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The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by euvolemic hyponatremia. Patients with SIADH continue to drink normal amounts of fluid, despite plasma osmolalities well below the physiological osmotic threshold for onset of thirst. The regulation of thirst has not been previously studied in SIADH. We studied the characteristics of osmotically stimulated thirst and arginine vasopressin (AVP) secretion in eight subjects with SIADH and eight healthy controls and the nonosmotic suppression of thirst and AVP during drinking in the same subjects. Subjects underwent a 2-h infusion of hypertonic (855 mmol/l) NaCl solution, followed by 30 min of free access to water. Thirst rose significantly in both SIADH (1.5 +/- 0.6 to 8.0 +/- 1.2 cm, P < 0.0001) and controls (1.8 +/- 0.8 to 8.4 +/- 1.5 cm, P < 0.0001), but the osmotic threshold for thirst was lower in SIADH (264 +/- 5.5 vs. 285.9 +/- 2.8 mosmol/kgH(2)O, P < 0.0001). SIADH subjects drank volumes of water similar to controls after cessation of the infusion (948.8 +/- 207.6 vs. 1,091 +/- 184 ml, P = 0.23). The act of drinking suppressed thirst in both SIADH and controls but did not suppress plasma AVP concentrations in SIADH compared with controls (P = 0.007). We conclude that there is downward resetting of the osmotic threshold for thirst in SIADH but that thirst responds to osmotic stimulation and is suppressed by drinking around the lowered set point. In addition, we demonstrated that drinking does not completely suppress plasma AVP in SIADH.

Objective: In this study we aimed to establish the frequency of postoperative diabetes insipidus and the incidence and characteristics of abnormalities of thirst in a cohort of patients with craniopharyngioma, in whom neurosurgery had been performed., Design: Diabetes insipidus was determined by either standard criteria for diagnosis in the immediate postoperative period, or by water deprivation test, in all craniopharyngioma and pituitary tumour patients who underwent surgery in Beaumont Hospital between the years 1986 and 1998. Osmoregulated thirst and vasopressin release were studied during a 2-h infusion of hypertonic (5%) saline followed by a 30-min period of free access to water., Patients: Data on the incidence of postoperative diabetes insipidus was collected in 26 patients with craniopharyngioma and 154 patients with pituitary adenomata. We recruited 16 healthy control patients, 16 patients with cranial diabetes insipidus following pituitary tumour surgery and 16 patients with cranial diabetes insipidus following craniopharyngioma resection for the hypertonic saline infusion study., Results: Twenty-five patients out of 26 (96%) patients developed diabetes insipidus after surgery for craniopharyngioma, a much higher incidence than after surgery for suprasellar (26/88, 30%, P < 0.001) or intrasellar pituitary tumours (9/66, 14%, P < 0.001). Hypertonic saline infusion identified abnormal thirst responses in five of the 16 craniopharygioma patients studied; all of the pituitary tumour patients had a normal thirst response. Three of the craniopharyngioma patients had adipsic diabetes insipidus whilst two had polydipsic diabetes insipidus., Conclusion: This study demonstrates following surgery for craniopharyngioma there is a high incidence of cranial diabetes insipidus and a significant incidence of abnormal thirst responses to osmotic stimuli.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest form of normovolaemic or dilutional hyponatraemia. The diagnosis of SIADH should be considered if the five cardinal criteria are fulfilled (hypotonic hyponatraemia, natriuresis, urine osmolality in excess of plasma osmolality, absence of oedema and volume depletion, normal renal and adrenal function). The clinical features are principally neuro-muscular and gastro-intestinal, the severity of which is related to both the absolute serum sodium concentration and its rate of fall, particularly if greater than 0.5 mmol/1/h. The dilutional hyponatraemia of SIADH develops due to persistent detectable or elevated plasma arginine vasopressin (AVP) concentrations in the presence of continued fluid intake. Osmoregulated inhibition of thirst failures to curb fluid intake. The major groups of causes of SIADH are: (i) neoplasia, (ii) neurological diseases, (iii) lung diseases and (iv) a wide variety of drugs. Inappropriate infusion of hypotonic fluids in the post-operative state remains a common cause. Four categories of osmoregulated AVP secretion have been described: (i) erratic AVP release, (ii) reset osmostat, (iii) persistent AVP release at low plasma osmolality and (iv) normal osmoregulated AVP secretion. For symptomatic patients with chronic SIADH, the mainstay of therapy remains fluid restriction. New antagonists to the antidiuretic action of AVP offer a new therapeutic approach.

GFR and renal plasma flow (RPF) decrease in preeclampsia, a serious hypertensive complication of pregnancy. Serial data derived in late pregnancy (LP) and >5 mo postpartum (PP) in 13 healthy controls and 10 preeclamptic women (13 and 5, respectively) returning PP for theoretical analysis of neutral dextran sieving curves (theta(D)), are presented and are used to calculate the key determinants of glomerular ultrafiltration. Normal LP hyperfiltration was associated with increases in RPF and the ultrafiltration coefficient (K(f)), as well as in the nondiscriminatory shunt pathway (omega(0)) and the SD of pore size (S). Preeclamptic LP showed the largest omega(0) and S values, indicating a loss of size-selectivity, accompanying reduced K(f) and RPF, both of which are implicated in the relative hypofiltration. Despite a 100-fold increase in urinary albumin excretion (UAE), LP preeclamptic theta(D) values were reduced for the equivalent neutral dextran (36A), providing indirect evidence for a loss of glomerular barrier charge-selectivity. All the determinants of GFR and all modeled parameters were comparable across both groups PP, strong evidence that preeclamptic glomerular dysfunction resolves.

The posterior pituitary hormone vasopressin is one of the principal endocrine regulators of fluid and electrolyte balance. Tests of posterior pituitary function are based on the physiology and pathophysiology of vasopressin, and involve studies that aim at defining the production and action of the hormone in response to fixed stimuli with reference to standard normal ranges.

In diabetes insipidus, the amount of water ingested and the quantity and concentration of urine produced needs to be carefully regulated if fluid volume and osmolality are to be maintained within the normal range. One of the principal mechanisms controlling urine output is vasopressin which is released from the posterior pituitary gland and enhances water reabsorption from the renal collecting duct. In diabetes insipidus, the excessive production of dilute urine, and the causes of this clinical picture can be divided into three main groups: the first is primary polydipsia where the amount of fluid ingested is inappropriately large; the second group is cranial diabetes insipidus where the production of vasopressin is abnormally low; and, the third group is nephrogenic diabetes insipidus where the kidney response to vasopressin is impaired. The history and examination may suggest an underlying explanation for diabetes insipidus but a range of baseline and more extensive investigations may be required before a diagnosis can be reached. These investigations are not without risk, and the results need to be interpreted carefully because children do not always segregate neatly into a particular diagnostic category on the basis of one test alone. Children with cranial diabetes insipidus typically respond to arginine vasopressin or its manufactured analogue, desmopressin, with an increase in urine osmolality and an associated reduction in urine output. Such children usually require neuroimaging to look for evidence of evolving CNS pathology, such as an intracranial tumour. Vasopressin "replacement" with desmopressin is the treatment of choice in patients with cranial diabetes insipidus although extreme caution is required when treating babies or small children because of the danger of fluid overload. Abnormal production of other pituitary hormones in children with CNS disease can also influence fluid balance. Nephrogenic diabetes insipidus can be due to abnormal electrolyte concentrations, therefore these should be measured as part of the initial assessment. In a small number of children the defect is a primary abnormality of the vasopressin receptor or one of the water channel proteins (aquaporins) involved in water transport. The treatment of these patients is difficult and typically involves therapy with a diuretic such as chlorothiazide, as well as indomethacin. These agents enhance urine osmolality by their effect on circulating volume and renal solute and water handling. The fluid intake of most young children with primary polydipsia can be safely reduced to a more appropriate level.

Objective: To investigate labour-associated changes in: 1. the myometrial contractile response to arginine vasopressin compared with oxytocin in vitro 2. fetal production of arginine vasopressin and 3. myometrial vasopressin V1a receptor mRNA., Design: The contractile response to vasopressin (compared with oxytocin) was investigated in paired myometrial strips in vitro. Blood was taken from the umbilical artery and vein at delivery and arginine vasopressin measured by radio-immunoassay. V1a receptor mRNA was determined by in situ hybridisation., Results: Myometrium was more sensitive to arginine vasopressin than oxytocin (P<0.05 for frequency, amplitude and activity integral in paired strips) after, but not before labour. There was a marked umbilical arteriovenous difference in arginine vasopressin concentration at delivery suggesting fetal production which was not influenced by labour. Myometrial vasopressin V1a receptor mRNA was not increased after the onset of labour., Conclusions: The human uterus is extremely sensitive to arginine vasopressin in vitro. Arginine vasopressin is produced by the fetus but fetal formation is not increased during labour.

Objective: To test the hypothesis that decreases in and maintenance of a new steady state in plasma osmolality and sodium level in ovarian hyperstimulation syndrome (OHSS) are due to altered osmoregulation of arginine vasopressin secretion and thirst., Design: Prospective study., Setting: IVF-ET program in a university-based assisted reproductive treatment center., Patient(s): Eight women undergoing superovulation for IVF-ET and five women with normal menstrual cycles., Intervention(s): Two-hour infusion of 5% saline on day 3 or 4 after hCG administration in patients undergoing IVF or in the early luteal phase in controls. A 5% saline infusion test was done on day 10 after hCG administration in one patient with OHSS and one patient without OHSS, both of whom were undergoing IVF., Main Outcome Measure(s): Comparison of changes in thresholds for thirst and plasma vasopressin to plasma osmolality. Changes in urine osmolality, plasma electrolytes, hemoglobin level, and hematocrit were assessed at baseline and during infusion of 5% saline., Result(s): The sensitivity of the changes in arginine vasopressin secretion and thirst after 5% saline infusion was similar in IVF patients on day 3 or 4 after hCG and controls. However, the osmotic threshold was significantly lower by 6 mOsm/kg in IVF patients. By day 10 after hCG, the lower osmotic thresholds for arginine vasopressin secretion and thirst persisted in OHSS, although the sensitivity to arginine vasopressin secretion was markedly reduced., Conclusion(s): The osmotic thresholds for arginine vasopressin secretion and thirst are reset to lower plasma osmolality during superovulation for IVF-ET. This new lower body tonicity is maintained until at least day 10 after hCG in OHSS. Decreases in plasma osmolality and plasma sodium levels in OHSS are due to altered osmoregulation rather than electrolyte losses; correction of apparent "electrolyte imbalance" in OHSS is therefore inappropriate.

To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P<0.001) rise in urine osmolality in controls (67.6+/-10.7 to 720+/-31.1 mosmol/kg, P<0.001) than in IDDM patients (64.3+/-21.6 to 516.7+/-89.3 mosmol/kg, P<0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8+/-105.6 fmol/mg creatinine) than in IDDM (462.0+/-94.9 fmol/mg creatinine, P = 0. 003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A(Ic) (r = -0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A(Ic) >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8+/-49.0; A, 640.0+/-137.2 mosmol/kg, P<0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 +/-69 to 375+/-280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.

Although autoimmune Addison's disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964de113) in United Kingdom subjects with APS1, by using the restriction enzymes Bst7II and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.

It is not known whether human labour is associated with increased fetal oxytocin production or transfer of oxytocin across the placenta. Previous reports are contradictory, due in part, to the influence of maternal analgesia on fetal production. We determined plasma oxytocin concentration in the umbilical artery and vein of women after vaginal delivery and after caesarean section with general anaesthesia before or after the onset of labour. The results demonstrate that fetal production of oxytocin is not influenced by general anaesthesia, thus enabling comparison of labour and nonlabour samples at caesarean section. Labour was not associated with an increase in fetal oxytocin production. Oxytocin was also measured in the umbilical artery and vein during maternal oxytocin infusion to assess placental transfer. The results do not support transfer of oxytocin across the placenta in women.

We present a case of a 40-year-old woman who developed major cardiovascular complications during anaesthesia for an elective clipping of a cerebral arteriovenous malformation. Postoperative investigation confirmed the diagnosis of an adrenal phaeochromocytoma. In retrospect, it became apparent that she had experienced a series of potentially life-threatening events over a 20-year period all of which are known complications of phaeochromocytoma. This case highlights the importance of investigating young patients who have unexpected and unexplained cardiovascular events during anaesthesia and surgery.

Aims/hypothesis: To test the hypothesis that subnormal thirst sensation could contribute to the development of the hypernatraemia characteristic of hyperosmolar coma, we studied osmoregulation in survivors of hyperosmolar coma., Methods: Eight survivors of hyperosmolar coma, eight control subjects with Type II (non-insulin-dependent) diabetes mellitus and eight healthy control subjects underwent water deprivation during which measurements of thirst, plasma osmolality and vasopressin were taken., Results: Water deprivation caused greater peak plasma osmolality in the hyperosmolar coma group (301.7 +/- 2.7 mmol/kg) than in Type II diabetic (294.3 +/- 3.2 mmol/kg, p < 0.01) or control group (296.9 +/- 3.0 mmol/kg, p < 0.01) and a greater increase in plasma vasopressin concentration (hyperosmolar coma, 5.8 +/- 1.3 pmol/l, Type II diabetes, 1.8 +/- 1.3 pmol/l, p < 0.001, control subjects, 2.2 +/- 1.8 pmol/l, p < 0.001). Thirst ratings were lower following water deprivation in the hyperosmolar coma group (3.5 +/- 0.8 cm) than in Type II diabetes (7.7 +/- 1.6 cm, p < 0.001) or control subjects (7.4 +/- 1.3 cm, p <0.001), and the hyperosmolar group patients drank less in 30 min following water deprivation (401 +/- 105 ml) than Type II diabetic (856 +/- 218 ml, p < 0.001) or control subjects (789 +/- 213 ml, p < 0.001)., Conclusion/interpretation: Survivors of hyperosmolar coma have subnormal osmoregulated thirst and fluid intake, which might contribute to the hypernatraemic dehydration typical of the condition.

The elderly are at increased risk of changes in body water and sodium, often accompanying comorbid disease states, which are associated with increased mortality. The clinical assessment of the hydration status of an elderly patient is difficult and the elderly care physician relies on both the clinical picture and laboratory investigation. Although still contentious, research suggests that the elderly may appreciate thirst less readily. However, healthy elderly may be able to produce an enhanced vasopressin response to osmotic stimulation compared to their younger counterparts, possibly in response to reduced renal function. The changes in these systems, when combined with coincident disease, place elderly patients at risk of water imbalance and electrolyte disturbance.

Aim: To examine the effect of intravascular volume expansion for the treatment of hypovolaemia in sick preterm neonates., Methods: An intravenous infusion of 20 ml per kg of 4.5% albumin was given to 14 preterm neonates. The effects on systolic blood pressure, central peripheral temperature difference (c-pT), and plasma arginine vasopressin concentration (pAVP) were measured., Results: Thirteen babies showed a rise in systolic blood pressure. The six babies with the highest initial values of pAVP and c-pT showed a fall in both of these after infusion. The babies with lower initial pAVP (below 4 pmol/l) showed either a rise (two) or no change (six) after albumin infusion. There was a significant correlation between c-pT and log pAVP before (r2 = 0.61; p < 0.05) and after infusion (r2 = 0.45; p < 0.05)., Conclusions: Plasma AVP concentration is related to c-pT in unwell preterm newborns. This study suggests that clinical assessment of hypovolaemia in preterm newborns is poor and could be improved by using c-pT.

Aim: To examine the effect of intermittent positive pressure ventilation (IPPV) on plasma arginine vasopressin concentration (pAVP) in preterm neonates., Methods: Thirty five neonates were classified, at the time of blood sampling, into three groups: unstable ventilated; stable ventilated; and stable non-ventilated. A modification of an extraction method for pAVP was developed for use in studies on very small babies, and sampling methods were compared., Results: The pAVP (median, range) was similar in the ventilated (1.85 pmol/l, 0.5 to 3.4) and non-ventilated (2.0, 0.5 to 2.6) stable babies, but was significantly higher (5.7, 1.1 to 25) in the unstable group. There was an inverse correlation between systolic blood pressure and pAVP concentration., Conclusions: This study shows that in preterm neonates pAVP concentration is affected by the clinical condition and blood pressure, but not by treatment with IPPV.

Patients with hypothalamic adipsic syndrome, especially in conjunction with diabetes insipidus, pose management difficulties. They are at risk of both under- and over-hydration. We present 4 patients with hypothalamic adipsic syndromes, due to different causes, illustrating the practical difficulties encountered in this condition. The principles of management, with a sliding scale of water intake related to changes in daily body weight, are discussed.

To further elucidate the role of atrial natriuretic peptide (ANP) in preeclampsia, its metabolic clearance (MCRANP) was determined concomitantly with its effects on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF). Ten untreated preeclamptic primigravidae (PET) were studied at 29-37 wk gestation and again 4 mo postpartum (PP). Basal plasma concentration of ANP was significantly increased in PET compared with PP (14.8 +/- 1.9 vs. 4.1 +/- 0.5 pmol/l, respectively; P < 0.0001). MCRANP in PET and PP was 5.0 +/- 0.8 and 4.9 +/- 0.5 l/min [not significant (NS)], respectively. In PET, infusion of ANP produced (basal vs. ANP) a natriuresis (UNa 0.14 +/- 0.02 vs. 0.28 +/- 0.04 mmol/min, P < 0.001) and an increase in GFR (97 +/- 7 vs. 106 +/- 8 ml/min, P < 0.05), with ERPF unchanged (609 +/- 24 vs. 634 +/- 29 ml/min, NS). In PP, ANP infusion also produced a natriuresis (UNa 0.20 +/- 0.02 vs. 0.25 +/- 0.02 mmol/min, P = 0.01), no significant change in GFR (109 +/- 7 vs. 102 +/- 4 ml/min), and a significant reduction in ERPF (514 +/- 22 vs. 409 +/- 18 ml/min, P < 0.0001). Analysis of variance demonstrated a greater natriuretic effect of ANP in PET compared with PP (P < 0.05), similarly a significant difference in the effect of ANP on ERPF (P < 0.01) and GFR (P < 0.05) was seen but not on filtration fraction (P = 0.35).

A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range < 450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to > 100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

We report the case of a patient who developed severe hypernatraemic dehydration following a head injury. Ten years previously he had been diagnosed to have lithium-induced nephrogenic diabetes insipidus, and lithium therapy had been discontinued. He remained thirsty and polyuric despite cessation of lithium and investigations on admission showed him to have normal osmoregulated thirst and vasopressin secretion, with clear evidence of nephrogenic diabetes insipidus. Lithium induced nephrogenic diabetes insipidus is considered to be reversible on cessation of therapy but polyuria persisted in this patient for ten years after lithium was stopped. We discuss the possible renal mechanisms and the implications for management of patients with lithium-induced nephrogenic diabetes insipidus.

At the time of cardiac transplantation all nerves from the donor ventricles are cut. These nerves may regrow, but there is no method of measuring any regrowth. Arginine vasopressin (AVP) release was studied during hypotension induced by head-up tilt and lower body negative pressure (LBNP) in transplant recipients and in normal controls. Subjects were tilted to 60 degrees for up to 60 min or until symptomatic. Lower body negative pressure (40 mmHg) was applied for 10 min after 30 min rest. Seven of 17 transplant recipients and 11 of 12 controls became symptomatic during tilt testing, and 9 of 12 controls and 9 of 17 transplant recipients became symptomatic after 10 min of LBNP. Symptoms during tilt did not predict symptoms during LBNP. Resting AVP levels were similar but osmolality was greater in transplant recipients. Resting haematocrit was reduced, and atrial natriuretic peptide increased in transplant recipients, suggesting increased plasma volume. In symptomatic subjects, changes in humoral concentrations were similar when compared between transplant recipients and normals, except that the rise in AVP at the time of symptoms was reduced in transplant recipients, with a comparable drop in blood pressure consistent with persistent cardiac afferent denervation in a subset of transplant recipients.

We report a 63-year-old woman who presented with clinical and biochemical features of ACTH dependent Cushing's syndrome secondary to a primary ovarian carcinoma. The tumour produced very high levels of ACTH precursors, consistent with defective POMC processing.

Objective: Our purpose was to determine whether human pregnancy alters the metabolic clearance and natriuretic effect of atrial natriuretic peptide., Study Design: The metabolic clearance rate of atrial natriuretic peptide (ANP 99-126) was measured serially in nine normotensive primigravid women studied in early and late pregnancy and again 4 months post partum (nonpregnant). Metabolic clearance of atrial natriuretic peptide was determined by use of a two-tier constant infusion technique (6 and 12 ng/kg/min, respectively). Sodium excretion was determined from 30-minute urine collections taken before and during infusion of atrial natriuretic peptide at both 6 and 12 ng/kg/min., Results: Basal plasma atrial natriuretic peptide levels increased with gestation: in early pregnancy 18.0 +/- 2.7 pg/ml, in late pregnancy 22.6 +/- 4.2 pg/ml, and post partum 19.5 +/- 3.6 pg/ml. Infusion of atrial natriuretic peptide at 6 and 12 ng/kg/min produced two distinct physiologic plasma levels of atrial natriuretic peptide. The metabolic clearance rates for nonpregnant women and those in early and late pregnancy at 6 and 12 ng/kg/min, respectively, were 3.4 +/- 0.4 and 2.9 +/- 0.4 L/min at plasma atrial natriuretic peptide levels of 86.2 +/- 13.2 and 179.8 +/- 42.5 pg/ml, respectively, 4.3 +/- 0.5 and 4.3 +/- 0.5 L/min at plasma atrial natriuretic peptide levels of 61.1 +/- 4.9 and 131 +/- 20.9 pg/ml (p < 0.01, nonpregnant vs early pregnancy), and 3.8 +/- 0.6 and 3.8 +/- 0.5 L/min at plasma atrial natriuretic peptide levels of 72 +/- 8.0 and 136 +/- 18.3 pg/ml (p < 0.05, nonpregnant vs late pregnancy), respectively. Infusion of atrial natriuretic peptide produced natriuresis in both pregnant and nonpregnant states; sodium excretion (basal to atrial natriuretic peptide infusion at 12 ng/kg/min) increased from 133 +/- 19 to 207 +/- 18 mumol/min, 129 +/- 21 to 374 +/- 35 mumol/min, and 128 +/- 20 to 221 +/- 33 mumol/min in nonpregnant women and those in early and late pregnancy, respectively., Conclusions: The metabolic clearance of atrial natriuretic peptide increased by 16 weeks' gestation and remained elevated thereafter. There appears to be no attenuation of the natriuretic effect of infused atrial natriuretic peptide in normotensive human pregnancy.

The effect of infused atrial natriuretic peptide (ANP) on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) was studied in 12 normotensive primigravidae at 32 wk gestation [late pregnancy (LP)] and again 4 mo postpartum [nonpregnant (NP)]. Three 20-min steady-state (renal) clearances of inulin and p-aminohippurate were used to measure GFR and ERPF, respectively, before and after infusion of ANP at 2 pmol.kg-1.min-1. Basal plasma ANP (pANP) was increased in LP compared with NP [7.8 +/- 0.6 vs. 3.3 +/- 0.4 pmol/l (P < 0.0001), respectively]. In LP, infusion of ANP increased pANP from 7.8 +/- 0.6 to 21.8 +/- 1.4 pmol/l (P < 0.00001), which produced a natriuresis [UNa of 0.18 +/- 0.02 vs. 0.25 +/- 0.03 mmol/min (P = 0.03), respectively], with no change in GFR (153 +/- 13 vs. 142 +/- 8 ml/min, P = 0.16) but a significant reduction in ERPF (766 +/- 52 vs. 660 +/- 31 ml/min, P = 0.002). In NP, ANP infusion increased pANP from 3.3 +/- 0.4 to 27.7 +/- 2.5 pmol/l (P < 0.00001), which produced no significant natriuresis [UNa of 0.22 +/- 0.07 vs. 0.26 +/- 0.09 mmol/min (P = 0.15), respectively] and no change in GFR (87 +/- 3 vs. 89 +/- 3 ml/min), but again a reduction in ERPF (486 +/- 17 vs. 414 +/- 9 ml/min, P < 0.001).

Objective: The best dynamic test for the assessment of the hypothalamic-pituitary-adrenal axis and the interpretation of the cortisol levels, remain a matter of controversy. We aimed to establish normal ranges with current assays, for both the short Synacthen (SST) and insulin stress tests (IST) and then to use these data to examine whether the SST can satisfactorily substitute for the IST in assessment of the hypothalamic-pituitary-adrenal axis., Design: Thirty SSTs and 27 ISTs were performed on different healthy volunteers. The results of all paired tests performed on patients in the last three years are reviewed., Setting: Programmed Investigation Unit., Subjects: Fifty-seven healthy volunteers and 166 patients., Main Outcome Measures: Basal serum cortisol concentration and cortisol values obtained at 30 and 60 minutes during the SST compared to the maximum obtained with adequate hypoglycemia (plasma glucose < 2 mmol/l) during an IST., Results: From normal data the mean-2SD 30-minute value during the SST was 392 nmol/l and 60-minute value was 497 nmol/l. The maximal cortisol response (mean - 2SD) during the IST was 519 nmol/l. Sixty patients failed the IST, none of whom had a basal cortisol > 450 nmol/l and only six (10%) had a 30-minute cortisol value > 600 nmol/l. The 30-minute value provided a better index than the 60-minute value. The basal, 30 and 60-minute values during the SST all correlated positively and significantly with the maximal cortisol on IST. The correlations persisted for all microadenomas and macroadenomas secreting prolactin, gonadotrophins or growth hormone, patients undergoing either pre or post-adenomectomy evaluation, and in those patients who had received long-term steroids provided that the medication had been reduced and stopped two days prior to admission., Conclusions: Using a 30-minute cortisol value > 600 nmol/l as a cut-off, the short Synacthen test provides a suitable substitute for the insulin stress test. Adopting this policy will decrease the number of insulin stress tests performed by one-quarter and thus provide a substantial saving without detriment to patient care.

This article reviews critically the investigation of polyuric states, hyponatremia with particular emphasis on the syndrome of inappropriate antidiuretic hormone secretion, and primary hyperaldosteronism. Details of some essential tests are given with comments on interpretation of results.

Objective: There have been anecdotal reports of increased maternal thirst during breast feeding, but the physiological mechanisms remain obscure. We have assessed and quantified the stimulation of maternal thirst during breast feeding (suckling), and correlated the changes with plasma oxytocin and vasopressin levels., Design: A within subject design was used with each subject acting as her own control. Each subject participated in a suckling period and a control non-suckling period the order of which was counterbalanced., Subjects: Ten healthy breastfeeding women ranging from 28 to 52 days post partum., Measurements: Thirst (assessed by a visual analogue scale), plasma vasopressin, plasma oxytocin (pOT), plasma osmolality and haematocrit, blood pressure, volume of milk transferred to baby, volume of water drunk immediately following each experimental period., Results: Thirst increased significantly more over a suckling period than over a comparable control period (P = 0.013). The peak level of thirst correlated with the volume of water consumed to satiety following the suckling period (r = 0.7, P = 0.024). As expected, pOT levels rose significantly in response to suckling (P < 0.001). Six women demonstrated a close relation between thirst and oxytocin response during the suckling period. Despite significant changes in thirst during suckling there was no increase in plasma vasopressin or in osmoregulatory parameters., Conclusions: This study confirms that suckling is a potent stimulus to thirst in the mother, and is not associated with vasopressin release or dependent on any measurable alterations in osmoregulation. What actually stimulates thirst during breast feeding remains unknown, but there are two potential explanations for these observations: (1) suckling sends nerve impulses to the paraventricular and supraoptic nuclei in the hypothalamus which may have afferents within the central nervous system which stimulates a thirst response simultaneous with oxytocin release; (ii) a learned anticipation of thirst may be occurring in a situation associated with expectant fluid loss to preserve homeostasis.

Background: Some patients with hypoxaemic chronic obstructive pulmonary disease (COPD) develop sodium and water retention and a subclinical autonomic neuropathy. The possibility that these might be associated has been investigated., Methods: The ability of 24 patients with COPD to excrete a 6 ml/kg 2.7% intravenous saline or 15 ml/kg oral water load was studied and changes in plasma electrolyte levels, osmolality, plasma aldosterone and vasopressin levels, urinary volume and sodium content, glomerular filtration rate, renal blood flow, and cardiovascular autonomic nerve function were measured. Patients were divided into groups of eight: those in group A (controls) had mild COPD with a Pa02 of > 9 kPa and no oedema, patients in group B were more hypoxaemic but had never been oedematous, whilst those in group C were hypoxaemic and mildly oedematous at the time of the study., Results: Patients in groups B and C excreted less sodium and water during saline loading and a lesser proportion of the water load. Patients in group C had a reduction in renal blood flow and glomerular filtration rate and all had a subclinical autonomic neuropathy, which was also found in three patients in group B. Their plasma aldosterone level was raised but did suppress appropriately on saline loading. Vasopressin levels were abnormally raised for the osmolality in patients in group C and in those with autonomic dysfunction throughout the water load and at 240 minutes after the salt load. Sodium and urine excretion was highly correlated with autonomic dysfunction, aldosterone levels at time zero, and renal blood flow. The 11 patients with autonomic dysfunction were more likely to be oedematous, more hypoxaemic, excreted much less urine and sodium, had lower glomerular filtration rate and renal blood flow, and higher aldosterone and vasopressin levels than the remaining patients., Conclusions: In patients with COPD the inability to excrete sodium and water is multifactorial. This is the first study to show that autonomic dysfunction is at least associated and might play an important part in the impaired sodium and water homeostasis seen in patients with severe COPD.

Objective: Osmoregulation is normally studied using a 5% saline infusion. This may be deleterious in fluid overloaded patients. Twenty per cent mannitol is another osmotic stimulant. This study aimed to compare 20% mannitol infusion with 5% saline as an osmotic stimulant to thirst and vasopressin secretion in normal volunteers., Design and Patients: Eight healthy volunteers studied on 2 occasions in random order. Each study involved a 2-hour infusion period of either hypertonic (5%) saline (0.06 ml/kg/h) or hypertonic (20%) mannitol (0.07 ml/kg/h)., Measurements: Plasma vasopressin (pVp), plasma sodium, plasma osmolality (pOsm), haematocrit (HCT), blood pressure, thirst, blood glucose and volume drunk at end of infusion., Results: Five per cent saline infusion stimulated significantly higher levels of pOsm, pVp and thirst than 20% mannitol. Plasma sodium rose significantly during 5% saline infusion and fell during 20% mannitol infusion. HCT fell and mean arterial pressure rose in both infusions but the changes were not clinically significant. Piecewise linear regression analysis defined the overall threshold for pVp release for the two solutions as 5% saline, 292 mosm/kg and 20% mannitol, 291 mosm/kg, and the post threshold slope as 5% saline, 0.46 pmol/l pVp per mosm and 20% mannitol, 0.30 pmol/l pVp per mosm. The threshold for thirst onset was 5% saline, 291 mosm/kg and 20% mannitol, 290 mosm/kg, and the post threshold slope, 5% saline, 0.58 cm thirst per mosm and 20% mannitol, 0.28 cm thirst per mosm. The differences between the calculated osmotic thresholds and slopes post threshold for the two infusions were not significant for the pVp versus pOsm relationship. The difference between the cumulative volume drunk following the two infusions did not reach statistical significance. Mannitol caused a significant diuresis., Conclusions: Twenty per cent mannitol infusion is an effective osmotic stimulant to thirst and vasopressin release in normal individuals, but is less potent than 5% saline infusion.

A new method is described for the estimation of blood volume in the rat using 113mIndium chloride. No in vitro labelling step is necessary as the isotope binds specifically to transferrin in vivo. Under anaesthesia, an external jugular vein was cannulated for blood sampling and indium chloride injected directly into a lateral tail vein. Three blood samples of 0.2 ml were taken at short intervals and radioactivity measured under standard conditions. Blood volume was found to be 7.46 +/- 0.14 (mean +/- SEM) ml/100 g body weight. Repeating the study of 5 animals gave similar values for blood volume on the 2 occasions (7.23 +/- 0.26 and 6.95 +/- 0.23 ml/100 g, P > 0.05). The new technique was compared with established methods using 51Cr labelled red blood cells and 125Iodinated albumin. In each animal, the 113mIndium technique produced values approximately 10% higher than those obtained using the sum of plasma and red cell mass, in keeping with the known difference between whole body and large vein haematocrit (Indium, 7.20 +/- 0.19 and Iodine with Chromium, 6.40 +/- 0.34 ml/100 g). Data on blood volume determined using 125Iodine as the tracer on these same animals were identical (Indium, 7.20 +/- 0.19 and iodine, 7.16 +/- 0.34 ml/100 g). The method is simple to perform and appears to be at least as accurate and reproducible as established methods for measuring blood volume.

We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone.

To explore the hypothesis that serotonin (5-HT) is important in osmoregulated arginine vasopressin (AVP) secretion, we administered (i.p.) fluoxetine (FL) a 5-HT reuptake inhibitor (10 mg/kg body weight), ritanserin (RIT), an antagonist at the 5-HT2 and 5-HT1c receptor subtypes (1 mg/kg body weight), 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2 receptor agonist (1 mg/kg body weight) or vehicle to rats 30 min before they were given an osmotic challenge. Rats received distilled water, normotonic saline (150 mmol NaCl/l) or hypertonic saline (500 mmol NaCl/l) (20 mg/kg i.p.) and were killed 30 min later. The osmotic stimulus alone produced significant (P < 0.001) effects on plasma osmolality and plasma sodium but FL, RIT and DOI did not have any significant effect on this stimulus. FL had no significant effect on the osmotic threshold of AVP release but significantly (P < 0.001) increased basal AVP secretion from 1.6 +/- 1.0 to 3.1 +/- 1.3 (S.E.M.) pmol AVP/l and significantly (P < 0.001) increased the AVP response to changes in plasma osmolality: vehicle-treated, 0.7 +/- 0.4; FL-treated, 1.7 +/- 0.2 pmol AVP/l per mOsm per kg. Neither RIT nor DOI had any significant effect on basal or stimulated AVP secretion. In a second study, RIT was administered 60 min i.p. prior to FL i.p. (doses as above), which was followed 30 min later by a hypertonic stimulus i.p. and rats were killed 30 min after hypertonic saline treatment. RIT had no significant effect on the AVP response to plasma osmolality and did not significantly alter the FL-augmented AVP response, suggesting that neither the 5-HT2 nor the 5-HT1c receptors are involved in the response of AVP to FL. We conclude that FL modulates osmoregulated AVP secretion but that the mechanism of this is unknown and is apparently not through the 5-HT2 or 5-HT1c receptor subtypes.

Objective: To determine the effect of early labour, maternal analgesia and fetal hypoxia on circulating fetal oxytocin concentrations., Design: Prospective observational study., Setting: Delivery suite in a District General Hospital., Subjects: Fifty women at term who did not require oxytocin administration or more than one form of analgesia. Study groups: vaginal delivery with (1) no analgesia, (2) pethidine, or (3) epidural analgesia. Caesarean section under regional analgesia (4) prior to, and (5) after the onset of labour., Interventions: Samples of blood were collected from the umbilical artery (UA) and umbilical vein (UV) immediately after fetal delivery prior to placental separation or oxytocic administration., Main Outcome Measures: Plasma oxytocin (OT) concentration, umbilical vein pH, cystine aminopeptidase activity., Results: The geometric mean UA-OT was significantly greater than UV-OT in all groups and was not altered by pethidine; however, epidural administration increased the UA-UV difference. The UA-UV difference at caesarean section was not significantly altered by the onset of labour. There was no correlation between UV pH and UA-UV plasma oxytocin. Cystine aminopeptidase activity was not detectable in UA and UV plasma., Conclusions: Fetal OT production is increased by epidural but not by pethidine analgesia. It is not influenced by the onset of labour or fetal hypoxia.

Since elderly people are prone to develop both hypo- and hyper-natraemia, we have investigated the biochemical and hormonal responses to overnight (9 h) abstinence from fluids and subsequent oral water load (20 ml/kg) in a group of healthy elderly (E) (mean age 68 years) and young (Y) (mean age 28 years) volunteers. The elderly subjects had significantly higher baseline plasma osmolality (E 293.5 +/- 0.5, Y 290.5 +/- 0.8 mOsm/kg, p < 0.05) but lower urinary osmolality (E 508 +/- 47, Y 842 +/- 52 mOsm/kg, p < 0.001) and lower plasma vasopressin (E 0.5 +/- 0.1, Y 2.3 +/- 0.6 pmol/l, p < 0.001) than the young. There was a significant difference in the mode of excretion, particularly maximum free water clearance (E 6.0 +/- 0.6, Y 10.1 +/- 0.8 ml/min) but no difference in the overall ability to excrete the water load (at 4 h E 93 +/- 8%, Y 92 +/- 5%, p > 0.05). The biochemical and hormonal results suggest that the elderly subjects were in a state similar to partial cranial diabetes insipidus which may predispose them to dehydration and hypernatraemia. The reduction in maximum free water clearance may predispose them to hyponatraemia if excess fluid is administered.

1. The metabolic clearance rate of arginine vasopressin was determined using a constant infusion technique in normal subjects and patients with chronic renal failure immediately before commencing dialysis. Endogenous arginine vasopressin was suppressed in all subjects before the infusion with a water load. 2. Plasma arginine vasopressin concentrations were determined using a sensitive and specific radioimmunoassay after Florisil extraction. The detection limit of the assay was 0.3 pmol/l, and intra- and inter-assay coefficients of variation at 2 pmol/l were 9.7% and 15.3%, respectively. 3. In normal subjects, the metabolic clearance rate was determined at two infusion rates producing steady-state concentrations of arginine vasopressin of 1.3 and 4.4 pmol/l. In the patients with renal failure, a single infusion rate was used, producing a steady-state concentration of 1.5 pmol/l. 4. At comparable plasma arginine vasopressin concentrations, metabolic clearance rate was significantly reduced in patients with renal failure (normal 1168 +/- 235 ml/min versus renal failure 584 +/- 169 ml/min; means +/- SD; P < 0.001). 5. Free water clearance was significantly reduced in normal subjects during the arginine vasopressin infusion from 8.19 +/- 2.61 to -1.41 +/- 0.51 ml/min (P < 0.001), but was unchanged in the patients with renal failure after attaining comparable plasma arginine vasopressin concentrations. 6. In normal subjects there was a small but significant fall in metabolic clearance rate at the higher steady-state arginine vasopressin concentration (1168 +/- 235 ml/min at 1.3 pmol/l versus 1059 +/- 269 ml/min at 4.4 pmol/l; P = 0.016).(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effect of atrial natriuretic peptide on osmotically stimulated thirst appreciation and consequent fluid intake was investigated in healthy man. 2. Six seated male subjects were studied on two occasions: synthetic alpha-human atrial natriuretic peptide (99-126) (2 pmol min-1 kg-1) or placebo (saline, 150 mmol/l NaCl) was infused intravenously for 105 min; 30 min after the start of atrial natriuretic peptide/placebo infusion, hypertonic saline (855 mmol/l NaCl) was infused (0.06 ml min-1 kg-1) for 60 min. Subjects were then allowed free access to water for the next 2 h; infusion of atrial natriuretic peptide/placebo continued for the first 15 min of the drinking period. 3. The plasma atrial natriuretic peptide concentration did not alter significantly during infusion of hypertonic saline and placebo; it rose to a steady state of 12.7 +/- 1.1 pmol/l (mean +/- SEM) during the infusion of atrial natriuretic peptide and hypertonic saline, and remained at this level during the first 15 min of the drinking period. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, similar increases in plasma osmolality (P less than 0.001) and plasma vasopressin concentration (P less than 0.005) occurred. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, thirst increased significantly over the time course of both studies (P less than 0.01), but the effect of atrial natriuretic peptide infusion compared with placebo infusion was to significantly decrease thirst at 60 min. 4. Drinking rapidly abolished thirst and vasopressin secretion before changes in plasma osmolality occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

A technique for complete oxytocinase inhibition has been combined with a rapid serial sampling strategy to determine plasma oxytocin concentrations in twelve women during the early and late first stage and in eight women throughout the second stage of labour. The progress of labour is not related to an increase in oxytocin concentration, uterine contractions are not associated with changes in plasma oxytocin concentration and hypocontractile labour does not appear to be the result of a deficit of oxytocin. The majority of patients do not demonstrate an increase in plasma oxytocin concentration during the second stage of labour; however, a minority produce a large surge immediately before delivery. The results do not support a role for oxytocin during spontaneous labour unless uterine activity is controlled by extremely low plasma hormone concentrations or the uterus becomes sensitive to a constant oxytocin concentration.

Objective: To examine the role of serotonin in pituitary hormone release by studying the effect of a specific 5HT2 receptor antagonist, ICI 169,369, on the ACTH, prolactin, growth hormone and AVP response to insulin-induced hypoglycaemia in healthy humans., Design: A double-blind, within-subject trial using a crossover design to compare the effect of placebo with two doses of ICI 169,369 on pituitary hormone responses to insulin-induced hypoglycaemia., Patients: Ten healthy subjects were studied in the low-dose (30 mg x 2) limb and 11 healthy volunteers in the high-dose (80 mg x 2) limb., Measurements: Plasma concentrations of prolactin, growth hormone, ACTH, cortisol and AVP, and blood glucose., Results: In the low-dose study, pretreatment with 30 mg ICI 169,369, 10 and 2 hours before the study, had no effect on the fall in blood glucose or the rise in plasma ACTH, prolactin, growth hormone, AVP or plasma cortisol following insulin injection, when compared with placebo. In the high-dose study the effect of a higher dose (80 mg) of ICI 169,369 on the pituitary hormone response to hypoglycaemia was compared with that of placebo. Although the fall in blood glucose was similar following drug (4.3 +/- 0.1 to 1.5 +/- 0.5 mmol/l, mean +/- SEM, P less than 0.001) and placebo (4.3 +/- 0.1 to 1.4 +/- 0.4 mmol/l, P less than 0.001), the rise in plasma AVP was lower (P less than 0.05) following pretreatment with drug (0.5 +/- 0.2 to 2.1 +/- 0.6 pmol/l, P less than 0.05) than with placebo (0.7 +/- 0.2 to 3.4 +/- 0.9 pmol/l, P less than 0.01)., Conclusions: The ACTH, prolactin, growth hormone and cortisol responses were unaffected by ICI 169,369. The data are compatible with an inhibitory effect of the serotonin antagonist ICI 169,369 on the AVP, but not the ACTH, prolactin or growth hormone response to insulin-induced hypoglycaemia in humans.