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The blood pressure response to the angiotensin II analog 1-sar-8-ala-angiotensin II, or saralasin, was studied in five patients with clinical and laboratory evidence of Cushing's syndrome. Plasma renin activity, plasma renin substrate, and plasma renin concentration were measured in all five patients. The renin system and the response to saralasin were measured after furosemide administration. Plasma aldosterone was measured after infusion of 2 liters normal saline. All patients studied showed a hypotensive response to saralasin, the mean BP changing from 163/108 mm Hg to 130/85 mm Hg (P less than 0.02). There was a significant elevation of the plasma renin activity and plasma renin concentration in the patients compared to normal subjects, although plasma renin substrate was not significantly different from normal values. There was normal suppression of plasma aldosterone after the infusion of 0.9% saline. The findings indicate that the hypertension of these patients with Cushing's syndrome was mediated in large part by angiotensin II.

A case of an adult with Bartter's syndrome (hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis) is described; the patient had the unusual manifestation of cardiomyopathy, probably secondary to severe hypokalemia. Results of metabolic studies and kidney biopsy were consistent with Bartter's syndrome; angiographic and hemodynamic findings were abnormal. The cardiomyopathy was confirmed at autopsy after the patient's sudden death. Conclusions from this case are that severe hypokalemia can pose a serious threat both immediately in the form of dangerous arrhythmias and in the long term in the form of cardiomyopathy.

An angiotensin II (A II) analogue (1-Sar-8-Ala-angiotensin II) (saralasin) was infused into 418 untreated hypertensive subjects during a 1-day evaluation while blood pressure was recorded every 2 minutes by Arteriosonade. At 5 mug/kg per min, saralasin produced a change in mean blood pressure which correlated significantly (r=-0.54, P less than 0.001) with the stimulated plasma renin activity (PRA) (after intravenous furosemide and ambulation for 2 hours. Saralasin caused a rise inmean blood pressure of at least 7.0 mm Hg in 97 hypertensive subjects, who also had a low stimulated PRA (1.3+/-SEM, 0.1 ng/ml per hour; normal range, 1.7-8.5). On a low sodium diet, the pressor response of hypertensive subjects to saralasin continued and was an even better indicator of a low stimulated PRA. Infusion of saralasin at 10 mug/kg per min into normal subjects on an unrestricted diet, a low sodium diet, and a high sodium diet produced, respectively, no change, a fall (P less than 0.05), and a rise (P less than 0.005) in blood pressure. The same saralasin dose in six hypertensive subjects who showed a pressor response to the analogue in the 1-day study also produced a rise in blood pressure when given on a low sodium diet, and this rise was more than twice that seen in normal subjects on a high sodium diet. Hypertensive subjects who showed the pressor response had a significantly greater (P less than 0.01) pressor sensitivity to A II than did hypertensive nonresponders to saralasin and noraml subjects on an uncontrolled diet. The affinity of the vascular receptors for the analogue was greater in the hypertensive group that showed the pressor response to saralasin. In summary, the pressor response to saralasin, as defined above, occurred in 23% of a large unselected group of hypertensive subjects and was associated with salt loading, a low stimulated PRA, and increased pressor sensitivity to A II.

Two patients are described in whom hypercortisolism occurred prepubertally as a consequence of bilateral adrenocortical hyperplasia. In contrast with the manifestations of Cushing's syndrome in adults, these children presented with obesity and reduced stature and no other symptoms. Both patients excreted amounts of urinary 17-OHCS before and during a conventional suppression test with dexamethasone (0.5 mg every six hours) which were within the usual normal range. However, when urinary 17-OHCS excretion was expressed per gram of urinary creatinine or per square meter of surface area, and when the dose of dexamethasone was tailored to body mass (20mug/kg/day) the results were clearly abnormal, as were plasma corticoids and (in one patient) cortisol secretion rate. Resumption of linear growth occurred after bilateral adrenalectomy in both patients and was associated, in the one patient so studied, by a return of hypoglycemia-stimulated increases in plasma growth hormone levels from previously suppressed values to the normal range, and by a slight increase in the fasting plasma somatomedin concentration. The observations suggest that pediatric patients with hypercortisolism are likely to be overlooked when conventional criteria for laboratory diagnosis are used, but can be recognized by the simple diagnostic modifications used in these studies.

Specific antagonists of angiotensin II (AII) such as saralasin might theoretically be of great value in the recognition of angiotensinogenic hypertension. Evidence is presented to show the importance of overcoming any existing sodium overload and of administering saralasin first in small and then in larger amounts by infusion (or injection). When this was done in 600 hypertensive patients, 62 showed a fall in blood pressure of more than 10/8 mm Hg. Further tests in 50 of these subjects indicated that the fall in blood pressure was associated with high peripheral levels of plasma renin activity (PRA) and/or abnormal renal vein PRA ratios in 94%. The procedure rarely failed to detect even mild forms of angiotensinogenic hypertension. In 62 patients found to have angiotensinogenic hypertension, the responsible lesions included unilateral renal arterial stenosis with good contralateral renal function (29%), bilateral renal disease (21%), Cushing's syndrome (6%), small vessel disease or specific excess of renin production - without other detectable renal disease - (31%) and incompletely evaluated disorders (13%). Saralasin has been of great value in simply and reliably demonstrating the presence or absence of an angiotensinogenic component in a large group of hypertensive patients.

The effect of L-epinephrine infusions (0.5-6.5 micrograms/min for up to 24 hr) in recumbency, on the renin-aldosterone system was studied in normal volunteers on diets containing 200 mEq sodium. Urinary sodium excretion was increased, potassium excretion was decreased, aldosterone excretion was suppressed while blood pressure and heart rate were minimally affected by epinephrine (1 microgram/min). Inulin and para-aminohippurate clearances changed transiently and slightly during epinephrine infusions over 10 hr in normal subjects. In separate experiments, epinephrine lowered serum K, raised serum Na, raised plasma renin activity and, usually lowered plasma aldosterone concentrations. There was an excellent correlation between epinephrine-induced changes in serum K and plasma aldosterone concentrations (r = +0.85, p less than 0.001). Significant dose-response relationships were found between L-epinephrine infusion rates of 0.5-6.5 micrograms/min and observed serum K concentrations. We conclude that L-epinephrine infusions at rates probably well within the physiological range, induce hypokalemia (by increased cellular uptake of K) which lowers aldosterone secretion depsite concomitant elevation of PRA and causes natriuresis for up to 24 hr.

1. 24 h aldosterone secretion rates (ASR) have been measured in six normal volunteers while recumbent all day and while standing for 12 h, on 200 and 10 mmol/day sodium diets and after salt-poor albumin infusions (75 g in 150 ml), which significantly expanded plasma volume. 2. The mean ASR on the 10 mmol/day sodium diet, both without and with the salt-poor albumin infusion, was highly significantly increased above the mean ASR on the 200 mmol/day sodium diet, both in the recumbent and in the upright posture. 3. There was no significant difference between the mean ASR values on the 10 mmol/day sodium diet alone and after the infusion of albumin either in the recumbent or in the upright posture. 4. The above abservations su;gest that sodium deprivation raises ASR by a mechanism or mechanisms unrelated to plasma volume.

Peripheral plasma renin activity (PRA) is not invariably elevated in patients whose ischemic renal lesion is causing hypertension. Infusions of an angiotensin II antagonist, 1-sar-8-ala-angiotensin II (P-113), have been used to determine whether the blood pressure responses might indicate angiotensin dependence in 221 consecutive hypertensive patients. In 32 patients P-113 infusion reversibly reduced blood pressure, and almost all of these "P-113 responders" had elevated renal vein and/or peripheral PRA levels, together with evidence of renal ischemia. Among the 189 "P-113 nonresponders," peripheral PRA was elevated in seven (3.8%), and renal vein PRA ratio was abnormal in two patients, who might represent exceptions to the otherwise successful record of the P-113 response in identifying "angiotensinoginic" hypertensives.

Six women, aged 24 to 53, presented with symptoms of diffuse aching, morning stiffness, and fatigue, but demonstrated no objective abnormalities on joint examination or in laboratory studies. Each was found to have idiopathic edema, a disorder of fluid retention probably related to an abnormality of capillary permeability in which transudation of fluid into the subcutaneous tissues of dependent parts may result in swelling and discomfort. The rheumatic symptoms improved when therapeutic measures were directed against the accumulation of edema fluid. This syndrome may account for a minority of cases of nonarticular rheumatism in women.

Thirty-four patients, most with a low-renin "essential" hypertension, and seven normal subjects were placed on diuretic therapy for 4 to 5 weeks. In the normal subjects, infusion of a highly specific, competitive angiotensin II analogue (1-sar-8-ala-angiotensin II, saralasin) did not significantly change recumbent blood pressure either before or after diuretic administration. In contrast, the hypertensive patients as a group had a low stimulated plasma renin activity before diuretic therapy and a rise in blood pressure during saralasin infusion. After therapy, the stimulated plasma renin activity was higher and saralasin produced a fall in blood pressure in some patients who were still hypertensive. The results suggest that short-term diuretic therapy, which is thought to act through its natriuretic effects, can convert some patients with essential hypertension, many with a low or a low-normal stimulated plasma renin activity, to individuals whose hypertension is supported by angiotensin II. The fall in blood pressure to saralsin infusion after diuretic therapy was directly proportional to the height to which diuretics elevated the stimulated plasma renin activity.

Transient hypertension occurred in 3 patients shortly after blunt injury to the abdomen. Renal trauma was suspected in all 3 patients and radiological evidence for renal injury was present in 2. Plasma renin activity definitely was elevated in 1 patient and probably was elevated in another. There was a decrease in blood pressure in all 3 patients during infusion of the angiotensin II analogue--saralasin--showing that the hypertension in these patients was angiotensin-mediated. Renal function as reflected by the blood urea nitrogen, creatinine and electrolytes was not impaired significantly. Thus, acute hypertension after blunt abdominal trauma may be angiotensinogenic and is not necessarily sustained.

The first half of this manuscript is devoted to a review of the methods used and the results obtained in the published measurements of the normal responses to tests of the three main types of hypothalamic-pituitary-adrenocortical (HPA) activity in man. These are, I, basal, unstressed activity leading to appropriate levels of total daily production of cortisol in the characteristic circadian pattern; II, responses to feedback stimulation of HPA activity by metyrapone administration; and III, responses to tests of the effects of stress on the HPA system including the effects of hypoglycemia, induced fever, vasopressin administration, and ACTH injections and infusions. The advantages and shortcomings of each type of procedure are discussed. The second half of this paper describes the authors' attempts to establish the limits of normality of standard and modified methods of evaluating the HPA system. The defined limits of normality have been used to assess the HPA function in 158 patients with known or suspected disorders of the HPA system. In normal controls, halfhourly plasma cortisol determinations established the normality of circadian and postprandial fluctuations and of mean plasma cortisol concentration, 6.2 +/- 0.3 (SEM) micrograms/dl, which were closely approximated by determinations every 6 h. Metyrapone, given in a dose of 500 mg every 2 h for 24 h increased urinary 17-OHCS excretion to 10.5-32.6 mg/day or to 1.7-7.8 times basal excretion rate. Increasing rates of insulin infusion disclosed significant relationships between resulting plasma glucose and cortisol concentrations. The slopes of the delta cortisol/delta glucose responses were similar after insulin infusions (0.46 +/- 0.05) and after insulin injections, 0.15 U/kg (0.43 +/- 0.09), and were always greater than 0.20 micrograms/mg. This index provides a useful objective measure of the normality of responses to hypoglycemic stress, 0.20-0.87 micrograms/mg. Adrenocortical responses to iv infusions of ACTH (cosyntropin 0.25 mg) may be equivocal at 2 h but are clear cut at 4, 6 and 8 h. Of 158 patients in whom hypopituitarism was known or suspected because of the presence of a pituitary tumor, acromegaly, hyperprolactinemia, or clinical features, HPA function was found to be entirely normal in 88 patients and partially or severely abnormal in the remaining 70 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The possibility has been explored of using a specific angiotensin ii antagonist, saralasin (P-113, 1-sar-8-ala-angiotensin ii) to recognize patients whose hypertension depends upon excessive angiotensin ii activity. Among 60 hypertensive patients, saralasin infusion reduced blood pressure in 16 "responders," but not in 44 "nonresponders." The "responders" had the following findings: elevated plasma renin activity in renal vein (or veins) or peripheral veins or both (16 of 16); reduced renal blood flow, shown by arteriography, isotopic studies or pyelography (15 or 16), or progressive azotemia (one of 16); and reduction in blood. These findings indicated that angiotensin ii probably caused hypertension in the "responders," One "nonresponder" had renal vein levels of plasma renin activity suggestive of angiotensinogenic hypertension. Since hypertension was invariably angiotensinogenic when it was reduced by saralasin and, with one possible exception, was never angiotensinogenic in "nonresponders," the antagonist appears to provide an efpressure to or toward normal after corrective operation (four of four) or propranolol therapy (eight of eight). fective means of recognizing angiotensinogenic hypertension.

In a 19 yr old male with familial hyperkalemic periodic paralysis, paralysis was consistently induced by the administration of potassium chloride, corticotropin-gel, and a variety of glucocorticoids (dexamethasone, 6-methylprednisolone, triamcinolone) but not by mineralocorticoids (D-aldosterone, deoxycorticosterone) or by adrenocorticotropin (ACTH)-gel plus metyrapone. Induced attacks were virtually identical with spontaneous attacks, being associated, after a latent period of a few hours, with a rise in plasma K(+) and HCO(3) (-) and a simultaneous fall in plasma Na(+) and Cl(-) concentrations to an extent implying exchange of 1 K(+) with 2 Na(+) and 2 Cl(-) between extracellular and intracellular fluid. ACTH-induced paralysis was preceded by rising serum inorganic P, and associated with increased plasma glucose, blood lactate, and serum creatine phosphokinase concentrations. In normal subjects ACTH, cortisol, and triamcinolone administration failed to change plasma electrolytes or strength, while ingestion of KCl produced no weakness and smaller changes in plasma K and Na than in the patient.Since the patient and normal subjects showed the same changes in renal excretion of K after the administration of cortisol and KCl, it seems likely that paralysis in the patient resulted from abnormally slow uptake (and/or excessive loss) of K by the muscle cells, possibly caused by an abnormal "ion-exchange pump." Normal adrenocortical function and absence of a peak in plasma 11-hydroxycorticoid (11-OHCS) concentration preceding spontaneous paralysis, indicated that spontaneous paralysis did not result from changes in cortisol secretion. Similar hyperkalemic paralysis was precipitated by ACTH-gel in a brother and first cousin of the propositus. Administration of acetazolamide and fludrocortisone reduced the rise in plasma K concentration and prevented the weakness which otherwise invariably followed KCl administration to the patient. He and two close relatives have been completely protected from severe attacks of paralysis in the past 14 months by treatment with these two medications.