Search

It has been reported that the renin-angiotensin-aldosterone (R-A-A) system is related to sodium retention in patients with heart failure. In 1946 "renin like material" was demonstrated to be present in renal venous blood.1) On the other hand, evidence that intrarenal distribution plays an important role in sodium regulation in man has led to increase in the interest in the use of Xenon-133 for assessing this function.2) We attempted to measure the intrarenal distribution of blood flow in patients with chronic congestive heart failure and to correlate the renal hemodynamics to the R-A-A system.

Continued administration of ACTH to normal gravidas results in marked sodium retention that is sustained, while aldosterone excretion declines below pretreatment levels. Since this is similar to results noted in nonpregnant subjects, where the cumulative sodium retention has been ascribed to increments in ACTH-dependent mineralocorticoids such as desoxycorticosterone (DOC) and corticosterone (B), a study was designed to evaluate effects of administered ACTH in pregnancy upon the urinary excretion of DOC and B metabolites, tetrahydro-DOC (THDOC) and tetrahydro-B (THB).

Two new C22 steroids, 21-methyl-9α-fluoroprednisolone and 21-methyl-6α,9α-difluoroprednisolone, and their respective C21 parent compounds are shown to possess life-maintaining activity in adrenalectomized young rats. These C21 steroids promote less growth than the parent compounds, probably because the former do not induce sodium retention. All steroids, in adequate dosage, cause thymus involution and adrenal a trophy, but lack androgenic activity. Attention is drawn to the masking action of certain steroid administering vehicles on survival tests and to the seeming unreliability of the thymus-involution assay for assessing or predicting anti-inflammatory activity of steroids.

A study of the pharmacological properties of glycyrrhetinic acid, or glycyrrhetic acid, a new anti-inflammatory drug from liquorice, shows it has an extremely low toxicity and is non-irritant to the skin. It has no adverse effects on the heart, circulation or respiration and shows no glucocorticoid-like activity. In large doses in animals it produces water retention, slight sodium retention and an increased excretion of potassium. These effects are not seen with smaller doses used in man.

SummaryA method is described for the assay of sodium-retaining substances in which desoxycorticosterone is employed as a standard. The sodium retention produced by the unknown is compared with that of desoxycorticosterone in a normal dog on a constant diet, over a 6-hour period.

IT HAD BEEN observed by one of us (D.L.M.) that adrenal extract alleviated many of the ill effects of fever therapy. Weakness, nausea and vomiting were reduced. Herpes was absent or less severe. Recovery was more rapid and subsequent treatments were tolerated better. The present study is an attempt to discover the underlying factors involved in this effect. The copious perspiration from fever therapy reduces the sodium chloride in the body. If the sodium depletion becomes marked, weakness and nausea may develop (1). Adrenal extract can cause sodium retention by the kidney in normal human beings (2). It might reduce the excretion of sodium through the skin and thus ameliorate the symptoms resulting from fever therapy insofar as they were due to sodium depletion. We have investigated the effect of adrenal extract on the electrolyte metabolism of patients treated by fever therapy. METHODS The Patients were treated by the Kettering Hypertherm. The Patient, with the exception of his head, was surrounded by cir...

An eighteen year old girl had clinical and laboratory evidence of hyperaldosteronism without an adrenal tumor or obvious adrenal hyperplasia. It is suggested this represents a distinctive form of congenital adrenal hyperfunction. The administration of ACTH led to increased aldosterone excretion and simultaneous sodium retention. Subtotal adrenalectomy after preoperative preparation with potassium resulted in correction of the abnormalities.

SummaryIn adrenalectomized rats, aldosterone and DCA exerted a greater effect on sodium retention than on potassium excretion or urine volume. Cortisone administered concomitantly with aldosterone enhanced the potassium excreting activity of aldosterone, and decreased the sodium retaining effect of aldosterone. The synergistic effect of these two types of steroids on potassium excretion was significantly diminished by spirolactone, suggesting that this increase in potassium excretion is related to secretion of this cation in the distal tubules.

Recent biological studies of 9-alpha-halo-11-oxygenated progesterones and of their 12-alpha-halogenated analogues outside of the corticoid area have resulted in the discovery of their antiuterotrophic and progestational properties. Adrenocorticoid activity of 9-alpha- and 12-alpha-haloprogesterones data have shown the gradual increase in glycogenic activity with decreasing atomic weight of the halogen atom. In the case of the sodium retention assay only the fluorinated derivatives show pronounced activity the activity of the remaining members of the series being negligible. The most quantitative parallelism of the activities of the 9-alpha- and 12-alpha-halo derivatives has served to support the hypothesis that the activity-enhancing properties of the halogen atom are a function of the latters electonegativity. Huggens and Jensen were the first to show that 9-alpha-halogenation of 11-oxygenated steroids could enhance potency outside of the corticoid area. In determining the inhibition of growth of the uterus by 9-alpha-fluorinated steroids it was shown that 9-alpha-fluorination enhanced the biological activity of the parent substance. Hertz and Tullner using the Clauberg technique were able to demonstrate classic progesteronelike activity for 9-alpha-steroids. In an effort to ascertain the effects of the different halogens on antiuterotrophic and progestational activity studies were extended to include all the 9-alpha- and 12-alpha-halo 11-beta-hydroxyprogesterones and 11-ketoprogesterones. In comparing the potencies of the various derivatives it was evident that the structure-activity relationships established for corticoid activity no longer obtained in this case. Turning to the progestational data obtained in the Clauberg assay it is noted that in contrast to progesterone itself this group of substances possesses activity when administered by both the parenteral and oral routes. Opposing trends in the structure-activity relationships in animals permit the selection of 9-alpha-bromo-11-ketoprogesterone as the most suitable agent for exploration of its progestational activity in man.

Adrenal venous blood was collected from rats 4 days after adrenal enucleation and from sham operated controls. The amount of regenerated cortical tissue was measured in serial sections of the glands. The newly regenerated adrenal cortex produced per unit adrenal tissue only about 14% of the amount of corticosterone and less than 12% of the amount of 18-OH-DOC secreted by the intact tissue, whereas the production of DOC was not decreased. The relative increase in the amount of DOC available to the rats bearing regenerating adrenal glands might contribute to the sodium retention observed in these rats during the first week after adrenal regeneration.

Administration of lithium carbonate to 16 manic-depressive and depressed patients was found to lead to an initial 1-2 days of sodium and water diuresis. In the subsequent 4-5-day period of treatment, sodium retention associated with a 50% increase in aldosterone excretion occurred, followed in the next several days by a return towards pre-lithium levels. These changes occurred in all patients and were apparently not related to the initial clinical state of the patient nor the presence or absence of symptomatic improvement with lithium.

At least two separate processes give rise to renal hypertension—sodium retention and secretion of a renal pressor substance. Experimental evidence suggests that sodium retention plays no role in hypertension due to unilateral renal ischaemia with the opposite kidney in situ. Where the opposite kidney is removed, sodium retention generally assumes major importance and produces a form of hypertension which is qualitatively different. This explains discrepancies in observations upon renin levels and juxtaglomerular activity in experimental hypertension. There are important similarities between this dual mechanism in the rat and the human patient.

IN FEBRUARY 1942, our laboratory was invited to undertake for the Committeeon Medical Research a quantitative biological comparison of certain extracts of the adrenal cortex. The objectives outlined for us by the Committee were: (a) the determination of the most reliable criteria of total adrenal cortical activity in adrenal cortical extracts; (b) the standardization of the assay procedure(s) in order to insure its (their) reproducibility in other laboratories; and (c) the evaluation of the potency of the several extracts in terms of suitable standards. Because of the divergent manifestations of adrenal cortical activity in the animal body it was necessary to select several bioassayprocedures based upon different physiological responses for the comparisons. The methodsfinally chosen were: (a) the test of growth and survival in immature adrenalectomized rats as described by Grollman (1941); (b) the test of renal function in adrenalectomized dogs as proposed by Pfiffner, et al. (1934); (c) the test of sodiu...

Is the glomemlar zone of the adrenal cortex the principal source of the sodium hormone? Evidence points that way. After hypophysectomy this zone does not atrophy. Although Nishida (1934), reported a decrease in plasma sodium concentration in the dog after such an operation, Houssay and Mazzocco (1922) found no significant change. Deane and Greep (1946) also observed thatN steroids and mitochondria persisted in this zone in the rat after hypophysectomy. Desoxycorticosterone caused atrophy of the glomerular zone (Greep and Deane, 1947). Although this synthetic substance is not a hormone of the adrenal cortex, it does cause sodium retention. If the glomerular zone is responsible for the production of the sodium hormone, enucleation of the adrenals, insofar as it leaves this zone undisturbed, should not greatly modify sodium retention or if it does, the effect should be transient. In the following experiments we have shown that adrenal enucleation does affect sodium retention

An attempt has been made to appraise the effects of naturally occurring stressful situations on certain metabolic indicators among a group of patients in the special social setting of the metabolic ward of a small research hospital. Variations in renal and fecal excretion were studied only in those patients who were on metabolic "balance" regimens and, except in special circumstances, on days when no complicating pharmacodynamic agents were being administered. The chemical data were kept separate from the personality studies of the individuals and judgments concerning stressful events and the prevailing atmosphere of the ward. It soon became evident that the metabolic ward had the special characteristics of a well defined community with its own pressures, values, prestige points and taboos. Prominent among the ingredients of prestige seemed to be the seriousness of illness of the patient and the length of time he had been a patient on the metabolic ward. Prominent among the values of the ward were an emphasis on good manners and restraint. There was a penalty for those patients who went too far with levity on the one hand or showed a maudlin concern with illness and death on the other. The "ground rules" of behavior seemed to reflect the personality of the head nurse more than any other one specific factor. Major metabolic changes in terms of urinary excretion of water, sodium, potassium, calcium, nitrogen and creatinine occurred repeatedly in situations of stress among the patients. Deviations in excretion of metabolites of greater than 2.0 S.D. occurred on sixty patient-days of a total of 213 for which data were available. There were several days considered to be stressful on which significant alterations in metabolic balance failed to occur. This failure correlated strikingly with the prevailing atmosphere of the ward. When the general atmosphere of the ward was disturbed 86 per cent of the presumed stressful events were accompanied by significant alterations in the balance data, while during relatively calm periods for the group as a whole only 48 per cent of presumably stressful episodes were accompanied by significant changes. Metabolic deviations of significant degree occurred on twelve of 146 (8 per cent) patient-days which had not been considered stressful. It was of special interest that among those who were capable of reacting with metabolic alterations to stress was a man whose pituitary had been largely destroyed by a chromophobe adenoma and was subsequently removed surgically. It could not be said that one patient was more reactive than another. The capacity for marked metabolic deviations in association with emotional responses was present in all, including the patient surgically hypophysectomized. Patterns of excretion suggestive of the activity of any single hormone were not clear-cut in association with any of the naturally-occurring stressful situations. ACTH and adrenal cortical hormones have variable effects upon excretion, depending upon the previous state of the patient; but they are usually associated with a potassium diuresis and sodium retention. In this study, potassium and sodium commonly showed deviations in the same direction, both being retained or lost simultaneously. The effects of other hormones are even more variable than that of ACTH. However, the impression gained was that the patterns of excretion were usually the resultant of multiple influences rather than the effect of any single hormonal agent. Interpersonal difficulties were much the most common sources of stress to be associated with metabolic deviations. These accounted for twenty-eight of the forty-six stressful situations associated with such deviations. In general, they seemed to center in the most significant relationships. Interpersonal stresses arising between individuals without strong ties were less often associated with significant repercussions in the metabolic data. For example, the two most important relationships for Mr. H. were with Miss R. and Mr. T. All significant metabolic deviations related to interpersonal stresses occurred in association with situations arising in these two relationships. Although he had difficulties in his dealings with Mrs. D., these were not associated with significant metabolic deviations. Of special interest were the effects of anxiety among the nursing staff on the patients who were unaware of this disturbing situation. Every one of the group who were on metabolic balance at the time showed predominantly negative balances for the two-day period during which this disturbance persisted. In conclusion, it is our opinion that this pilot study has demonstrated that the metabolic ward is not necessarily a "neutral environment" and that adequate interpretation of metabolic deviations in patients must include an appraisal of their life situations and emotional state at the time.

Sodium is excluded from the tops of many plants (1-4, 7, 8), and hence accumulation of this ion in the leaves of;such plants which apparently are rather sensitive to it (2) is avoided. The barrier to sodium transport is effective at moderate external sodium concentrations. At high external concentrations (2, 7, 8), and as a result of prolonged growth in a saline medium (1), sodium contents are found to increase in the stems and sometimes also in the leaves of so-called Na nonaccumulator plants. Gauch and Wadleigh (4) assumed that sodium movement might be restricted by the membranes of certain extrastelar tissue, excluding it from the vascular system. Huffaker and Wallace (8) suggested that the term Na nonaccumulator plant should be considered as a quantitative rather than a qualitative expression. Bernstein et al. (1) found comparable levels of sodium accumulation in the roots, wood, and bark of young apricot trees grown for one year in saline plots; only the leaves and twigs of these plants exhibited restricted sodium accumulation. The authors supposed that sodium had entered the vascular tissue of the trees and that its translocation into the leaves via the transpiration stream had been restricted by retention in the living wood parenchyma cells. During the third year of these experiments sodium levels increased also in the leaves of various stone-fruit trees. Bernstein et al. (1) consider this increase to be due to the development of heart wood during the third year of growth, release of sodium by the senescent parenchyma and its subsequent translocation into the leaves via the transpiration stream. No direct proof has been brought forward for any of the hypotheses regarding the location of the barrier to sodium transport and the mechanism of its rupture at high external concentrations. The interpretation proposed by Bernstein et al. (1) for sodium leakage to the leaves during the third year of their experiment would not be adequate to explain the gradual advance of sodium in the stem with increasing external concentrations as found in brief tracer experiments (7, 8). The present work is an attempt to supply more data about sodium transport and distribution in bean plants-a Na nonaccumulating species-in order to provide evidence for the elucidation of these phenomena.

NTIL RECENTLY, diuretic agents were usually administered to patients with congestive heart failure only when digitalization-often to the point of toxicity-sedatives, and restriction of activity had failed to restore compensation. The indication for their use was the persistence of such obvious manifestations of failure as rales at the lung bases or dependent edema, and their efficiency was measured by the increase in urinary output. The demonstration of the role of sodium retention in congestive failure led to the abandonment of the restriction of fluid intake in favor of decreasing the salt content of the diet. This noteworthy advance had but little effect on the manner in which diuretics were employed.

Three patients with rheumatoid arthritis who had been maintained on cortisone treatment for periods of at least two and one-half years, were subjected to detailed clinical and metabolic study immediately prior to and following abrupt cessation of cortisone therapy. Clinical manifestations resembling adrenal insufficiency could be differentiated from those of active rheumatoid arthritis. The latter were accompanied by striking sodium retention and evidences of increased plasma volume. Although the symptoms of adrenal insufficiency disappeared four days after stopping cortisone, steroid excretion studies indicated that reduced and abnormal adrenal cortical function persisted for a longer period than this and suggested that this could not entirely be attributed to a failure of pituitary response. Tres patientes con arthritis rheumatoide, qui habeva essite mantenite per un therapia a cortisona durante periodos de al minus duo annos e medie, esseva subjicite a detaliate studios clinic e metabolic ante e post le cessation abrupte del mentionate medication. Manifestationes clinic simile a illos de insufficientia adrenal poteva esser differentiate ab illos de active arthritis rheumatoide. Iste ultimes esseva accompaniate de marcate grados de retention de natrium e evidentia de augmentos del volumine de plasma. Ben que le symptomas de insufficientia adrenal dispareva quatro dies post le cessation del curso de cortisona, studios del excretion de steroides indicava que le reduction e anormalitate del function adreno-cortical persisteva plus longemente. Le datos suggereva que iste phenomeno non esseva integremente attribuibile al disfallimento del responsa pituitari.

THE STUDY of electrolyte changes in affective disorders is receiving increasing attention. The possibility has been considered by some authors that the reported changes are not simply secondary,' but are related in a more essential way to the basic pathophysiological changes in the central nervous system. I SCHOTTSTAEDT el gL found a decreased sodium and potassium excretion and water retention during depressed periods in normal subjects. 2 RUSSELL, however, using conventional balance techniques, was unable to find a statistically significant change in the balance of sodium, potassium and water with recovery from depression, a Although COPPEN and SHAW also found a fall in exchangeable sodium with recovery from depression, the results were not statistically significant. 4 The fall in residual sodium, however, after recovery averaged 180 m-equiv, and was highly significant at the

1. 1. In patients who are recovering from heart failure, a moderate increase in the ingestion of sodium chloride may produce, within four to eight days, a clinical picture which is indistinguishable from that of congestive heart failure. Such an effect is obviated by digitalization. 2. 2. Under similar conditions, an increase to 3,000 c.c. in the daily intake of water for as long as eight days results in no measurable or noticeable harmful effects. 3. 3. The harmful effects of an increase in the intake of sodium chloride are apparently related to the degree of sodium retention, rather than the increased intake as such. 4. 4. The possible mechanism of sodium retention is discussed. 5. 5. It is suggested that, since there is a significant degree of sodium retention during upper respiratory infections, the latter may play a role in the oft-observed relationship between infection and the precipitation or aggravation of heart failure.

IN A MAJORITY of tKe mammals which have been studied the adrenal maintains the plasma sodium at a higher level than that found after adrenalectomy. Whether the animal is adrenalectomised or not, the injection of adrenal extracts or the synthetic compound, desoxycorticosterone acetate, causes retention of sodium. From the work of Silvette and Britton (1936) and the more recent investigation in our own laboratory (Hartman, et al. 1943) it appears that this does not occur in the opossum. Following adrenalectomy there is little change in plasma electrolytes, even in animals surviving for many months, except during such a stress as diarrhea or lactation (Britton and Silvette, 1937). If the opossum adrenal produces a sodium factor the animal should respond to injections of the same. In this paper the results are reported of a study of the influence of adrenal preparations and of desoxycorticosterone on sodium in the plasma.

The 9 alpha halogenated adrenal steroids such as cortisone, hydrocortisone, corticosterone and certain derivatives of progesterone originally prepared by Fried et al. (1953, 1954, 1955a, 1955b), constitute a remarkable group of physiologically active compounds. They are unique in that some of them display potencies considerably in excess of the naturally occurring parent steroids both as to glucocorticoid and mineralocorticoid activity. The surprising feature of these 9α-halo corticoids consists primarily of the fact that substitution of a halogen atom at the 9 alpha position should so greatly enhance their potency both as to liver glycogen deposition and sodium retention (Fried et al., 1953, 1954, 1955a, 1955b). Through the cortesty of Dr. J. Fried of the Squibb Institute for Medical Research, New Brunswick, New Jersey, the writers obtained sufficient of these modified steroids for testing their life-maintaining and mineralocorticoid activity in adrenalectomized dogs. Few investigations have appeared to ...

1. In the rabbit overdosage with cortexone and salt leads to a deterioration of general condition, sodium retention and potassium loss, muscular paralysis and effusions in the pleural, pericardial and peritoneal cavities. In general rabbits are more sensitive to overdosage with cortexone and salt than rats. 2. Contrary to the rat in none of the animals a definite increase of blood pressure has been observed. 3. Kidney extracts prepared from animals pretreated with cortexone and salt showed a loss of pressor activity if tested semiquantitatively in the nephrectomised rat. It can be concluded that the disappearance of pressor active material from the kidney (renin) is not responsible per se for the development of hypertension. 4. There are various factors which may be responsible for the lack of blood pressure response in the rabbit.

DESPITE THE WIDE USE OF ADRENAL cortical extracts, both clinically and experimentally, no quantitative method for determining their activity has been generally accepted. Of the various procedures advocated (1–5) many are too laborious or require the use of so many animals to avoid the normal biological variation as to preclude their general use. The majority of the advocated procedures which are satisfactory from a technical standpoint are based on non-specific reactions easily vitiated and hence entirely unreliable as standard methods of procedure. Thus, the fact that certain steroids derived from adrenal cortical extracts cause sodium retention in the adrenalectomised animal has suggested that this reaction might be used as a method of assay. However, the fact that many steroids having no adrenal cortical activity exert a similar sodium-retaining effect would preclude the use of this reaction as a method of assay.

THE USUAL EXTRACT of the whole adrenal or of the adrenal cortex will prevent II the loss of sodium which occurs in adrenal insufficiency. It will alsocause retention of sodium in the normal mammal (1). Such an extract can be divided into two fractions, one responsible for sodium retention and the other capable of maintaining the health of adrenalectomised animals without influence on sodium retention. The substance primarily responsible for sodium retention has been designated by us as the Na factor. The substance in the second fraction, responsible for maintenance of adrenalectomized animals but without influence on Na, we have tentatively designated as cortin (2). The separation of these two fractions was impossible until a method had been devised for the detection and assay of the Na factor. This is so essential to the present study that we shall present it in detail.

IN 1927 BAUMANN and KURLAND (I) demonstrated that plasma sodium falls in adrenal insufficiency. Six years later Loeb et al. (2) and Harrop et al. (3) showed that this was due to loss of sodium through the kidney. Recently we (4) have shown that the disturbance in sodium metabolism is due to a separate factor without which it is possible to maintain life. We have called this the Na factor. The hormone essential for life but without influence on sodium retention, we designated as cortin (5). In this paper we are reporting a study of the effects of cortin and the Na factor on adrenalectomized animals. Methods. All animals were selected from a colony which had been kept in our laboratory for many weeks in order to be sure that they were in good condition and that they thrived under laboratory conditions. The dogs and cats were freed from worms as indicated by low eosinophil count and the dogs were immunized against distemper. Adrenalectomy was performed in 2 stages under aseptic conditions.

In der Pathogenese der renal bewirkten Natriumretention bei hydropischer Herzund Leberdekompensation lies sich bisher der ursachliche Anteil von Aldosteronaktivitat und Reduzierung des Glomerulusfiltrates nicht quantitativ abgrenzen. Erst die statistische Korrelierung der Ergebnisse aus Clearancemethodik und gleichzeitiger Aldosteronbestimmung im Harn gestatten nun, den Einflus der glomerularen und der vom Aldosteron beeinflusten tubularen Faktoren hierbei zu unterscheiden. Die multiple Korrelationsberechnung zwischen Glomerulusfiltrat plus Aldosteronaktivitat und Natriumausscheidung ergab fur kompensierte und dekompensierte Herzkranke eine sehr enge negative Korrelation zwischen Aldosteron- und Natriumausscheidung (P

An attempt was made to ascertain the circumstances under which unilateral nephrectomy maximally sensitized rats to hypertensive cardiovascular disease induced by desoxycorticosterone acetate in the presence of augmented NACl intake. The experiments showed that animals in which hormone treatment was delayed until 2 weeks after uninephrectomy were much more sensitive than animals in which hormone treatment was begun on the day of kidney removal. This was indicated by earlier onset and greater severity of hypertension; by a larger percentage of animals in such groups being affected, and by a greater incidence and severity of cardiovascular lesions in the former as compared with the latter. The much greater kidney size of the former clearly makes it difficult to ascribe the greater sensitivity to a reduction in renal mass as such. It is thought that during active compensatory renal hypertrophy the renal tubules are probably less responsive to the action of the hormone and therefore less prone to develop sodium retention and hence hypertension.

Because the pineal gland appears to influence sodium retention, and because the production of several pineal hormones appears to be inhibited by light, saline and water choice intake was investigated in rats given normal and sodium-deplete diets under diurnal and constant lighting conditions. Under dirunal lighting pinealectomized animals ingested more saline than sham-operated controls. Total fluid intake declined when both groups of animals were placed on a sodium-free diet; this decline was generally due to a decrease in the amount of water ingested. Water intake was highly similar for pinealectomized animals regardless of lighting condition but water intake decreased for the sham-operated controls in the constant lighting condition. While total saline intake did not increase after animals were placed on a sodium-free diet, the proportion of saline ingested in choice with water did increase under diurnal lighting conditions.

SummaryThe anti-inflammatory, liver glycogenic, and sodium retaining activities of a series of 6α-fluoro and 16α-methyl steroids and their parent compounds were determined. The 6α-fluoro substitution increased liver glycogenic activity in all compounds studied, and anti-inflammatory potency in all but one of compounds. This modification also produced variable effects on sodium retention. The 16α-methyl group did not consistently increase liver glycogenic or anti-inflammatory activities. Sodium retention effect of the corticoids was not increased by 16-methylation if parent compound did not possess mineralo-corticoid activity. In examples where parent steroid was a sodium retainer, addition of 16α-methyl group caused reduction of this activity.