of the renin-angiotensin system in enhancing the aldosterone response to adenocorticotropin during acute sodium depletion in normal subjects

The role of the renin-angiotensin system in enhancing aldosterone responsiveness to ACTH during acute sodium depletion was studied in 14 healthy medical students. Acute sodium depletion was achieved by oral treatment with 80 mg furosemide and 200 mg SQ 14,225 for 1 day. The im administration of 250 micrograms alpha ACTH-(1-24) or vehicle was performed at 0800-0900 h both on the day after ad libitum diet (control) and 1 h after the oral administration of 50 mg SQ 14,225 on the day after acute sodium depletion. Treatments with furosemide and SQ 14,225 before both ACTH and vehicle administration induced a reproducible sodium depletion, accompanied by a marked increase in PRA and no significant increase in plasma aldosterone. The administration of ACTH, but not of vehicle, produced significant increases in plasma aldosterone in both control and acute sodium-depleted subjects. However, the ACTH-induced increases in plasma aldosterone and their maximal net and percent increments during acute sodium depletion were significantly greater than control values. It is concluded that angiotensin II does not play an important role in enhancing the aldosterone-stimulating activity of ACTH during acute sodium depletion and that sodium depletion per se may be responsible for this enhancement.     

A NEW FAMILY WITH DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM: ALDOSTERONE UNRESPONSIVENESS TO ANGIOTENSIN II

A family with nine siblings in which three siblings have been shown to have dexamethasone-suppressible hyperaldosteronism was studied. All three showed no significant changes of plasma aldosterone during angiotensin II infusion at incremental rates under baseline conditions. After dexamethasone administration (2 mg/d for 4 weeks) plasma renin activity (PRA) rose to normal-supranormal range, while plasma and urinary aldosterone were maintained at low-normal levels. No restoration of aldosterone response to angiotensin II was observed on dexamethasone. Two other siblings were found to be hypertensive with normal baseline data; however, both showed plasma aldosterone hyperresponsiveness to ACTH. In the four normotensive siblings aldosterone response to ACTH was normal. The family pedigree was consistent with autosomal dominant transmission of the disorder. HLA typing showed haplotype A3 Bw35 in all five hypertensive sibs and in one normotensive. In conclusion, low aldosterone compared to PRA, and plasma aldosterone unresponsiveness to angiotensin II infusion before and during dexamethasone, show functional impairment, at least temporary, of the zona glomerulosa. These findings support the hypothesis that aldosterone may be derived from the zona fasciculata in this disorder.     

Angiotensin II-induced aldosterone stimulation in man is not dependent upon adrenocorticotropin

To document a possible role of ACTH in the aldosterone response to angiotensin II, we measured plasma aldosterone levels during physiological increments in plasma angiotensin II in normal male volunteers on two occasions, once with suppression of endogenous ACTH secretion (dexamethasone or hydrocortisone) and again without ACTH suppression. The subjects were studied under standardized conditions of dietary sodium (40 mmol/day) and potassium (100 mmol/day) intake and controlled body posture. Glucocorticoid pretreatment did not alter the plasma levels of angiotensin II attained during incremental infusions (0.5, 1, 2, and 4 ng/kg . min) of the octapeptide. Baseline plasma aldosterone levels were significantly lowered by glucocorticoid pretreatment. However, aldosterone responsiveness to infused angiotensin II (change and percentage of change from baseline levels) was not altered by suppression of endogenous ACTH production. Serum potassium levels were not increased by the administration of angiotensin II. The results demonstrate that in normal males on a sodium-restricted diet, baseline aldosterone levels are controlled in part by ACTH. The aldosterone response to angiotensin II, however, is not dependent upon endogenous ACTH secretion, an action of angiotensin II on the pituitary to release ACTH, or a rise in serum potassium.     

Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effect of captopril on aldosterone secretory responses to endogenous or exogenous adrenocorticotropin

The aldosterone secretory response to Captopril (12.5 mg, orally) was studied in five normal men. Endogenous ACTH and epinephrine secretion was stimulated by the induction of hypoglycemia. Normally this stimulus increases plasma cortisol, GH, aldosterone, and PRA. Administration of captopril resulted in a blunted plasma aldosterone response to hypoglycemia, but no concomitant blunting of the plasma cortisol response. The responses of other hormones, with the exception of PRA, were not affected. When exogenous ACTH was administered to the same men with and without captopril, the plasma aldosterone response was again blunted by captopril, while the plasma cortisol response was unaffected. We conclude that angiotensin II may be required for ACTH to stimulate aldosterone secretion. Alternatively, the possibility that captopril may selectively inhibit aldosterone secretion at the adrenal cellular level cannot be excluded.     

Desmopressin and hexarelin tests in alcohol-induced pseudo-Cushing's syndrome

BACKGROUND: A challenge in clinical endocrinology is the distinction between Cushing's disease (Cushing's syndrome dependent by adrenocorticotrophic hormone (ACTH)-secreting tumours of pituitary origin) and alcohol-dependent pseudo-Cushing's syndrome. Patients with Cushing's disease are known to have high ACTH/cortisol responses to desmopressin (DDAVP, a vasopressin analogue) and to hexarelin (HEX, a synthetic GH-releasing peptide). OBJECTIVE: To compare the ACTH/cortisol responses to desmopressin and to hexarelin of subjects with alcohol pseudo-Cushing's syndrome with those obtained in patients with Cushing's disease and in normal controls. DESIGN: Randomized, single-blind study. SETTING: University medical centre. SUBJECTS: Eight alcoholics with pseudo-Cushing's syndrome, six patients with Cushing's disease and nine age-matched normal controls. INTERVENTION: Three tests at weekly intervals. The dexamethasone (1 mg) suppression test (DST) was carried out first. The desmopressin (10 microg intravenously at 09:00 h) test and hexarelin (2 microgram kg-1 intravenously at 09:00 h) test were carried out in random order. MEASUREMENTS: Plasma ACTH and cortisol levels. RESULTS: The basal plasma levels of ACTH and cortisol were significantly lower in normal subjects than in patients with Cushing's disease and in alcoholic subjects; these latter groups showed similar basal hormonal values. All normal controls, two patients with Cushing's disease and two alcoholics showed suppression of plasma cortisol levels (<5 microgram dL-1) after dexamethasone administration. Both desmopressin and hexarelin induced striking ACTH/cortisol responses in patients with Cushing's disease, whereas hexarelin, but not desmopressin, slightly increased ACTH/cortisol secretion in the normal controls. Neither desmopressin nor hexarelin administration induced any significant change in ACTH/cortisol secretion in alcoholics. CONCLUSIONS: These data suggest that either the hexarelin or desmopressin test can be used to differentiate patients with Cushing's disease from subjects with alcohol-dependent pseudo-Cushing's syndrome.     

Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients

OBJECTIVE: To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin. SUBJECTS AND METHODS: Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment. RESULTS: In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment. CONCLUSIONS: We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.     

The dissociation of renin and aldosterone during critical illness

A syndrome of elevated PRA accompanied by inappropriately low plasma aldosterone (ALDO) levels has been identified in some critically ill patients. To determine whether this phenomenon is due to a disturbance in factors that stimulate ALDO, we measured PRA, angiotensin II (AII), potassium (K+), and ACTH levels in 83 patients admitted to an intensive care unit. In 59 patients, PRA was greater than 2.0 ng/ml X h. Of these, 24 had an ALDO to PRA ratio (ALDO/PRA) below 2 (group I), and 35 had an ALDO/PRA ratio of 2 or more (group II). An ALDO/PRA ratio below 2 was deemed inappropriately low. Despite markedly elevated PRA [34 +/- 12 (+/- SE) ng/ml X h], the group I patients had inappropriately low ALDO levels (19 +/- 5 ng/dL). Patients in group II had significantly higher ALDO levels (48 +/- 6 ng/dL) despite lower PRA (9 +/- 1 ng/ml X h). AII levels were appropriately elevated in group I (39 +/- 26 pg/mL) and significantly greater (P less than 0.5) than those in group II. PRA correlated well with AII in both groups. There were no differences in plasma ACTH or K+ in these 2 groups, and plasma cortisol levels were similarly elevated in both groups of patients. Of 66 consecutively studied patients, 14 (21%) had inappropriate ALDO (group I). Mortality was significantly greater in group I (75%) than in group II (46%; P less than 0.001). In summary, a significant subset (21%) of seriously ill patients have inappropriately low ALDO levels despite elevated PRA. This dissociation is not due to an impairment of AII production or changes in plasma ACTH or K+. This phenomenon is associated with a higher mortality during critical illness. In light of evidence of decreased adrenal androgen secretion during severe illness, this dissociation of renin and aldosterone may represent an additional adrenal adaptation designed to promote cortisol production in critically ill patients.     

Effects of angiotensin I converting enzyme inhibitor (SQ 14,225) on the responses of blood pressure and steroid hormone to angiotensin II and ACTH infusion in hypertensive subjects

The effects of the converting enzyme inhibitor, SQ 14,225, on the renin-angiotensin system, adrenal function and blood pressure were investigated in 14 hypertensive patients, i.e., 10 with essential hypertension (EH) and 4 with renovascular hypertension (RVH). The mean blood pressure (MBP) and plasma aldosterone showed significant decreases in the EH with normal renin (NR) group and in the RVH group but no significant changes in the EH with low renin (LR) group. Plasma renin activity (PRA) increased significantly in the EH and NR group and in the RVH group but showed no significant change in the EH with LR group. Significant correlations were found between the fall in MBP after SQ 14,225 treatment and the pretreatment levels of PRA or plasma aldosterone. In an ACTH infusion study, the response of plasma aldosterone to ACTH revealed significant decreases after SQ 14,225 administration. In an angiotensin II (A II) infusion study, the response of plasma aldosterone was unchanged after SQ 14,225 administration. However, the pressor responses to A II infusion with SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 may be due mainly to the decrease in levels of endogenous A II and that the reduction in plasma aldosterone after SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 administration may be due to reduction of endogenous A II levels by converting enzyme inhibition.     

Selective hypoaldosteronism with hyperreninemia in a diabetic patient.

A 62-yr-old diabetic woman exhibited low plasma and urinary aldosterone levels in the face of markedly elevated PRA during the course of nonketoacidotic hyperglycemic precoma with dehydration, hyponatremia, and hyperkalemia, for which she was hospitalized. Studies performed after her recovery from precoma revealed hyperreninemic hypoaldosteronism with normal adrenoglucocorticoid function. While the patient was supine, PRA on a 256-meq sodium intake was at or above the upper limit of the normal range for a 200-meq sodium intake; furthermore, after sodium depletion with furosemide and 4 h of ambulation, PRA markedly increased. No increases in plasma inactive renin were found. Plasma renin substrate concentration was normal. Plasma levels and urinary excretion of aldosterone were low and increased slightly during sodium restriction with insulin treatment, accompanied by hyperkalemia and sodium loss, despite markedly elevated PRA. Repository ACTH administration induced sodium retention and potassium loss with a normal increase in urinary 17-hydroxycorticosteroids. Plasma levels of deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone were normal, while plasma aldosterone was low. Levels of these mineralocorticoids remained unchanged during angiotensin II infusion on both 256-meq and 100-meq sodium intakes. Rapid ACTH administration produced normal increases in plasma deoxycorticosterone and corticosterone but caused a subnormal increase in plasma aldosterone. These results suggest adrenal insensitivity to angiotensin II, possibly a defect in adrenal angiotensin II receptors, as the cause of hypoldosteronism with hyperreninemia in this patient.     

Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II

With increasing case reports, it has been indicated that some cases with adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) show abnormal responses in cortisol to various stimulation tests. Here we report a case of AIMAH that showed an aberrant response to angiotensin II via AT1 receptor in cortisol hypersecretion. A 53-yr-old man was admitted to our division seeking further examinations for the possible diagnosis of Cushing's syndrome. He had hypertension, diabetes mellitus, and physical stigmata, such as moon face and central obesity. His plasma ACTH level was undetectable, and plasma cortisol level was high. Plasma cortisol showed no normal diurnal rhythm and was not suppressed after the administration of 8 mg of dexamethasone. Abdominal computed tomography demonstrated nodular enlargement of bilateral adrenal glands. He was diagnosed with Cushing's syndrome owing to AIMAH. An injection of arginine vasopressin (AVP) increased plasma cortisol and aldosterone levels, whereas ACTH remained undetectable. After 4 h in an upright position, plasma cortisol and aldosterone levels were increased. Pretreatment with candesartan, angiotensin II receptor AT1 antagonist, blocked the increase in plasma cortisol level. These results suggested a possibility of adrenal hypersensitivity to angiotensin II and AVP in cortisol secretion. Bilateral laparoscopic adrenalectomy was performed. The histological findings of the specimen were compatible with AIMAH. In summary, we have made the first report on a case of AIMAH with possible hypersensitivity to angiotensin II.