The effect of alpha human atrial natriuretic peptide on plasma volume and vascular permeability in normotensive subjects.

Low dose infusion of alpha human atrial natriuretic peptide (ANP) has been shown to cause a shift of intravascular fluid to the interstitial space. No studies have been reported on the effect of ANP on capillary permeability to plasma proteins. We studied the effect of low dose ANP (2.5 pmol/kg.min) or equal volume of saline control when infused over 90 min, on plasma volume, transcapillary escape rate of intravascular albumin, and the rate of reentry of albumin to the vascular space in eight normal subjects. Intravenous injection of 125I-human serum albumin was used for measurement of plasma volume and intravascular albumin escape rate. A significant ANP-induced fall in plasma volume (P < 0.01) was observed. Transcapillary escape rate of intravascular albumin when corrected for concurrent plasma volume changes showed a significantly greater escape during ANP infusion than during saline control (P < 0.05). The mean +/- SEM changes in plasma albumin concentration were +0.36 +/- 0.22 g/L.h during ANP infusion and -0.46 +/- 0.50 g/L.h during placebo. Plasma sodium, red cell volume, and urinary albumin and radioactivity remained unchanged. The mass of albumin reentering the circulation per hour showed no significant difference between the 2 days. In summary, low dose ANP infusion in healthy subjects caused a shift of plasma water and electrolytes from the circulation, with albumin escape as a secondary phenomenon.

Rickets in adult cystic fibrosis with myopathy, pancreatic insufficiency and proximal renal tubular dysfunction.

Rickets is reported in a 19 year old white man with cystic fibrosis in whom pancreatic and hepatic involvement was advanced. There was evidence of secondary hyperparathyroidism with proximal renal tubular acidosis, aminoaciduria, phosphaturia and hypophosphatemia. Treatment with oral pancreatic and parenteral vitamin D supplements led to full recovery of the rachitic syndrome and the proximal renal tubular dysfunction.

Plasma levels of atrial natriuretic peptide in hyperthyroidism.

We measured plasma atrial natriuretic peptide (ANP) levels in 17 patients with newly diagnosed thyrotoxicosis. ANP was elevated compared to a group of healthy controls and fell to normal after treatment. Plasma cyclic guanosine monophosphate was also raised in untreated patients. Elevated circulating levels of ANP may play a part in the haemodynamic changes of hyperthyroidism.

Prolactin and gonadal function.

PIP: Much information has been gathered on the role of human prolactin in both physiological and pathological lactation since it was identified in 1971. Although estrogens increase the number and activity of the prolactin-secreting cells, they block the action of prolactin on the breast. As a result, circulating prolactin levels rise 20-50 fold during pregnancy, but lactation does not start until estrogen levels have fallen after delivery. Prolonged breast feeding maintains high serum prolactin levels. After suckling there is an additional rise. These high serum prolactin levels act to impair fertility by several mechanisms: the ovaries are resistant to gonadotropin stimulation; the frequency of pulsatile pituitary gonadotropin secretion is reduced, and there is suppression of the normal pre-ovulatory gonadotrophin surge in response to rising estradiol levels. The contraceptive effect of lactation has proved unreliable in individual women. Small amounts of prolactin circulate in males and non-pregnant females but have no identified function. Sustained hyperprolactinemia causes galactorrhea and hypogonadism in both sexes: amenorrhea or infertility in females and relative or absolute impotence in males. Sustained hyperprolactinemia is most often the result of a prolactin-secreting pituitary tumor. The management of hyperprolactinemic patients calls for consideration of the endocrine abnormalities and of the pituitary tumor if 1 has been found.^ieng

Halothane-related hepatitis. A clinical study of twenty-six cases.

Twenty-six patients are described who had otherwise unexplained hepatitis after halothane anaesthesia. Twenty-four (92 per cent) had multiple exposures, and 11 (42 per cent) died. In eight patients a characteristic pattern of delayed postoperative pyrexia has been found. Obesity was common, but the clinical features and complications were those of any severe hepatitis. Obesity, early onset of jaundice after anaesthesia, and low thrombotest, were associated with a fatal outcome. None of those who were followed up after recovery developed clinical or biochemical evidence of chronic liver disease. The differential diagnosis of postoperative jaundice is discussed, and it is shown that halothane patients with hepatic encephalopathy are significantly older (25.4 plus or minus 11.6 years) than those referred to this unit with viral hepatitis of equal severity (34.1 plus or minus 16.4 years). Unexplained jaundice or delayed pyrexia after a previous administration of halothane should be a contraindication to its further use.

Different opioid mechanisms are involved in the modulation of ACTH and gonadotrophin release in man.

Both the pituitary-adrenal axis and the pituitary-gonadal axis are under the tonic inhibitory control of endogenous opioid peptides in man. However, the precise opioid receptor involved in the modulation of these hormones remains unknown. The effect of a dose of intravenous naloxone on serum levels of luteinising hormone (LH), follicle-stimulating hormone (FSH) and plasma cortisol was therefore investigated in ten normal subjects. In the male subjects, naloxone at a dose of 25 micrograms/kg caused a significant increase in serum LH and FSH; no increase in response was seen at the two higher doses (100 micrograms/kg and 250 micrograms/kg). The lowest dose (6 micrograms/kg) caused no change in serum LH and FSH. In the female subjects, tested in the early follicular phase of their cycles, no dose of naloxone significantly increased circulating gonadotrophins. In both male and female subjects, naloxone only stimulated a rise in serum cortisol at the highest dose (250 micrograms/kg). A second study in six normal subjects demonstrated that the rise in cortisol with the highest dose of naloxone was secondary to a rise in plasma ACTH. It is concluded that the opioid receptor(s) controlling gonadotrophin release in man are naloxone-sensitive, and are probably epsilon-receptors; the naloxone insensitivity of the pituitary-adrenal axis suggests that these responses are modulated by kappa- or delta-receptors.

Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea an the response to bromocriptine therapy.

Serum gonadotrophin concentrations were measured every 15 min for 8 h in six patients before and at weekly intervals during initiation of bromocriptine treatment of hyperprolactinaemic amenorrhoea. Before treatment mean gonadotrophin levels were similar to those found in the normal follicular phase, but LH secretion was characterized by infrequent pulses of large amplitude. In three subjects the patterns of LH pulsatility and serum oestradiol levels returned to normal within 7 days of starting bromocriptine. The other three subjects responded with an increase in the frequency of LH pulses and mean LH levels, but little rise in oestradiol. Thus some hyperprolactinaemic subjects have a defect in the ovarian response to endogenous gonadotrophin stimulation, which may persist for a few weeks after return of prolactin levels to normal. The restoration of a normal rate of LH pulsatility with bromocriptine can occur without any change in serum oestradiol concentration.

Posterior mediastinal venous masses in patients with portal hypertension.

Of 304 consecutive splenic venograms performed for suspected portal hypertension, oesophageal collateral veins were filled in 145. In seven patients massively dilated paraoesophageal collaterals were visible on the plain chest radiograph as a retrocardiac posterior mediastinal mass. Erect and supine radiographs have been compared in four patients, and the Valsalva and Mueller manoeuvres performed in one patient. The size of the masses was unchanged by these procedures, which were therefore of no value in differential diagnosis. The mass was still present immediately after portocaval anastomosis in one patient, but in another is no longer seen on radiographs taken seven years postoperatively. All seven patients also had submucosal oesophageal varices and therefore the barium swallow remains the most useful study to clarify the nature of a retrocardiac mass. Correct identification of pseudotumoural venous collaterals may avoid unnecessary further investigation.

The effect of naloxone on pulsatile gonadotrophin release in normal subjects.

The gonadotrophin response to naloxone infusion has been investigated in three adult males, and three adult females in the early follicular phase. The frequency of LH secretory episodes and the mean LH levels increased in both sexes. The data suggest that the pulsatile release of LH is under inhibitory opiate control.

The effect of renal transplantation on plasma atrial natriuretic peptide.

The changes in plasma atrial natriuretic peptide (ANP) were studied in four adult patients after cadaveric renal transplantation. In three patients who achieved good renal function, the correction of volume overload, as reflected by reduction in weight and right atrial pressure, was associated with a steady fall in plasma ANP and a parallel decrease in both fractional excretion of sodium and plasma cyclic guanosine monophosphate. The fourth patient, with severe acute rejection, developed severe peripheral oedema, and fractional sodium excretion remained low despite high values of ANP.

Prolactin pulsatility in patients with gonadal dysfunction.

Serum prolactin concentrations have been measured at 15 min intervals for 2 h on 240 occasions in 227 patients with symptoms which could have been due to hyperprolactinaemic gonadal dysfunction. Of the 227, 138 had at least one elevated random prolactin level. Overall, 22% showed no significant fluctuation in prolactin. In 38% the levels fell progressively from the start of the sampling period, this pattern being found most commonly in patients complaining of infertility. The sampling method yielded a basal or unstressed prolactin concentration which was, on average, 27% lower than random prolactin concentrations. However, a comparison with clinical data, the radiological appearances of the pituitary fossa, and the response to bromocriptine therapy, has shown that there is no predictive information in the multiple sampling results that could not have been obtained from two or three random prolactin levels.

The relationship between prolactin levels and clinical ratings in manic patients treated with oral and intravenous test doses of haloperidol.

Twelve manic patients were treated for 2 weeks with oral haloperidol; in 6 patients treatment commenced with intravenous haloperidol, and intravenous 'test' doses were given after 1, 3-5 and 14 days of oral medication. From 24 hours to 14 days baseline serum prolactin levels rose towards a plateau, as did the improvement in clinical ratings. After the first intravenous test doses of haloperidol, prolactin levels peaked at 1 hour; however, they fell to a low point at 24 hours, and no response to further test doses was seen for 3-5 days. The response tended to return at 14 days. The mechanisms underlying the changes in prolactin levels, and in clinical state, are discussed.

Use of bumetanide in the treatment of ascites due to liver disease.

Bumetanide is an effective diuretic for the treatment of ascites. Fifteen out of 17 patients with chronic liver disease responded satisfactorily and the incidence of hepatic encephalopathy and electrolyte disturbances was similar to that previously observed with frusemide. Colicky abdominal pain was reported in three patients but no other adverse effects were noted. An unexpected response was obtained in two patients who had diuresis without natriuresis.

The effects of low dose intravenous 99-126 atrial natriuretic factor infusion in patients with chronic renal failure.

The aim was to study the renal and hormonal effects of intravenous 99-126 atrial natriuretic factor (ANF) infusion in a mixed group of patients who had moderate to severe chronic renal failure (CRF) and who were not treated with dialysis. The peak mean plasma level of ANF achieved during the experiment was at the upper limit of an absolute range of basal values previously recorded in a larger group of patients with similar degrees of renal impairment. A significant tissue effect was confirmed by rises in plasma and urinary cyclic guanosine monophosphate, the 'second-messenger' of ANF. ANF infusion increased sodium excretion rate by a mean of 68% compared with a fall of 40% in a placebo group, and significant increases in urinary albumin excretion occurred during the peptide infusion. Thus, the high levels of plasma ANF found in CRF may have a role in the maintenance of sodium balance. In addition, the proteinuric effect may be detrimental to long-term renal function.

Effects of physiological infusion of atrial natriuretic factor on healthy subjects and patients with the nephrotic syndrome.

We followed the renal and hormonal effects of physiological intravenous infusions of atrial natriuretic factor (ANF) in 6 water-loaded patients with nephrotic syndrome and 7 healthy subjects. Two of the patients had impaired renal function, 3 had active sodium retention, and none took drugs. The ensuing natriuresis, increase in plasma and urinary cyclic guanosine monophosphate and suppression of the renin-aldosterone axis were similar in normals and nephrotics. In both groups, significant increases in filtration fraction (inulin/PAH clearance) were observed, and in the nephrotics, major increases also occurred in both the absolute and fractional urinary albumin excretion. The renal and hormonal responses to ANF are not impaired in the nephrotic syndrome.

Opiate mediation of amenorrhoea in hyperprolactinaemia and in weight-loss related amenorrhoea.

Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high-doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight-loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (less than 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight-loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight-loss amenorrhoea, there is an important endogenous opiate-mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.

Reduction of pituitary-tumour size in patients with prolactinomas and acromegaly treated with bromocriptine with or without radiotherapy.

69 patients with prolactin-secreting or growth-hormone-secreting pituitary tumours were treated with bromocriptine with or without pituitary irradiation and followed up for 6 months to 6 1/2 years. Of 26 patients with prolactinomas, 11 had external pituitary irradiation in addition to bromocriptine. There was evidence of shrinkage of the pituitary tumour (either a reduction in fossa size or loss of visual-field defects) in 6 of these patients (23%), 3 of whom had been treated with bromocriptine alone. Of 43 acromegalic patients, 30 received external pituitary irradiation. 8 (19%) showed evidence of shrinkage of the pituitary tumour, including 2 who had received no radiotherapy. 1 patient treated with bromocriptine alone showed striking reduction in the size of his suprasellar extension, as assessed by serial computed-tomography scans over 11 months. At the same time his visual-field defects resolved and his deficient corticotrophin and thyrotrophin reserves returned to normal. Bromocriptine can reduce the size of both prolactin-secreting and growth-hormone-secreting pituitary tumours, and this is of potential importance in their management.

The opioid control of LH and FSH release: effects of a met-enkephalin analogue and naloxone.

The effect of long-acting analogue of met-enkephalin (DAMME) and naloxone on gonadotrophin secretion has been investigated in man. In menopausal women DAMME induced a progressive fall in LH to approximately 60% of basal levels at 3 h, which was blocked by naloxone; there was a smaller fall in FSH that did not attain statistical significance. However, the LHRH-induced rise in LH and FSH in young male volunteers was unaffected by pretreatment with a high-dose DAMME infusion. Naloxone infusion in young male and female normal subjects produced a significant rise in both LH and FSH. Long-term infusion of naloxone appeared to increase the rate, and possibly the amplitude, of LH pulsatility. These results suggest that met-enkephalin-like opioid peptides exert a tonic inhibitory control of LH release in both menopausal and young subjects of both sexes. This control is most likely to be at the level of the hypothalamus, and involves modulation of pulsatile LHRH release.

Pregnancy in patients presenting with hyperprolactinaemia.

Ninety-two pregnancies occurred in 76 hyperprolactinaemic patients treated with bromocriptine. Half conceived within three months of attempted conception. There was no evidence of an increased rate of spontaneous abortion, fetal abnormality, or multiple pregnancy; the three twin pregnancies occurred in women who were additionally treated with clomiphene and human chorionic gonadotrophin. Thirty-one patients had radiological evidence of a pituitary tumour; 14 with major radiograph changes in the pituitary fossa or serum prolactin concentrations greater than 100 ng/ml received pituitary irradiation before conception. None of the latter showed evidence of enlargement of the tumour during pregnancy. In contrast two of the four patients with similar tumours but who were not irradiated developed visual field defects, one with gross destruction of the pituitary fossa. Prophylactic treatment to limit subsequent tumour expansion during pregnancy in patients with prolactinomas is indicated, and pituitary irradiation before conception appears to be a safe and effective method to achieve this goal.