Issue published December 1, 1967

E xperiments were done to investigate mechanisms of appearance of both 7 S and 11 S IgA in nasal secretions. Three IgA preparations, (a) 11 S IgA from nasal secretions, (b) 7 S IgA from homologous serum, and (c) 7 S IgA from autologous serum, were isolated, labeled, and injected intravenously into volunteers. The rate of disappearance from plasma and the extent and nature of their appearance in nasal secretions were examined in detail. After intravenous injection, 11 S IgA from nasal secretions disappeared rapidly from plasma. However, only negligible amounts of 11 S IgA were detected in nasal secretion, which suggested that rapid selective secretion of circulating 11 S IgA does not occur as a mechanism of IgA accumulation in nasal secretions. Both the homologous and autologous 7 S IgA preparations disappeared from plasma at a normal rate, and both appeared in nasal secretions unchanged in sedimentation behavior. The specific activity of IgA in nasal secretions, when related to the total IgA concentration, was about 30-fold less than that in serum. When related to only the 7 S IgA concentration of nasal secretions, the specific activity was about one-half that of serum. These studies are consistent with the following hypotheses: (a) circulating 7 S IgA is a source of part of the 7 S IgA found in nasal secretions. The remainder of the nasal secretion 7 S IgA may be synthesized locally in the tissues of the upper respiratory tract; (b) 11 S IgA in nasal secretions is not assembled from serum 7 S IgA components; and (c) 11 S IgA in nasal secretions is synthesized de novo in the tissues of the upper respiratory tract.

S ystemic and renal hemodynamics were studied by indicator dilution techniques before and after infusion of 500 ml of dextran 40 in 21 patients with renal failure developing in the course of decompensated cirrhosis.Cardiac index was directly correlated with total blood volumes. Renal blood flow was low and renal vascular resistance elevated in 13 of 15 patients. Renal vascular resistance was directly related to total systemic nonrenal vascular resistance. Two patients with the highest cardiac outputs in the group were oliguric with high renal blood flow.Plasma volume expansion increased cardiac output in 19 of 21 patients and increased renal blood flow in 12 of 14. The patients were divided into two groups on the basis of control cardiac index. Those with lower cardiac index had lower blood volumes and responded to dextran with a 73% increase in cardiac output, a 148% increase in renal blood flow, and a rise in renal fraction. Those with high control cardiac index had significantly higher blood volumes and responded to dextran with only a small average rise in cardiac output and renal blood flow.Systolic arterial pressure was less than 100 mm Hg in 12 patients. When compared to the normotensive subjects, this hypotension was characterized by a lower vascular resistance, a tendency for a lesser rise in renal blood flow after volume expansion, and a more rapid demise.The prompt circulatory improvement after volume expansion in many of these patients indicates that functional plasma volume depletion may be an important factor in the renal vasoconstriction of oliguric hepatic failure. In an attempt to sustain volume expansion, reinfusion of ascitic fluid was accomplished in four patients. Normal renal blood flow was maintained during reinfusion and a diuresis always occurred, but the response usually was not maintained after the infusion was terminated.

T he fate of an intravenous dose of tritiated vitamin D₃ was studied in seven normal subjects, four children with vitamin D-resistant rickets, and four adults with a familial history of vitamin D-resistant rickets and persistent hypophosphatemia. An abnormal metabolism of vitamin D in vitamin D-resistant rickets was defined and characterized by a decrease in the plasma fractional turnover rate, a marked increase in plasma water-soluble metabolites, and a relative decrease in the conversion of vitamin D to a polar, biologically active metabolite. Alterations in vitamin D metabolism in the adults with persistent hypophosphatemia were similar but less severe than those of affected children with vitamin D-resistant rickets. It is tentatively concluded that the abnormalities in vitamin D metabolism documented in patients with vitamin D-resistant rickets and familial hypophosphatemia may account for the observed osseous and biochemical changes.

F ollowing hypophysectomy in the rat, there was a progressive decline in the rate of adrenal protein synthesis in vivo during the ensuing 24-48 hr, and an accompanying decrease in the acute corticosterone secretory response to an intravenous injection of ACTH. There was a similar decrease in the in vitro conversion of Δ⁵-pregnenolone, progesterone, and deoxycorticosterone to corticosterone. These in vivo and in vitro effects of hypophysectomy could be reversed by the administration of depot ACTH for an additional 7 hr period. However, if cycloheximide, an inhibitor of protein synthesis, was administered concomitantly with the depot ACTH, then the restorative actions of ACTH on the steroid biosynthetic pathway were prevented. These experiments suggest that ACTH maintains not only the general structure of the adrenal cortex, but also the level of the steroid biosynthetic mechanism, through its effects on adrenal protein synthesis.

F ollicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been measured by specific bioassays in pooled urine samples from prepubertal children, aged 2-6 yr, and from male adults. For children the mean urinary excretion of FSH was 2.2 U 2nd International Reference Preparation (2nd IRP) per liter and the mean urinary excretion of LH was 0.44 U 2nd IRP per liter. For adults the mean FSH excretion was 5.6 U 2nd IRP per liter and the mean LH excretion was 4.7 U 2nd IRP per liter. Our data show a 2.5-fold increase of FSH, a 10.7-fold increase of LH, and a consequent decrease in the FSH: LH ratio from 5 to 1 between childhood and adulthood. FSH and LH in urine from three patients with gonadal abnormalities have also been studied. The results from normal children, adults, and abnormal patients form a spectrum and reveal that sexual maturity is accompanied by a marked increase in the excretion of LH with relatively smaller increases in FSH.

B one marrow and peripheral blood from patients who had received chloroquine phosphate were studied to determine the effect of this drug on the ultrastructure of cytoplasmic granules in leukocytes. Neutrophils from approximately one-half of the patients who were treated developed abnormal cytoplasmic granules. Vacuolar, lamellar, and particulate components within abnormal, large granules were present in myelocytes from certain patients who received chloroquine therapy. Mature neutrophils and lymphocytes from these patients showed variable numbers of large, membrane-bounded structures containing myelin figures. Cytoplasmic granules in eosinophilic myelocytes from patients treated with chloroquine did not contain the usual crystalloid structure, but instead contained small whorls of osmiophilic material. The granules in abnormal mature eosinophils were replaced by large vacuoles which contained amorphous material. The abnormal granules seen in these various white cells after chloroquine therapy may either reflect defective granule formation or autophagy.

N eutrophil kinetics of acute experimental infection were studied with diisopropylfluorophosphate-³²P labeling in 31 dogs inoculated intrabronchially with pneumococci. In vitro neutrophil labeling indicated a rapid transit time through the blood in early infections, with an elevated marginal granulocyte pool sometimes preceding an elevation of the circulating granulocyte pool. 13 hr after infection, the circulating and total blood granulocyte pools were increased but the rate of neutrophil transit through the blood was normal. During the recovery from infection there was a marked prolongation of neutrophil blood transit time, suggesting virtually complete cessation of bone marrow release of neutrophils into the blood. Labeling of neutrophils in vivo indicated an increased rate of emptying of the bone marrow storage pool proportional to the severity of infection as measured by the fever index. The change in the blood ratio of nonsegmented to segmented neutrophils was a much more accurate index of the severity of infection than the blood granulocyte concentration, correlating significantly with the fever index.

T he plasma insulin responses of normal weight and obese, diabetic, and nondiabetic subjects to intravenous glucose was only 30-40% of that seen after oral glucose, indicating that alimentary mechanism(s) in addition to the arterial blood sugar concentration regulate insulin secretion. Observations made in subjects with diverted portal circulation indicate that the alimentary insulinogenic mechanism is located in the intestinal tract. The insulinogenic potency of the alimentary and glycemic stimuli expressed in terms of insulin secretion per gram of glucose were remarkably similar within each group of individuals. Between these groups, however, there were considerable differences. Obesity, with or without associated diabetes, was associated with a true hypersecretory responsiveness, whereas diabetes was characterized, with or without obesity, by a marked impairment in insulin secretion. The experimental design used in these studies permitted quantitation of the magnitude of the glycemic component of an oral glucose load. As a consequence of impaired insulin secretion, a greater than normal proportion of the oral glucose load escapes initial hepatic extraction in the maturity-onset diabetic and enters the peripheral circulation. Therefore, in the noninsulin-requiring maturity-onset diabetic, the glycemic insulinogenic stimulus for a given oral glucose load is significantly greater than in normal subjects and accounts for the excessive plasma insulin responses observed late in the course of an oral glucose tolerance test.

T he importance of plasma protein concentration, renal vascular resistance, and arterial pressure as mediators of the natriuretic response to volume expansion was investigated in anesthetized dogs.Saline loading depressed plasma protein concentration and increased arterial pressure but did not decrease renal vascular resistance. Restoring plasma protein concentration by infusing hyperoncotic albumin increased sodium reabsorption and decreased sodium excretion during saline loading despite simultaneous decreases in renal vascular resistance and increases in arterial pressure.Infusion of “plasma” did not depress plasma protein concentration and produced natriuresis associated with increased arterial pressure and marked decreases in renal vascular resistance. Unilateral hemodynamic natriuresis was produced before “plasma” loading by the renal arterial infusion of acetylcholine, and the subsequent infusion of “plasma” resulted in much smaller increases in sodium excretion by the vasodilated kidney than by the control kidney. If perfusion pressure to both kidneys was then reduced by aortic constriction sodium excretion by the vasodilated kidney could be reduced to preloading (vasodilated) levels without reduced glomerular filtration, despite continued natriuresis in control kidneys which underwent vasodilatation in response to the infusion of plasma.Infusion of equilibrated whole blood did not alter plasma protein concentration or the hematocrit, and renal vascular resistance did not decrease. Sodium excretion was increased minimally or not at all by the infusion of blood despite increased arterial pressure and glomerular filtration. However, in kidneys vasodilated before infusing blood sodium excretion increased in response to the infusion in association with increased arterial pressure. This increased excretion of sodium by vasodilated kidneys during infusion of blood could be abolished by reducing perfusion pressure to the preloading level.These observations indicate that changes in plasma oncotic pressure, renal vascular resistance, and arterial pressure either alone or in combination are important variables determining the natriuretic response to volume expansion, and that the relative importance of each of these factors depends on the manner in which volume is expanded (viz., the infusion of saline, plasma, or blood).

U sing autologous ¹³¹I-fibrinogen, we made studies of the metabolism and distribution of fibrinogen in 10 patients with hemophilia A. In two patients simultaneous studies of autologous ¹³¹I-fibrinogen and homologous ¹²⁵I-fibrinogen prepared from healthy donors' plasma were carried out. The average value for the plasma volume was 42.1 ± 8.8 ml/kg; for the plasma fibrinogen concentration, 349 ± 90 mg/100 ml; for the intravascular fibrinogen, 144 ± 32 mg/kg; for the interstitial fibrinogen, 30 ± 11 mg/kg; for the slower half-life of ¹³¹I-fibrinogen, 2.34 ± 0.17 days; for the transcapillary transfer rate of fibrinogen, 109 ± 37 mg/kg per day; and for the catabolic and synthetic rates of fibrinogen, 51.7 ± 13.1 mg/kg per day. Comparison of these results with those of the previous study in healthy male subjects showed that in patients with hemophilia A the catabolic and synthetic rates of fibrinogen are markedly increased, whereas the plasma fibrinogen concentration, intravascular and interstitial fibrinogen, and the transcapillary transfer rate of fibrinogen are not significantly different. The simultaneous studies of autologous ¹³¹I-fibrinogen and normal homologous ¹²⁵I-fibrinogen in two subjects revealed that the two preparations behaved very similarly. Based on these findings, we concluded that our present findings are not due to the qualitative difference between the hemophilia A and normal fibrinogens, but that they are due to the difference in the host condition with respect to the fibrinogen metabolism, which is either an increased rate of direct breakdown of fibrinogen or an increased rate of fibrinogen breakdown after fibrin formation, or both.

T he rate of endogenous carbon monoxide production (˙Vco), determined by the closed rebreathing system technique, was elevated above the normal range in four of five patients studied with ineffective erythropoiesis (four patients with primary refractory anemia, one with thalassemia). The mean molar ratio of ˙Vco to ˙Vheme (rate of circulating heme catabolism, determined from ⁵¹Cr red cell survival curves) was 3.0 ± 0.6 (SE), indicating that most of the CO originated from sources other than circulating erythrocyte hemoglobin, in contrast to previous findings in patients with hemolytic anemia, where ˙Vco paralleled ˙Vheme closely.After administration of glycine-2-¹⁴C to these patients, endogenous CO was isolated by washout of body CO stores at high pO₂ or by reacting peripheral venous blood samples with ferricyanide. The CO was then oxidized to CO₂ by palladium chloride and trapped for counting in a liquid scintillation spectrometer. “Early labeled” peaks of ¹⁴CO were demonstrated which paralleled “early labeled” peaks of stercobilin and preceded maximal labeling of circulating heme. Production of “early labeled” ¹⁴CO in patients with ineffective erythropoiesis was greatly increased, up to 14 times that found in a normal subject.The increased ˙Vco and “early ¹⁴CO” production shown by these patients are presumably related mainly to heme catabolism in the marrow. The possibility exists that hepatic heme and porphyrin compounds may also contribute significantly to ˙Vco, as suggested by the finding of a high ˙Vco in an additional patient with porphyria cutanea tarda.

I n order to evaluate the possible role of sodium- and potassium-activated adenosine triphosphatase in the active transport of sodium by the renal tubules, we examined the effect of large changes in the tubular reabsorptive load of sodium on the Na-K-ATPase activity of rat kidney homogenates. Glomerular filtration and tubular reabsorption of sodium per gram of kidney tissue increased progressively after contralateral uninephrectomy. This was paralleled by an increase in Na-K-ATPase per milligram of protein in a microsomal fraction of kidney cortex. The importance of this change is underlined by the absence of simultaneous increases in other microsomal enzymes such as glucose-6-phosphatase and Mg⁺⁺-dependent ATPase, or in succinic dehydrogenase or glutaminase. Similar increases in Na-K-ATPase were observed when the net tubular reabsorption of sodium was increased by feeding the animals a high-protein diet or after injection of methylprednisolone. On the other hand, Na-K-ATPase was lowered when tubular transport of sodium was reduced by bilateral adrenalectomy. The results of these experiments show that renal Na-K-ATPase changes in an adaptive way when renal reabsorption of sodium is chronically increased or diminished and support the hypothesis that this enzyme system is involved in the process by which sodium is actively transported across the renal tubule.

P lasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis.Tyrosine tolerance tests in patients with cirrhosis were characterized by larger than normal increments in tyrosine levels and by delayed returns toward fasting levels.The results of phenylalanine conversion tests were abnormal in approximately one-half of patients with either hepatitis or biliary obstruction and four-fifths of patients with cirrhosis. Abnormalities were characterized by elevated fasting plasma tyrosine levels, or small and delayed increments in tyrosine levels, or both. Abnormal phenylalanine conversion test results in patients with cirrhosis did not correlate closely with any clinical feature of cirrhosis or with the results of any standard liver function test; there was positive correlation only with abnormal ammonia tolerance, a test of portalsystemic shunting. Tests of tyrosine metabolism do not appear to be useful for routine clinical assessment of liver function. Tyrosine tolerance tests and phenylalanine conversion tests done for purposes of diagnosis of other diseases may yield misleading results in patients with liver disease.

T he metabolic behavior of C′3 labeled with radioactive iodine was investigated in 10 normal subjects and in 20 patients with diseases in which complement is thought to play a pathophysiological role. The mean fractional catabolic rate of C′3 in normal subjects was 2.3 ± 1.0% of the plasma pool per hr, whereas the fractional catabolic rate of C′3_i, the inactive conversion product of C′3 produced by complement activation, was at least five times as great.Increased catabolic rates were found in some patients with acute glomerulonephritis, systemic lupus erythematosus, idiopathic nephrotic syndrome of childhood, and progressive glomerulonephritis. Depressed synthesis was found in each of four studies of patients with progressive glomerulonephritis and seemed to be the major factor in the lowering of plasma C′3 concentrations regularly observed in patients with this disease. Of three patients with acute glomerulonephritis, synthesis rates of C′3 were markedly depressed in one subject, at the lower limit of normal in another, and entirely normal in the third. Increased extravascular: plasma pool ratios were observed in the studies of C′3_i metabolism in a normal subject, and of C′3 metabolism in two of three patients with acute glomerulonephritis, in one of four patients with systemic lupus erythematosus, and in one patient with idiopathic nephrotic syndrome. The increased pool ratios are possibly compatible with tissue attachment of part of the injected C′3 or its conversion products.No important abnormalities of metabolism were found in patients with acquired hemolytic anemia, paroxysmal nocturnal hemoglobinuria, hereditary angioneurotic edema, or rheumatoid arthritis.By means of antigen-antibody crossed electrophoresis, C′3_i could be demonstrated in the fresh plasma of three of eight patients who had acute glomerulonephritis. This finding was used as evidence for in vivo complement activation in this disease. Since C′3_i was demonstrated only in plasma from patients with very low plasma concentrations whose onset of symptoms was very recent, there may be two phases in the metabolism of C′3: early complement activation with resultant increased catabolism and later depressed synthesis, both of which lead to lowered serum concentrations.

A technique is described for preparation in the guinea pig of an in situ, isolated, vascularized gall bladder that exhibits normal absorptive functions. Absorption of labeled bile pigments from the gall bladder was determined by the subsequent excretion of radioactivity in hepatic bile.Over a wide range of concentrations, unconjugated bilirubin-¹⁴C was well absorbed, whereas transfer of conjugated bilirubin proceeded slowly. Mesobilirubinogen-³H was absorbed poorly from whole bile, but was absorbed as rapidly as unconjugated bilirubin from a solution of pure conjugated bile salt.Bilirubin absorption was not impaired by iodoacetamide, 1.5 mM, or dinitrophenol, 1.0 mM, even though water transport was affected. This indicated that absorption of bilirubin was not dependent upon water transport, nor upon energy-dependent processes. The linear relationship between absorption and concentration of pigment at low concentrations in bile salt solutions suggested that pigment was transferred by passive diffusion. At higher pigment concentrations or in whole bile, this simple relationship was modified by interactions of pigment with bile salts and other constituents of bile. These interactions did not necessarily involve binding of bilirubin in micelles.The slow absorption of the more polar conjugates and photo-oxidative derivatives of bilirubin suggested that bilirubin was absorbed principally by nonionic, and partially, by ionic diffusion.Concentrations of pure conjugated bile salts above 3.5 mM were found to be injurious to the gall bladder mucosa. This mucosal injury did not affect the kinetics of bilirubin absorption.During in vitro incubation of bile at 37°C, decay of bilirubin and hydrolysis of the conjugate proceeded as first-order reactions. The effects of these processes on the kinetics of bilirubin absorption, and their possible role in the formation of “white bile” and in the demonstrated appearance of unconjugated bilirubin in hepatic bile, are discussed.

A technique is described for studying the distribution of blood flow to the maternal and fetal placental vessels in sheep and dogs with radioactive labeled macroaggregates of albumin.When the maternal animal breathed room air the distribution of maternal placental blood flow was uneven among the cotyledons as well as within a given cotyledon. Fetal blood flow was also distributed nonuniformly among and within the cotyledons. The relation of maternal to fetal placental blood flow was also markedly uneven (coefficient of correlation, τ = 0.066). After the animal was made hypoxic by breathing 10-12% O₂ the distribution of maternal, fetal, and maternal/fetal placental flows became more uniform. The coefficient of correlation of maternal to fetal flow was high (τ = 0.53, P < 0.01). While the maternal animal breathed room air, after ligation of a major branch of the umbilical artery the distribution of maternal, fetal, and maternal/fetal flows in the remaining two-thirds to three-fourths of the placenta became more uniform. The correlation coefficient for maternal to fetal flow was high (τ = 0.35, P < 0.01).It appears that under normal circumstances with uneven distribution of blood flows there is a considerable portion of the placenta that does not receive blood flow in optimum quantities to promote efficient O₂ exchange. Failure to consider the influence of nonuniform maternal flow/fetal flow will result in overestimation of mean maternal-fetal oxygen tension gradients, and thus underestimation of the placental diffusing capacity for oxygen.In response to maternal hypoxia or compromise of the fetal placental circulation the distribution of maternal, fetal, and maternal/fetal flows becomes more uniform, thereby increasing the efficiency of placental O₂ exchange.

A method for the simultaneous measurement of gastrointestinal protein loss and total albumin turnover entailing the use of a combination of ¹²⁵iodine- and ⁵¹chromium-labeled albumin is described. Albumin turnover was calculated by the measurement of albumin-¹²⁵I plasma decay and cumulative urinary excretion, and the results obtained agreed closely with previous studies utilizing albumin-¹³¹I. Gastrointestinal catabolism was calculated from the rate of fecal excretion of ⁵¹Cr and the specific activity of plasma albumin-⁵¹Cr, and these data were related to the calculated albumin turnover results. During the period of 6-14 days after administration, the ratio of specific activties of albumin-¹²⁵I and -⁵¹Cr in plasma and in extravascular spaces or gastric and biliary secretions remained almost identical. Fecal excretion of ⁵¹Cr was also quite stable at this time. In six normal subjects gastrointestinal catabolism accounted for less than 10% of total albumin catabolism. Excessive gastrointestinal protein losses did not contribute to the low serum albumin in three patients with cirrhosis or in two adults with the nephrotic syndrome. Multiple mechanisms leading to hypoalbuminemia were demonstrated in other subjects with a variety of gastrointestinal disorders.

H ereditary spherocytosis (HS) red cells lose membrane lipids excessively during incubation in vitro. Individual phosphatides as well as cholesterol are lost in proportion to their content in membranes, suggesting that fragments of membrane are removed. Supplementation of HS red cells with glucose during incubation has no consistent protective effect, whereas diminishing the excessive sodium flux through these cells by suspending them in either sodium-free or hypertonic media prevents membrane fragmentation. The characteristic excessive increase in osmotic fragility which occurs in incubated HS red cells results both from inordinate accumulation of intracellular sodium ions which produces osmotic swelling, and from depletion of surface material which generates microspherocytosis. Inhibiting both of these processes by incubating HS red cells in sodium-free media completely prevents increases in osmotic fragility despite prolonged incubation.Normal red cells rendered hyperpermeable to cations by exposure either to n-butanol or to inhibitors of membrane sulfhydryl groups, lose membrane lipid upon incubation in a similar fashion to untreated HS red cells; perfectly smooth microspherocytes, akin to those seen in HS, are thereby generated.I conclude that depletion of membrane lipids in HS which leads to microspherocytosis is correlatable with the excessive cation flux and possibly to the stimulated metabolism of acidic phosphatides in these red cells. It is suggested that this relation is derived from the fact that these phosphatides are in some way involved in maintaining the proper alignment of repeating membrane lipoprotein units, and that this function is adversely affected when these molecules are turning over more rapidly in response to increased cation flux.

A constant infusion of ³H-testosterone and ¹⁴C-androstenedione was administered to four human subjects, two males and two females, until the concentrations of radioactive testosterone and androstenedione in systemic plasma became constant. At that time the concentrations of radioactive testosterone and androstenedione in hepatic vein plasma were determined. Splanchnic extraction of testosterone and androstenedione and the contribution of the splanchnic system to the blood interconversion of testosterone and androstenedione were calculated.Androstenedione is extracted by the splanchnic system more efficiently than testosterone since 82.3% of androstenedione and 44% of testosterone were removed from the plasma after one passage.The fraction of testosterone entering the splanchnic system that is transferred to blood androstenedione was 0.011 and the maximum possible transfer due to recirculation was 0.026. This was 28% of the total blood transfer from testosterone to androstenedione. The fraction of androstenedione entering the splanchnic system that is transferred to blood testosterone after one passage was 0.005, whereas the maximum possible transfer in this system was 0.006. This represented only 16% of the total transfer from androstenedione to testosterone. Therefore, a large fraction of the interconversion of testosterone and androstenedione in vivo occurs outside the splanchnic system.

T he effect of various factors on the conversion of corticosterone to aldosterone was studied in an isolated mitochondrial system from rat adrenal glands. The adrenal mitochondrial fraction from rats on a low sodium diet has a greater capacity for converting corticosterone to aldosterone than mitochondria from rats fed a normal diet. After 1 day on a low sodium diet the amount converted was 162% and after the 2nd and 4th day the amounts converted were 239 and 242%, respectively, compared to a value of 100% for the control rats. Sodium and(or) potassium added in vitro did not affect the conversion of corticosterone to aldosterone.The specificity of the sodium depletion stimulus on the conversion of corticosterone to aldosterone was established by comparing two other mitochondrial enzymes from glomerulosa cell mitochondria. Succinic dehydrogenase and 11 β-hydroxylase were measured in normal and sodium-depleted rats and no difference in activity of either enzyme was found.The data are consistent with the view that sodium depletion stimulates the last step in aldosterone biosynthesis by causing a specific enzymatic change in adrenal mitochondria.

T he effects of intravenous administration of angiotensin II on renal water and electrolyte excretion were examined during hydropenia, water diuresis, and hypotonic saline diuresis in anesthetized normal dogs and dogs with thoracic inferior vena cava constriction and ascites (caval dogs). The effects of unilateral renal artery infusion of a subpressor dose were also examined.During hydropenia angiotensin produced a decrease in tubular sodium reabsorption, with a considerably greater natriuresis in caval dogs, and associated with a decrease in free water reabsorption (T^c_H2O). Water and hypotonic saline diuresis resulted in an augmented angiotensin natriuresis, with a greater effect still observed in caval dogs. In these experiments free water excretion (C_H2O) was limited to 8-10% of the glomerular filtration rate (GFR), although distal sodium load increased in every instance. In the renal artery infusion experiments a significant ipsilateral decrease in tubular sodium reabsorption was induced, particularly in caval dogs.These findings indicate that angiotensin has a direct effect on renal sodium reabsorption unrelated to a systemic circulatory alteration. The attenuation or prevention of the falls in GFR and effective renal plasma flow (ERPF) usually induced by angiotensin may partially account for the greater natriuretic response in caval dogs and the augmentation during water or hypotonic saline diuresis. However, a correlation between renal hemodynamics and the degree of natriuresis induced was not always present and, furthermore, GFR and ERPF decreased significantly during the intrarenal artery infusion experiments. Therefore, the present experiments indicate that another mechanism is operative in the control of the angiotensin natriuresis and suggest that alterations in intrarenal hemodynamics may play a role.The decrease in T^c_H2O and the apparent limitation of C_H2O associated with an increase in distal sodium load localize the site of action of angiotensin to the ascending limb of Henle's loop and the proximal tubule.