THE ROLE OF PLASMA OSMOLALITY, ANGIOTENSIN II AND DOPAMINE IN VASOPRESSIN RELEASE IN MAN

A sensitive and specific radioimmunoassay for arginine vasopressin was used to compare the relative importance of changes in plasma osmolality, angiotensin II and dopamine in the regulation of vasopressin secretion in man. One hour after water loading plasma vasopressin fell from 0.40 to 0.06 pmol/l, while 8 h and 24 h fluid restriction resulted in a rise of vasopressin from 0.29 to 0.54 and 1.37 pmol/l respectively. In contrast neither dietary sodium deprivation, when plasma angiotensin II increased 5-fold, nor dopamine infusion, at a rate which increased circulating dopamine levels up to 244-fold, had any effect on basal plasma vasopressin values. These results confirm that, under physiological conditions, osmoregulation is the major mechanism controlling vasopressin release and suggests that circulating angiotensin II and dopamine have no significant part to play.     

EVIDENCE FOR THE PARTICIPATION OF ENDOGENOUS OPIOIDS IN THE SYMPATHOADRENAL RESPONSE TO HYPOGLYCAEMIA IN MAN

The effects of the long acting met-enkephalin analogue D-Ala2-MePhe4-met-enkephalin-O-ol (DAMME) and the opiate antagonist naloxone on the plasma catecholamine responses to insulin-induced hypoglycaemia have been investigated in two separate studies. DAMME depressed basal noradrenaline and adrenaline at 15 min, and blunted both the noradrenaline and adrenaline responses to hypoglycaemia. Naloxone did not alter basal plasma catecholamines, but caused a significant enhancement of the adrenaline response to hypoglycaemia. Neither DAMME nor naloxone altered the blood glucose response to insulin-induced hypoglycaemia. These data are consistent with an inhibitory modulation of endogenous opioids in the sympathoadrenal response to insulin-induced hypoglycaemia in man.     

ENDOGENOUS OPIOIDS INHIBIT OXYTOCIN RELEASE DURING NICOTINE-STIMULATED SECRETION OF VASOPRESSIN IN MAN

The effects of the opioid antagonist naloxone on the vasopressin (AVP) and oxytocin (OT) responses to nicotine were studied in male non-smokers (21-30 years old). Either saline (n = 6) or naloxone (4 mg bolus + 6 mg/h, n = 6) was infused i.v. during the study. After 60 min infusion the subjects smoked one high-nicotine content cigarette. Naloxone infusion for 60 min did not alter basal plasma AVP or OT levels. Smoking led to a significant rise in plasma vasopressin in both saline and naloxone-infused subjects (P less than 0.05). There was no significant difference in the plasma AVP response to smoking between the two groups. Saline-infused subjects did not show any change in plasma OT in response to smoking. Naloxone infusion was associated with a significant rise in OT from 1.3 +/- 0.1 pmol/l to 4.3 +/- 2.4 pmol/l 5 min after smoking (P less than 0.05). We conclude that there is endogenous opioid-mediated inhibition of OT which prevents its release when AVP is secreted in response to nicotine in man.     

MUSCARINIC CHOLINERGIC, BUT NOT SEROTONINERGIC MEDIATION OF ARGININE VASOPRESSIN RESPONSE TO METOCLOPRAMIDE IN MAN

The possibility that metoclopramide (MCP) stimulates arginine vasopressin (AVP) secretion in man through a serotoninergic and/or a cholinergic muscarinic pathway was studied. Twenty normal male subjects were tested with MCP (10 mg in an i.v. bolus) alone or in the presence of the 5HT1 serotoninergic antagonist metergoline (10 mg/day p.o. in five divided doses for 4 days), the 5HT2 receptor blocker ketanserin (10 mg i.v. 5 min before MCP) (n = 10), the M1 and M2 muscarinic antagonist atropine (1.2 mg i.v. just before MCP administration) or the M1 muscarinic receptor blocker pirenzepine (40 mg i.v. 10 min before MCP) (n = 10). AVP doubled in response to MCP. the MCP-induced AVP rise did not change after metergoline, ketanserin or pirenzepine administration, whereas it was abolished by atropine. Additional experiments were performed in order to evaluate the effect of 1.2 mg atropine, given alone, on circulating AVP levels and whether the effect of atropine on the AVP response to MCP depends on the amount of the muscarinic antagonist (dose-response study). For these purposes, atropine was given alone to the same subjects previously tested with MCP plus atropine; furthermore, eight additional male subjects were tested with MCP plus atropine given in doses ranging from 0.8 to 1.4 mg. The results of these additional studies failed to show an effect of atropine alone on AVP secretion and demonstrated a dose-related inhibition of MCP-induced AVP rise by increasing atropine administration from 0.8 mg to 1.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE CARDIOVASCULAR EFFECT OF VASOPRESSIN IN RELATION TO ITS PLASMA CONCENTRATION IN MAN AND ITS RELEVANCE TO HIGH BLOOD PRESSURE

The cardiovascular response and the changes of plasma arginine vasopressin (AVP) concentration following graded doses of AVP infused intravenously have been defined in six normal young men.The same measurements were also made during fluid deprivation in a patient with both nephrogenic diabetes insipidus and systemic hypertension. When, following AVP infusion, mean diastolic arterial pressure increased from 72·3 mmHg (SEM) to 78·2 mmHg (SEM) in the normal subject group, mean plasma AVP increased by 14·5 fmol/ml. When the patient was deprived of water, diastolic pressure increased, despite the fluid loss, from 90 to 105 mmHg, with a comparable increase of plasma AVP concentration of 15·3 fmol/ml. Further increases of plasma AVP concentration in either the normal subjects or in the patient were not associated with further increments of arterial pressure. We suggest that under pathophysiological circumstances in man plasma AVP concentrations may achieve levels which have a significant cardiovascular effect.     

PLASMA CORTICOTROPHIN-RELEASING FACTOR AND VASOPRESSIN RESPONSES TO HYPOGLYCAEMIA IN NORMAL MAN

The plasma cortisol, ACTH, AVP and corticotrophin-releasing factor (CRF) responses to insulin-induced hypoglycaemia were investigated in six normal men using a controlled, randomized, cross-over design. Hormonal concentrations were determined following insulin or saline injection. The maximum cortisol response was seen at 90 min while plasma ACTH, AVP and CRF concentrations peaked at 45 min following insulin injection. The responses of the insulin-treated and control groups were compared by assessing the incremental response from baseline (pre-injection) to peak hormone levels. A significant increase was observed for each hormone following insulin injection. The mean of the incremental responses between 30 and 120 min in each subject was also statistically greater for each hormone in the insulin-treated group when compared with the control group. These results are consistent with the hypothesis that AVP and CRF are both physiological mediators of ACTH secretion induced by a hypoglycaemic stress.     

EFFECT OF FENOLDOPAM ON THE ALDOSTERONE RESPONSE TO METOCLOPRAMIDE IN MAN

The effect of fenoldopam, a selective DA1-agonist, on the plasma aldosterone response to metoclopramide was studied in six hypertensive patients included in a multicentre double-blind placebo controlled cross-over study of the antihypertensive effects of fenoldopam. Fenoldopam significantly increased baseline plasma renin activity (PRA); baseline plasma aldosterone levels rose slightly. Baseline PRL and the PRL response to metoclopramide were not altered by fenoldopam. After metoclopramide, a significant increase of plasma aldosterone was observed during treatment with fenoldopam, as well as in the placebo-period. The peak values were not significantly different and occurred at 15 min during both treatment periods. These results indicate that fenoldopam does not reduce metoclopramide-induced aldosterone secretion and therefore suggest that the adrenal dopamine receptor is not identical to the vascular DA1 receptor.     

IMMUNOASSAY OF PLASMA VASOPRESSIN IN MAN

A radioimmunoassay for arginine vasopressin has been developed that is sensitive to the hormone at 1 pg/ml. When plasma was filtered on G-25 Sephadex, immunoreactivity was detected in three regions. Endogenous arginine vasopressin was the third and smallest of the peaks and was recovered just after the salt. By combining gel filtration with immunoassay, we have made precise measurements of arginine vasopressin in a few milliliters of plasma.     

THE EFFECT OF VASOPRESSIN INFUSION ON GLUCOSE METABOLISM IN MAN

Studies on intact animals and isolated rat hepatocytes have shown that arginine vasopression (AVP) stimulates glycogen phosphorylase to break down glycogen and raise plasma glucose concentrations. Since no similar work has been performed on healthy human adults, the effect of moderate (25 pmol/min) and high (75 pmol/min) dose AVP infusion on plasma glucose, intermediary metabolites, glucose kinetics, and circulating glucagon and insulin concentrations was investigated. After AVP infusion, plasma glucose rose from 4.9 +/- 0.1 to a peak of 5.7 +/- 0.2 mmol/l (P less than 0.001), but no changes in blood lactate, pyruvate, alanine, glycerol or 3-hydroxybutyrate concentrations were observed. The glucose rise was accounted for entirely by an increase in the rate of appearance of glucose from 11.19 +/- 0.43 to 13.38 +/- 0.63 mu mol/kg/min (P less than 0.001). Infusion of AVP also increased plasma glucagon concentrations from 38 +/- 8 to 79 +/- 20 pg/l (P less than 0.01). The hyperglycaemic effect of AVP may be mediated solely by stimulation of glucagon release, but we cannot exclude direct stimulation of glycogen phosphorylase activity.     

EFFECTS OF THE GABAERGIC AGENT SODIUM VALPROATE ON THE ARGININE VASOPRESSIN RESPONSES TO HYPERTONIC STIMULATION AND UPRIGHT POSTURE IN MAN

In order to evaluate the possible influence of GABAergic neurotransmission on the arginine vasopressin (AVP) response to osmotic and pressure volumetric stimuli, the GABAergic drug sodium valproate was administered by mouth (200 or 400 mg 16 h, 8 h and just before tests) to eight normal men before osmotic (i.v. infusion of 0.51 , NaCl for 2 h) and orthostatic (standing upright and maintaining an orthostatic position for 20 min) tests. In both experimental conditions, the AVP rise was significantly lower in the presence than in absence of sodium valproate. The maximum AVP responses in the control orthostatic and osmotic tests were respectively 2.3 and 2.5 times higher than basal levels. When 600 mg sodium valproate was given, the maximum AVP rise in response to hypovolaemic and osmotic stimuli were respectively 1.75 and 2.1 times higher than basal value. Similar results were obtained giving 1.2 g sodium valproate. These results suggest that in man a GABAergic pathway is involved in the AVP responses to hypovolaemic and hyperosmotic stimuli.     

THE RESPONSE OF THE BLOOD PRESSURE TO AN INFUSION OF ANGIOTENSIN IN PATIENTS WITH ESSENTIAL,MALIGNANT AND RENOVASCULAR HYPERTENSION

The angiotensin infusion test was performed on 251 patients. The results of the test were reproducible and not affected by hypotensive therapy in the case of patients with essential hypertension. The mean pressor dose was the same for normotensive subjects and for patients with hypertension with or without disease of the renal parenchyma. The mean pressor dose for patients with renal artery stenosis or malignant hypertension was increased. The pressor dose fell to normal when hypertension was controlled. Renal artery surgery improved hypertension in nine patients. The pressor dose was normal pre-operatively for four patients. The angiotensin infusion test was able to detect most patients with renal artery stenosis. The large number of false positive responses and the occurrence of some false negative responses reduce its value as a screening test.     

THE EFFECT OF ENDOGENOUS AND EXOGENOUS GONADOTROPHIN-RELEASING HORMONE ON THE PROLACTIN RESPONSE TO TRH

The prolactin response to TRH in a group of patients with Kallmann's syndrome was found to be significantly lower compared to a group of hypergonadotrophic hypogonadal patients. Since levels of testicular products are comparably low in both groups, we hypothesize that high endogenous LHRH production might be associated with an increased prolactin response to TRH. In support of this, we were, indeed, able to establish a positive correlation between the magnitude of the prolactin response to TRH and basal and LHRH-stimulated LH/FSH levels (the latter serving as an index of endogenous LHRH production) in: (1) eugonadal men, (2) men with Kallmann's syndrome, (3) oestrogen-treated agonadal men, (4) men with severely impaired spermatogenesis and, (5) agonadal men. A direct relation between LHRH and the prolactin response to TRH was demonstrated in a group of eugonadal men, the prolactin response to TRH being greater after prolonged LHRH pretreatment. We speculate that an increase of endogenous or exogenous LHRH might be associated with decreased hypothalamic dopamine secretion which could directly increase prolactin synthesis. Indirectly, decreased dopamine secretion could augment the potency of TRH in releasing prolactin.     

NALOXONE INCREASES THE NICOTINE-STIMULATED RISE OF VASOPRESSIN SECRETION IN MAN

Intravenous nicotine was administered to a group of six subjects during the concurrent intravenous infusion of either the opiate antagonist naloxone, or of saline. Nicotine stimulated vasopressin secretion in all subjects. Naloxone infusion increased both the plasma vasopressin response to nicotine and the resulting rise in urine osmolality.     

EFFECT OF OBESITY AND WEIGHT LOSS ON THE ARGININE VASOPRESSIN RESPONSE TO INSULIN-INDUCED HYPOGLYCAEMIA

Arginine vasopressin (AVP) response to insulin-induced hypoglycaemia was evaluated in 16 men with normal weight and in 9 obese men. Obese subjects were restudied following substantial weight loss. The decrease in blood glucose concentrations after insulin injection (0.15 U/kg i.v. bolus) had a similar pattern and magnitude in the normal controls and in the obese subjects both before and after weight loss. Basal plasma insulin concentrations in the obese patients were significantly higher than in the normal weight subjects, but were back to normal after weight reduction. During all tests, blood osmolality, haematocrit and blood pressure remained constant. The AVP rise during the insulin tolerance test (ITT) was significantly lower in the obese patients than in the normal controls. The mean peak plasma AVP level was 2.3 times higher than the basal value in the normal controls, but only 1.6 times in the obese patients. After weight loss, the obese men regained normal AVP responses during the ITT. These data indicate that a hypothalamic pituitary disorder affects the AVP response to insulin-induced hypoglycaemia in obese men.     

THE PLASMA ARGININE VASOPRESSIN RESPONSE TO INSULIN-INDUCED HYPOGLYCAEMIA IN CHILDREN WITH SHORT STATURE IS RELATED TO AGE AND THE ONSET OF PUBERTY

The plasma arginine vasopressin (AVP) response to insulin-induced hypoglycaemia was investigated in 27 children with short stature. None had diabetes insipidus. Six patients were excluded from further analysis because of hypothalamo-pituitary dysfunction. Of the remainder, 14 were prepubertal (Tanner 1) and seven were pubertal (Tanner 2-4). Both groups had similar height velocity retardation. There was a significant rise of AVP of 3.4 +/- 1.3 pmol/l at 30 min in the pubertal group (P less than 0.05) but no significant change in prepubertal patients. There was a significant relationship between chronological age and AVP response 30 min after insulin (r = 0.45, P less than 0.05) and a closer correlation between bone age and AVP response (r = 0.62, P less than 0.01). The data suggest that insulin-induced hypoglycaemia does not reliably stimulate AVP secretion in children and that this response is related to age and pubertal stage.     

THE HALF-LIFE OF ENDOGENOUS INSULIN AND C-PEPTIDE IN MAN ASSESSED BY SOMATOSTATIN SUPPRESSION

The in-vivo half-lives of insulin and C-peptide have been assessed in normal man by a method which examines the decline of endogenously produced insulin and C-peptide after somatostatin suppression of secretion. Venous blood samples were taken each minute from seven normal subjects: i.v. glucose (0.1 g/kg ideal body weight) was given over 1 min to stimulate secretion, followed by a bolus of 250 micrograms of somatostatin-14 and an infusion of a further 250 micrograms somatostatin-14 over the subsequent 30 min. Plasma samples were analysed for C-peptide, glucose and insulin. The initial mono-exponential half-lives over 8 min were 3.9 +/- 0.3 and 10.2 +/- 0.7 min respectively (mean +/- SEM), with subsequent slower declines. Log transformed insulin and C-peptide yielded biphasic declinations which were assessed by a two-pool model. The rate constant of clearance of insulin implied avid uptake, while the kinetics of C-peptide clearance were slower, and irreversible loss might be explained by glomerular filtration alone. The somatostatin suppression method of measuring hormone kinetics could be used for newly described hormones which are not available for in-vivo studies.     

THE INFLUENCE OF ADRENERGIC DENERVATION ON THE RESPONSE TO FEEDING OF THE GASTROENTEROPANCREATIC SYSTEM IN MAN

The effect of adrenergic denervation on the metabolic and hormonal response to a standard meal was studied in six tetraplegic subjects (pre-ganglionic sympathectomy) and compared with six normal subjects. Gastric emptying, estimated by isotope scintiscanning, was similar in both groups. Following the meal the mean blood glucose and plasma insulin rose in both groups, but were higher and remained elevated for longer in the tetraplegic subjects. There were no significant differences in the secretion of pancreatic glucagon, enteroglucagon, gastric inhibitory peptide (GIP) and neurotensin between the two groups. The mean basal and post-prandial levels of pancreatic polypeptide and motilin were significantly higher in the tetraplegic group. This study confirms the presence of mild glucose intolerance in tetraplegic subjects which is not explicable on the basis of abnormal insulin or pancreatic glucagon secretion or abnormal gastric emptying. In addition the results provide evidence for a sympathetic inhibitory influence on the secretion of pancreatic polypeptide and motilin in man, which is probably adrenergically-mediated.     

THE EFFECT OF PAIN ON PLASMA ARGININE VASOPRESSIN CONCENTRATIONS IN MAN

The effect of pain on plasma AVP concentration in man has previously been studied only during major surgery with general anaesthesia. Plasma AVP concentration (pAVP) and plasma osmolality (pOsm) were measured in thirty-six patients seen in a surgical emergency department complaining of pain and in fifty-one control subjects. No significant difference in pOsm was found, but pAVP was significantly higher in the emergency room patients in pain (M +/- SEM = 4.94 +/- 0.98 pmol/1 compared to 2.31 +/- 0.32 pmol/1 in control subjects, P less than 0.01). In the control subjects, age was found to have a low but significant inverse correlation with pAVP (r = 0.37, P less than 0.01). Chronic smoking was associated with significant elevation of pAVP (3.81 +/- 0.99 pmol/1 in smokers vs. 1.89 +/- 0.28 pmol/1 in non-smokers, P less than 0.02). Neither smoking nor age could account for the difference in pAVP between the pain and control groups. Thus, pain is a non-osmolar factor capable of elevating AVP in conscious man.     

SPECIFIC INHIBITION OF ALDOSTERONE RESPONSES TO ENDOGENOUS AND EXOGENOUS ANGIOTENSIN II BY SOMATOSTATIN

Aldosterone and renin responses to head-up tilt (60 degrees for 1 h) and angiotensin II infusions (2,5 and 10 ng/kg/min) 1 h later were compared in six normal subjects during infusions of somatostatin (3 micrograms/kg/min) or saline. The infusions were performed on separate days two weeks apart. The increase in aldosterone due to exogenous angiotensin II and orthostasis were significantly attenuated by somatostatin. Neither the increase in plasma renin activity (PRA) nor the angiotensin II mediated suppression of PRA were affected by somatostatin. These findings are consistent with the recent observation that somatostatin suppresses aldosterone release in response to angiotensin II in rat adrenal cells in culture and they indicate a possible role for somatostatin in the regulation of aldosterone secretion.     

EFFECT OF METOCLOPRAMIDE ON PLASMA VASOPRESSIN IN MAN

The effect of metoclopramide, a dopamine blocker, on arginine vasopressin (AVP) secretion was investigated in normal males. After a bolus injection of metoclopramide (10 mg), all subjects (n = 7) demonstrated an increase of 80.3% (from 0.71 +/- 0.12 (Mean +/- S.E.) to 1.28 +/- 0.24 pg/ml, P less than 0.005) in plasma AVP at 15 min. In controls (n = 7) plasma AVP levels did not change after saline injection (2 ml). Because plasma osmolality and blood pressure did not change, the elevation of plasma AVP levels induced by treatment with metoclopramide may be due to its central effect as a dopamine inhibitor. Although plasma AVP levels increased again at 90 and 120 min after a bolus injection of metoclopramide, accompanying falls in blood pressure (4-5%) make the interpretation concerning the contribution of dopamine to AVP secretion in a late phase uncertain. In summary, plasma AVP levels were shown to be significantly increased by a metoclopramide bolus, suggesting that AVP secretion is under tonic inhibition by dopamine.