Patients with intracranial disorders are prone to develop hyponatremia with inability to prevent the loss of sodium in their urine. This was originally referred to as "cerebral salt wasting," but more recently is thought to be secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Blood volume determinations were made in 12 unselected neurosurgical patients with intracranial disease who fulfilled the laboratory criteria for SIADH. Ten of the 12 patients had significant decreases in their red blood cell mass, plasma volume, and total blood volume. The finding of a decreased blood volume in patients who fulfill the laboratory criteria for SIADH is better explained by the original concepts of cerebral salt wasting than by SIADH. The primary defect may be the inability of the kidney to conserve sodium.

The effect of systemically-administered cholecystokinin octapeptide (CCK) on hypothalamic oxytocin, vasopressin, and corticotropinreleasing hormone neurons was studied by analysis of c-fos antigen expression in immunocytochemically-characterized neurons in the supraoptic and paraventricular nuclei. CCK (100 pglkg intraperitoneally) caused a marked increase in nuclear c-fos immunocytochemical staining, which peaked at 60 to 90 min after injection. C-fos expression was found in most magnocellular oxytocin neurons in the supraoptic nucleus and in all magnocellular subdivisions of the paraventricular nucleus, but in no vasopressin neurons in either area. C-fos expression was also found in several parvocellular subdivisions of the paraventricular nucleus: in oxytocin neurons within the medial and lateral, but not the dorsal, parvocellular subdivisions, and in corticotropinreleasing hormone neurons in the medial parvocellular subdivision. Injection of lower doses of CCK showed that c-fos expression closely paralleled the pattern of pituitary oxytocin secretion in response to CCK, with a threshold for activation at 1 pglkg, near maximal responses by lopglkg, and maximal responses by 100pglkg. These studies demonstrate that the pattern of c-fos expression in hypothalamic magnocellular neurons following systemic CCK administration mirrors the neurosecretory response of these neurons, both with regard to specificity for the peptides secreted as well as intensity of secretion. They also demonstrate that systemic CCK administration activates c-fos expression in parvocellular oxytocin and corticotropin-releasing hormone neurons, and therefore likely causes secretion of oxytocin and corticotropin-releasing hormone within the brain at the terminal fields of these neurons.Previous studies from this and other laboratories have shown that systemic administration of cholecystokinin (CCK) stimulates pituitary secretion of oxytocin (OT) but not vasopressin (AVP) in rats (1, 2). Electrophysiological recordings from hypothalamic supraoptic nucleus (SON) neurons have confirmed that CCK causes activation of magnocellular neurons rather than simply releasing OT from pituitary axon terminals (3). Additional studies have demonstrated that the well-known effects of CCK to inhibit food intake (4) and gastric emptying and motility (5-7) are correlated with its effects to stimulate pituitary OT secretion (1, 5, 7-10). However, because peripheral infusions of OT do not affect either food intake (10) or gastric motility (11) in rats, we have postulated that centrally-projecting parvocellular OT neurons may be activated in concert with the pituitary-projecting magnocellular neurons to produce or modulate these diverse behavioral and physiological effects (8, 12).Recent studies have demonstrated that the antigen of the protooncogene c-fos is expressed in the nucleus of many activated neurons, including those in the hypothalamus (13). The present studies utilized immunohistochemical staining for c-fos antigen (14) to identify those hypothal...

RIA for the measurement of oxytocin in human plasma is described. Extraction of oxytocin from larger peptides in plasma used acetone precipitation with a 75% +/- 2 SEM recovery of oxytocin. Nonspecific binding of the assay was less than 4%, and the minimum level of detection was 0.2 microunits/tube. No cross-reactivity was noted with neurophysins, arginine, or lysine vasopressin. The mean basal level (+/- SEM) of oxytocin in men was 1.80 +/- 0.07 microunits/ml and was not different in normal women (1.71 +/- 0.07 microunits/ml). Changes in posture had no effect on the levels of oxytocin. Samples obtained every 15 min over 4 h showed no pulsatile secretion of oxytocin. In women chronically receiving estrogen as an oral contraceptive, oxytocin was greater than normal, (4.59 +/- 0.51 microunits/ml; P less than 0.01). Estrogen-stimulated neurophysin was also elevated (8.45 +/- 1.99 ng/ml; P less than 0.005). Acute ingestion of estrogen caused an increase in the level of oxytocin in plasma by 12 h and a concomitant elevation of estrogen-stimulated neurophysin. When the neurophysin was isolated from plasma obtained from a subject after ingestion of estrogen, the neurophysin from plasma comigrated on a polyacrylamide gel with a human pituitary standard of estrogen-stimulated neurophysin. In the studies in which neurophysin was elevated, the correlation between the level of oxytocin and the level of estrogen-stimulated neurophysin in plasma was significant (P less than 0.01). The observation that estrogen administration stimulates the release of oxytocin and estrogen-stimulated neurophysin provides additional evidence that this neurophysin is the oxytocin-neurophysin of man.

Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal nonapeptide arginine vasopressin, has enhanced antidiuretic potency, markedly diminished pressor activity, and a prolonged half-life and duration of action compared to the natural hormone. Desmopressin is the treatment of choice for central diabetes insipidus and can be administered either intranasally or parenterally. A newly approved indication is treatment of mild classical hemophilia and von Willebrand's disease, in which deficient concentrations of factor VIII and von Willebrand's factor are transiently increased to levels that allow minor surgery.

The mechanisms which regulate the serum level of T-globulin (or other serum proteins) are poorly understood, although a balance between the rate of production (synthesis) and rate of removal (catabolism) must exist for the maintenance of a constant serum level. T-Globulin synthesis has been demonstrated in plasmacytes and related cells of the spleen, lymph node, bone marrow, and other tissues following antigenic stimulation (1-3), and the turnover of T-globulin has been determined by means of radioisotopically labeled protein. The anatomic and cellular sites of degradation are still unknown, however, and the mechanisms regulating the rate of T-globulin catabolism are poorly understood.Several observations indicate that the rate of ~,-globulin catabolism may be related to the serum T-globulin level. T-Globulin catabolism is generally accelerated in patients with increased T-globulin levels due to inflammatory diseases (4-9) or plasma cell malignancy (7-11). Similarly in mice with plasma cell tumors and large amounts of T myeloma proteins, T-globulin catabolism is accelerated (12). Conversely, prolonged T-globulin survival has been found when the serum T-globulin level is low (9,11,13,14). Two variable factors, however, were present in these studies; i.e., the amount of serum gamma globulin and the number of plasma cells. Patients with low T-globulin levels had reduced numbers of plasma cells, and patients with large amounts of ~-globulin had increased numbers of plasma cells. Soons and Westenbrink (15), on the basis of isotopically labeled protein studies, obtained some evidence that plasma cells might be the site of T-globulin destruction. If this is the case, then T-globulin catabolism would be increased when the number of plasma cells is increased and decreased with plasma cell reduction. Because of the uncertainty about the roles of the plasma cells and the serum gamma globulin level, the present studies were undertaken to clarify the factors determining the rate of T-globulin catabolism. Inbred BALB/c mice were used (a) to reduce genetic variability to a minimum, (b) because fl, A-globulins as well as ~,-globulins from BALB/c mice were available in large quantities, (c) because transplantable * Work done as

Synthetic oxytocin (OT) was infused iv in four men at 3 mU/min, and the rate was doubled every 90 min for a total of three infusion periods. The mean (+/- SEM) OT MCR was 16.4 +/- 1.7 ml/kg X min and was independent of the rate of infusion. A method for measuring OT in urine was developed using an octadecasilyl-silica column for extraction of the hormone. The extracted residue was reconstituted in potassium phosphate buffer, pH 7.4, for RIA. The minimum detectable level of OT in urine was 0.2 microU/ml (defined as a bound to free ratio of approximately 90%). The mean recovery of OT was 77 +/- 2%. The mean (+/- SEM) concentration of endogenous OT in urine was 10.2 +/- 1.4 microU/ml. Endogenous OT in urine eluted from a reverse phase high pressure liquid chromatography column as a single peak of OT immunoreactivity in the position of synthetic OT. Urinary OT excretion during infusion of synthetic OT was linearly correlated with plasma OT concentration whether calculated as microunits of urinary OT per mg creatinine (r = 0.89) or urinary OT per min (r = 0.93). Mean urinary fractional clearance of OT (OT clearance/creatinine clearance) was 3.6% renal clearance of OT (5.5 ml/min or 0.43% of MCR). Thus, OT MCR was constant over a wide range of physiological plasma OT levels and was similar to MCR in pregnant women studied previously in this laboratory. Less than 1% of OT was cleared in urine. This study defines the relationship between urinary and plasma OT during steady state infusion of physiological concentrations of the hormone and indicates that measurements of OT in urine by RIA may prove helpful for pharmacokinetic and physiological studies of OT-related events in humans.

Oxytocin (OT) and the oxytocin-neurophysin (OT-Np) were measured by RIA in samples of cerebrospinal fluid (CSF) obtained sequentially at 0600, 1200, 1800, and 2400 h from six patients in whom intrathecal catheters were temporarily placed for CSF rhinorrhea. The highest levels of OT in CSF were found at 1200 h. An analysis of variance of sequential measures of the concentration of OT in samples of CSF obtained every 6 h over a 30-h period showed the mean levels (+/- SEM) of OT at 1200 h, 6.41 +/- 1.13 microU/ml and 5.06 +/- 0.58 microU/ml, to be significantly higher (p less than 0.05) than mean levels of OT at 0600 h, 2.50 +/- 0.65 microU/ml; 1800 h, 2.63 +/- 0.61 microU/ml and 2.64 +/- 1.21 microU/ml; and 2400 h, 2.86 +/- 1.13 microU/ml. The levels of OT-Np in CSF did not show a similar peak. In three of the patients simultaneous samples of blood were obtained for measurement of the same peptides, but no corresponding peak of OT or its Np was found in plasma of these three patients. The level of OT in CSF at all times was also significantly higher (p less than 0.05) than the level of OT in plasma of these three patients. Levels of OT and OT-Np were measured by RIA of samples of plasma obtained hourly for a 24-h period from six healthy men and six healthy women. No diurnal variation of OT or its Np in the plasma of men or women was found. This pattern of OT in the CSF of humans is similar to the pattern of OT in the CSF of the Rhesus monkey, but in contrast to the lack of a clearly defined peak of OT in the CSF of the cat or the rat. These observations in humans reinforce the differences among species of the secretion of OT in the CSF.

No abstract