Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man.

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)

Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs.

The pathogenesis of hyperadrenergic orthostatic hypotension was studied in eight patients. Correction of the abnormal orthostatic changes by an inflated pressure suit (MAST) confirmed previous evidence of excessive gravitational pooling of blood in the leg veins. Intravenous L-norepinephrine infusion raised diastolic blood pressure in the same relationship to the infusion-induced increments in plasma norepinephrine concentrations as in normal subjects, indicating normal arteriolar responses. Contractile responses of the veins to infused L-norepinephrine were measured with a linear variable differential transformer (LVDT). The venous responses of hand veins in the patients fell within the 95% confidence limits of the responses of normal hand veins, as did the responses of foot veins in the seven normal subjects. However, foot veins of the patients with hyperadrenergic orthostatic hypotension, and both hand and foot veins of patients with "diffuse" autonomic failure, were supersensitive to norepinephrine, as reflected by a steeper slope of the regression of log (norepinephrine infusion rate) on percentage reduction in venous distensibility, and a significantly lower ED50 (i.e., norepinephrine infusion rate that induced 50% reduction in venous distensibility). The findings suggest anatomical or functional postganglionic denervation of lower limb veins causing excessive gravitational blood pooling with consequent orthostatic hypotension in these patients.

Studies on hyperkalemic periodic paralysis. Evidence of changes in plasma Na and Cl and induction of paralysis by adrenal glucocorticoids.

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.

The renin-angiotensin-aldosterone system in diabetic patients with hyperkalemia.

Seven long-standing diabetic patients with spontaneous and intermittent hyperkalemia were studied in an effort to assess the normality of their renin-aldosterone axis. The administration of oral glucose, in the absence of insulin, caused a paradoxical rise in serum potassium with no significant change in plasma aldosterone concentration from controls. All displayed subnormal aldosterone-secreting capacity to known stimuli of aldosterone secretion such as low salt diet, angiotensin II infusion, and ACTH infusion. The paradoxical rise in serum potassium with hyperglycemia was corrected in all by concomitant administration of insulin or pretreatment with a mineralocorticoid. Our observations question the role of aldosterone deficiency in the phenomenon of glucose-induced hyperkalemia.

Action of cortisol on sodium transport in canine erythrocytes.

Incubation of blood from deoxycorticosterone-treated, adrenalectomized dogs with glucose, (22)NaCl, and cortisol, added in vitro, revealed log dose-related acceleration of sodium influx, of glucose utilization, and of lactate formation by cortisol in concentrations between 150 and 1000 microg/liter. Addition of 2-deoxyglucose, or preincubation of the blood until blood glucose concentration had fallen below 2.0 mg per 100 ml, reduced or abolished the acceleratory action of added cortisol on sodium influx but had no effect on sodium influx in the absence of added cortisol. Cortisol did not change the ATP or ATPase content of erythrocytes, or the metabolism of glucose via the pentose phosphate pathway, or the rate of efflux of (22)Na from the erythrocytes. The acceleratory actions of cortisol on sodium, influx, glucose utilization, and lactate formation were significantly correlated. Cortisol (1000 microg/liter) enhanced sodium influx by approximately 8.7 mmole per liter erythrocytes per hour for each 1 mmole cortisol-induced increment in ATP production. It is concluded that sodium influx in canine erythrocytes comprises a passive component, unchanged by cellular metabolism, and a second component which is accelerated and inhibited in proportion to prevailing plasma concentrations of cortisol and aldosterone, and which (for cortisol) depends upon accelerated ATP production via glycolysis. These steroid actions probably result from effects on enzyme activity rather than on new enzyme induction.

Delayed orthostatic intolerance.

In seven patients who presented with lightheadedness, fatigue, "weakness," and sometimes syncope, blood pressure was found not to fall after standing for 3 to 4 minutes but to fall severely, frequently with syncope or presyncopal symptoms, after 13 to 30 minutes when measured every minute with an automatic device. This delayed orthostatic hypotension could be corrected with inflation of a pressure suit to 45 mm Hg. Its mechanism was further investigated with measurements of plasma catecholamines, plasma cortisol and aldosterone responses to corticotropin, and the effects of norepinephrine infusions on blood pressure and venous contractility. There was normal or excessive orthostatic norepinephrine release in all patients, evidence of impaired venous innervation in the legs in some, and various disorders in the other patients. Since therapeutic improvement in the orthostatic hypotension greatly reduced the symptoms, we concluded that orthostatic hypotension occurring after more than 10 minutes of standing is a potentially debilitating and often correctable disorder.

Primary hyperepinephrinemia in patients without pheochromocytoma.

Clinical features of epinephrine release led to the finding of spontaneously elevated plasma epinephrine concentrations in five patients, in four of whom plasma norepinephrine concentrations were normal. Adrenal medullary hyperplasia was suspected in one patient, whose first cousin had multiple endocrine neoplasia type IIa, and in two others, all of whom have experienced relief from symptoms during propranolol or atenolol administration. The other two patients had unilateral adrenal cysts, with negative metaiodobenzylguanidine scans and no histological evidence of pheochromocytoma, but complete relief of symptoms by excision of the cysts. In one patient, Cushing's syndrome and associated hypertension, diabetes, and ischemic finger-tip ulceration all disappeared after surgery. It is concluded that spontaneous hyperepinephrinemic manifestations can be received by beta-blockers or, when an adrenal mass is present, by unilateral adrenalectomy even when the metalodobenzylguanidine test result is negative.

Role of angiotensin in lethal cerebral hypoperfusion during treatment of acute hypertension.

A 23-year-old man developed lethal cerebral hypoperfusion associated with angiographically demonstrable cerebral arterial spasm while being treated for acute angiotensinogenic hypertension due to a traumatic coarctation of the aorta. This complication occurred even though the treatment maintained his blood pressure at normotensive to mildly hypertensive levels, without producing more than rare and fleeting periods of hypotension. To explain this enigmatic development, we propose that the high concentration of angiotensin II in the blood constricted the cerebral arteries and thus prevented adequate cerebral autoregulation when his blood pressure was lowered by drug therapy.

Effect of posture on plasma atrial natriuretic hormone and renal function during salt loading in patients with and without postural (idiopathic) edema.

The effect of posture on plasma atrial natriuretic hormone (ANH) and renal function was studied in subjects with idiopathic edema. Sixty-five subjects with edema but with no clinical evidence for cardiac, renal, or pulmonary diseases were studied after they had been off all medication for 1 week or more. They had nothing by mouth after midnight and were admitted to the Clinical Research Center at 0800 h. They voided, were weighed, and had their blood pressure and pulse measured in the recumbent and upright positions. A needle was inserted, and subjects were recumbent for 0.5 h, after which blood was drawn for measurement of plasma ANH, serum sodium, potassium, and (in 35 subjects) creatinine. They were then given 150 mL 0.14% sodium chloride solution to drink every 0.5 h for the next 6 h. Urine was collected every 0.5 h for measurement of sodium, potassium, and creatinine. After 4 h of recumbency repeat blood samples were drawn, subjects ambulated for 2 h, after which final repeat blood samples were drawn. Subjects were considered to have postural edema if their upright urinary sodium/previous 2-h urinary sodium was less than 33%, and to have a normal response if it was 33% or more. The clinical characteristics of the 34 patients with postural edema and 31 patients with a normal response were similar. Plasma ANH levels (initial, after oral saline, and after standing) were similar in the two groups, and there was no relationship between changes in ANH and urinary sodium with standing. In conclusion, under conditions of mild oral sodium chloride loading, changes in plasma ANH do not cause the abnormal sodium retention found in patients with postural edema.

The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test.

Despite unequivocal published evidence that patients with subnormal hypothalamic-pituitary-adrenal (HPA) function may respond normally to ACTH, such normal results are still considered reliable indications of unimpaired HPA function. This view was tested in four patients with clinical features suggesting corticotropin deficiency, in whom cosyntropin (0.25 mg, i.v.) raised serum cortisol above 560 nmol/L (20 micrograms/dL) at 1 h. All four patients had subnormal responses to metyrapone and excellent persistent improvement during subsequent glucocorticoid therapy. Serum cortisol concentrations 1 h after cosyntropin treatment in these patients closely resembled cortisol concentrations 1 h after uncomplicated cholecystectomy in six other patients. However, the rapid ACTH test in the patients with hypopituitarism failed to indicate whether more prolonged stimulation by ACTH or their endogenous stress would stimulate the normal continuing rise in serum cortisol, which reached 1358 +/- 170 nmol/L (+/- SE) 5 h after the incision in the cholecystectomized patients. As the three hypocorticotropic patients who were recognizably stressed had unstressed serum cortisol levels despite persistent adrenocortical reserve (shown by their ACTH responses) and recovered during glucocorticoid therapy, the ACTH test, if interpreted to indicate normal HPA function, would probably have had disastrous consequences. We conclude that a normal response to the rapid ACTH test can be dangerously misleading, particularly in incomplete ACTH deficiency states.

Effect of sodium balance and calcium channel blocking drugs on blood pressure responses.

To study the role of calcium movements in mediating the effects of sodium chloride on the response of blood pressure to angiotensin II (ANG II), we infused ANG II before and after giving calcium channel blocking drugs (nifedipine and diltiazem) and calcium infusions to normal subjects during high and low sodium intakes. ANG II was also in nine patients with essential hypertension eating a low sodium diet. In preliminary studies, the effects of nifedipine, 20 mg p.o., on blood pressure and plasma renin activity were determined. Sensitivity to infused ANG II was calculated as the slope of the linear regression of the increase in diastolic blood pressure (DBP) expressed as a function of the ANG II infusion rate (mm Hg/ng ANG II/kg/min). During intake of a high sodium diet (Na, 200 mEq/day) both drugs significantly (p less than 0.05) reduced ANG II sensitivity, while on a low sodium diet (10 mEq Na), neither drug reduced ANG II sensitivity. There was a significant (p less than 0.001) inverse correlation between the initial ANG II-DBP sensitivity and the change in sensitivity induced by the calcium channel blocking drugs in normal subjects (r = -0.78) and in hypertensive patients (r = -0.70). Five hypertensive patients had greater than normal ANG II-DBP sensitivity that was significantly (p less than 0.05) reduced by nifedipine. Calcium infusion did not affect the ANG II-DBP sensitivity on either diet. The results suggest that in normal subjects increased DBP responses to ANG II, induced by an increase in sodium intake, are partially mediated by increased extracellular to intracellular calcium movements, since they are blocked by the structurally different calcium channel blocking drugs nifedipine and diltiazem. In hypertensive patients on a low sodium diet, increased DBP responses to ANG II infusion were blocked by nifedipine, indicating they are at least partly mediated by increased extracellular to intracellular calcium flux.

Effect of sodium balance and calcium channel-blocking drugs on plasma aldosterone responses to infusion of angiotensin II in normal subjects and patients with essential hypertension.

To study the role of calcium movements in mediating the effects of sodium chloride on the response of plasma aldosterone to angiotensin II (AII), we administered calcium channel-blocking drugs (nifedipine and diltiazem) and calcium infusions to normal subjects during high and low sodium intakes before and after AII infusion. AII was also infused in 13 patients with essential hypertension eating a high sodium diet. In preliminary studies, the effects of nifedipine (20 mg, orally) on blood pressure, PRA, plasma aldosterone, and plasma cortisol concentrations were determined. Sensitivity to infused AII was calculated as the slope of the linear regression of the increase in plasma aldosterone as a function of the AII infusion rate (nanograms per dl/ng AII/kg X min). During sodium restriction (10 meq Na/day), both drugs significantly (P at least less than 0.05) reduced AII sensitivity. During the high sodium diet (200 meq Na/day), only diltiazem decreased AII sensitivity, and the reduction was less (P less than 0.05) than that during the low sodium diet. There was a significant (P less than 0.001) inverse correlation between the initial plasma aldosterone sensitivity to AII and the change in sensitivity induced by the calcium channel-blocking drugs in normal subjects (r = -0.89) and hypertensive patients (r = -0.70). Five hypertensive patients had greater than normal aldosterone sensitivity to AII, which was significantly (P less than 0.05) reduced by nifedipine. Calcium infusion increased the aldosterone sensitivity to AII during the low sodium diet, but not during the high sodium diet. The results suggest that in normal subjects, increased plasma aldosterone responses to AII induced by reduction in sodium intake are partially mediated by increased extracellular to intracellular calcium movements, since they are blocked by the structurally different calcium channel-blocking drugs nifedipine and diltiazem. In hypertensive patients eating a high sodium diet, increased aldosterone responses to AII infusion were blocked by nifedipine, indicating that they are at least partly mediated by increased extracellular to intracellular calcium flux.

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease.

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.

Role of angiotensin II in the aldosterone secretory response to adrenocorticotropin in sodium-restricted normal human subjects.

A study was performed to determine the possible role of angiotensin II (AII) in mediating the increased adrenal aldosterone response to infused alpha 1-24-ACTH, induced by sodium deprivation. Nine normal subjects, aged 18-31 yr. received 8-h infusions of 1) alpha 1-24-ACTH (0.5 U given over 8 h) while on a diet with unrestricted sodium content; 2) saralasin at 0.5 micrograms/kg/min or ACTH alone (0.5 U over 8 h) on the 7th day of a 10 meq sodium diet; and 3) ACTH and saralasin together on the 8th day while still on sodium restriction. AII was administered for the last 2 h of infusion 3. Plasma cortisol and aldosterone concentrations were measured at hourly intervals during the infusions and plasma renin activity was measured at 2 hourly intervals. ACTH infusion produced an increase in the plasma aldosterone concentration which was significantly greater during sodium restriction than when sodium intake was unlimited. This increase was not associated with an ACTH-induced rise in the plasma renin activity and was not significantly altered when ACTH was administered with saralasin. The rise in plasma cortisol concentration induced by ACTH was not significantly different when the normal subjects were on liberal and restricted sodium intakes. It is concluded that AII plays little if any acute role in increasing the stimulatory action of ACTH on aldosterone secretion during sodium restriction.

Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension.

Hypothyroidism has been known to be associated, at times, with diastolic hypertension. We have found in 40 thyrotoxic patients that the induction of hypothyroidism by radioiodine therapy significantly increased diastolic blood pressure, raising it above 90 mm Hg in 16 (40%) of the patients. Restoration of euthyroidism with thyroxine administration significantly reduced the systolic and diastolic blood pressures in these patients, with a fall in diastolic pressure below 90 mm Hg in nine of 16 patients. The prevalence of hypothyroidism was determined by measurements of serum thyroxine and thyrotropin concentrations in 688 consecutive hypertensive patients, referred for evaluation and therapy of their hypertension. Hypothyroidism was found in 25 (3.6%) of the patients. Restoration of normal serum thyroxine and thyrotropin levels with thyroid hormone replacement therapy lowered diastolic blood pressure to levels below 90 mm Hg in 32% of these patients who could be followed up after withdrawal of all antihypertensive drug therapy when euthyroidism had been restored (i.e., 1.2% of the 688 patients). It is concluded that diastolic hypertension resulting from hypothyroidism is a relatively common disorder, present in 1.2% of our referred hypertensive patients, that should be sought and treated.

Clinical significance of cognitive performance by hypertensive patients.

Fifty-four subjects with uncomplicated essential hypertension and 54 normotensive subjects were compared with regard to a widely employed clinical index of cognitive dysfunction (the Average Impairment Rating) calculated from neuropsychological tests that discriminate between brain-damaged and neurologically normal persons. Hypertensive subjects exhibited lower mean scores on this index when education was ignored, but results were not the same for highly educated and less well educated groups. There were no differences between exceptionally well educated hypertensive and normotensive subjects, but in the less well educated group, hypertensive subjects performed more poorly than normotensive subjects. The percentages of hypertensive and normotensive subjects scoring in a cognitively impaired range on the Average Impairment Rating were low and did not differ for either education group. These data indicate the important role of subtle differences in education level with respect to positive or negative findings for studies comparing hypertensive and normotensive subjects and illustrate the important role of clinical neuropsychological indices of cognitive dysfunction when one wishes to make meaningful inferences regarding cerebral cortical function in hypertensive subjects.

Evidence for an angiotensinogenic mechanism of the hypertension of Cushing's syndrome.

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.

Orthostatic hypertension. Pathogenetic studies.

Among 1800 referred hypertensive patients, 181 had recumbent diastolic blood pressures (DBP) below 90 mm Hg and standing DBP above 90 mm Hg. Orthostatic increments in DBP were greater in these orthostatic hypertensive patients than in 181 persistently hypertensive patients and 134 normotensive subjects. In 12 patients with orthostatic hypertension, the orthostatic fall in cardiac output (27.3 +/- 2.9%, measured by a respiratory method) was double that in 8 normotensive subjects (13.3 +/- 3.7%, p less than 0.01). An inflated pressure suit over the pelvis and lower limbs prevented the excessive fall in cardiac output and significantly reduced (p less than 0.02) the excessive rise in standing DBP in orthostatic hypertensive patients. Gravitational pooling of blood in the legs and reduction of blood in the head was measured by external gamma counting of autologous erythrocytes labeled with sodium pertechnetate Tc 99m through ports in fixed positions over the leg and the temple. Orthostatic intravascular pooling was significantly greater (p less than 0.01) in orthostatic hypertensive subjects than in normotensive subjects, and the magnitudes of orthostatic pooling and orthostatic increases in DBP were closely correlated (r = +0.85). Plasma norepinephrine concentrations were similar in recumbency and after sustained handgrip exercise, but significantly greater (p less than 0.01) after 5 to 60 mins of standing in orthostatic hypertensive subjects than in normotensive subjects. Our results indicate that orthostatic hypertension is common and that its mechanism in representative patients involves excessive orthostatic blood pooling, which results in decreased venous return, decreased cardiac output, increased sympathetic stimulation (presumably through low-pressure cardiopulmonary receptors), and excessive arteriolar, but not venular, constriction.

Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis.

Our aim was to determine the frequency of orthostatic edema (OE) in patients with idiopathic intracranial hypertension (IIH). We evaluated 30 women with IIH for evidence of OE by comparing sodium and water excretion in the recumbent and standing postures and morning and evening body weights. Data were compared with findings in 30 women with OE, 22 weight-matched obese normal subjects, and 20 lean normal subjects. The effect of treatment with diuretics or diuretics plus sympathomimetic agents was compared. Seventy-seven percent of IIH patients had evidence of peripheral edema and 80% had significant orthostatic retention of sodium or water. Excretion of a standard saline load and of a tap water load was significantly impaired in the upright posture in the IIH and OE patients compared with the lean and obese normal subjects. Diuretic therapy induced weight loss (up to 9 kg) and decreased mean weight gain from morning to evening in 5 of 12 patients treated. In seven patients also treated with diuretics plus sympathomimetic drugs, the diuretic-induced morning weight loss and morning to evening weight gain were both significantly improved with the addition of sympathomimetic agents. Therapy reduced the frequency or severity of headaches in seven patients and reduced papilledema in four patients who received no other concurrent treatment for IIH. The orthostatic retention of sodium and water and the consequent edema is very similar in IIH and OE patients, suggesting a common pathogenesis for both disorders. Diuretic therapy, dietary salt and water restriction, and planned periods of recumbency merit study as a treatment for these patients.

Dyspnea in patients with hyperbradykininism and excessive venous pooling.

In the original description of the syndrome of hyperbradykininism, dyspnea on exertion was not described. However, in five women with the syndrome, ages 31 to 58, four of whom had at least one elevated value of blood kinin as determined by radioimmunoassay, dyspnea on exertion was a prominent complaint. During treadmill walking at a constant power requirement against gravity, expired air gas collections and equilibrium carbon dioxide rebreathing were performed. Seventeen apparently healthy women, ages 18 to 48, served as control subjects. Although oxygen uptake was the same in both groups by design (oxygen uptake 0.91 liters per minute, 0.11 standard deviation [SD], in the control subjects; oxygen uptake 0.97 liters per minute, 0.12 [SD] in the patients), cardiac output was significantly reduced in the patients (cardiac output 8.4 liters per minute, 1.3 [SD], in the control subjects; cardiac output 6.3 liters per minute, 0.9 [SD], in the patients, p less than 0.01). End-tidal carbon dioxide tension was significantly lower in the patients (end-tidal carbon dioxide tension 41 torr, 3 [SD], for the control subjects; end-tidal carbon dioxide tension 33 torr, 7 [SD], for the patients). In one patient, repeated studies over a 12-month period demonstrated a positive relationship between end-tidal carbon dioxide tension and the respiratory exchange ratio. (Respiratory exchange ratio = 0.01 + 0.027 X end-tidal carbon dioxide tension, 0.073 standard error of the estimate [SEE], 0.71 regular correlation coefficient, n = 20). This relationship was opposite to that expected with voluntary overbreathing; it was interpreted to mean that reduced cardiac output with exercise occurred to a variable degree and was the cause of hyperpnea and hypocapnia. In the same patient, studies at exercise with and without the Jobst (antigravity) garment and studies at exercise in the supine and erect position were consistent with the hypothesis that dyspnea and exercise intolerance were caused by venous pooling when standing. It is concluded that hyperbradykininism is characterized not only by orthostatic hypotension and tachycardia with light-headedness, as originally described, but also by severe dyspnea on exertion with exercise intolerance. The mechanism remains obscure, and the treatment is unsatisfactory, but temporary improvement in the abnormal physiology can be achieved in some patients with the use of an antigravity garment.