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.     

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.     

EFFECT OF METOCLOPRAMIDE ON ALDOSTERONE AND REGULATORY FACTORS IN MAN

To determine the role of known secretagogues in the aldosterone response to dopamine blocking agents, plasma levels of ACTH, angiotensin II, potassium and plasma catecholamines were measured in five normal male subjects before and after intravenous injection of saline or 10 mg metoclopramide. There were no consistent changes in hormone levels after saline injection. After metoclopramide, plasma aldosterone increased three-fold to peak values at 20 min post-injection. A significant increase in aldosterone was observed within 10 min during which period there was no significant change in plasma ACTH, plasma renin activity AII or K. Plasma levels of cortisol, noradrenaline, adrenaline and dopamine showed no significant changes after injection of metoclopramide which induced a ten-fold rise in plasma prolactin. These results provide direct evidence that factors other than the plasma concentration of ACTH, AII and K--or fluctuations in plasma catecholamines--are likely to be responsible for the acute increase in plasma aldosterone after metoclopramide injection in normal man.     

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.     

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.     

LACK OF EFFECT OF ETHANOL ON PLASMA CORTISOL IN MAN

The effects of acute administration of ethanol were studied in a total of 18 normal male subjects. Sixteen men were given oral ethanol (2·5 ml/kg vodka or gin) and four received intravenous infusions of ethanol (1 ml/kg), at two times of day, 0900 h and 1800 h. Neither intravenous nor oral ethanol caused a specific rise in plasma cortisol, in contrast to previously reported work. There was no evidence for circadian variation in response. Since ethanol does not release plasma cortisol in normal individuals, the pathogenesis of ‘alcohol-induced pseudo-Cushing's syndrome’ should be re-considered.     

LACK OF EFFECT OF INTRAVENOUS LHRH ON PLASMA NORADRENALINE IN MAN

One hundred μg of LHRH was given intravenously to two male and two female subjects. Plasma noradrenaline did not change following LHRH, in contrast to findings reported by others. There was no change in heart rate and systolic arterial blood pressure. LH increased significantly as expected.     

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)     

SUPPRESSIVE EFFECT OF METYRAPONE ON PLASMA CORTICOTROPHIN IMMUNOREACTIVITY IN NORMAL MAN

Short term alterations of plasma corticotrophin immunoreactivity (ACTH) and cortisol were studied in healthy men under basal conditions and during intravenous administration of metyrapone. In the intravenous experiment, a low dose (1 g/5 h) and a high dose (4 g/5 h) of metyrapone ditartrate were infused. In the early phase of the metyrapone experiments, plasma ACTH fell from 9.46 +/- 0.95 (SE) pmol/l at 08.00 h to 7.7 +/- 1.1 pmol/l at 09.00 h (P greater than 0.05) in the low-dose experiment, and from 7.0 +/- 1.6 pmol/l to 4.6 +/- 0.9 pmol/l (P less than 0.05) in the high-dose experiment. A significant delayed increase of plasma ACTH secondary to the hypocortisolaemic stimulus was apparent in the high-dose experiment, in which plasma cortisol was maximally suppressed to 14 +/- 3 nmol/l at 13.00 h. No significant increase was observed in the low-dose experiment, the maximal suppression of plasma cortisol being 46 +/- 9 nmol/l at 14.00 h. The present data suggest dual effects of metyrapone on plasma ACTH: 1) a suppressive effect, the mechanism of which is not yet understood, and 2) the known increasing effect of 'feed-back' stimulation, which seems to be very sensitive to alterations of plasma cortisol only at cortisol levels lower than about 50 nmol/l. The suppressive effect of metyrapone may account for the frequently described inadequate response of plasma ACTH to metyrapone-induced hypocortisolaemia. Particularly, the diagnostic validity of the very short versions of the metyrapone test would seem to be seriously questioned.     

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.     

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.     

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 METOCLOPRAMIDE ON SERUM PROLACTIN LEVELS IN HUMANS

The effect of acute and chronic administration of metoclopramide on serum prolactin levels in normal subjects was studied. Metoclopramide 10 mg i.v. induced a prompt rise in serum prolactin levels in all subjects. At 180 min the levels remained high. Prolactin levels were markedly elevated during a 5 day course of treatment with metoclopramide in six subjects. It is suggested that metoclopramide could be used in the functional exploration of the hypothalamic-pituitary axis.     

心钠素和精氨酸加压素对血液透析患者高血压的影响

采用放射免疫学方法测定血液透析患者和正常人血浆心钠素（ＡＮＰ）及精氨酸加压素（ＡＶＰ）的浓度。结果：慢性肾功能衰竭（ＣＲＦ）患者血浆ＡＮＰ和ＡＶＰ水平明显高于正常人（Ｐ＜０．０１）；血透后血压正常组随着透析、超滤，血浆ＡＮＰ和ＡＶＰ浓度下降，但高血压组ＡＶＰ水平明显增高，并与血压上升、血钠改变呈显著正相关（分别为ｒ＝０．７８，Ｐ＜０．０１；ｒ＝０．６３，Ｐ＜０．０５）。提示血透患者高血压发病除与Ｃ     

THE EFFECT OF ISOPRENALINE ON PLASMA RENIN ACTIVITY IN MAN: A DOSE-RESPONSE CURVE

Four normal subjects on a free sodium intake received intravenous isoprenaline in doses of 2, 4, 8 and 16 μg over 2 min. Three of the subjects received a second infusion of 8 μg. The rate of renin release indexed by changes in plasma renin activity increased in all subjects at each dose level. The mean peak leveles of plasma renin were 9%, 29% and 77% above the mean control levels at doses of 2, 4 and 8 μMg respectively. The response of 16 μg was no different from that seen with 8 μg. The renin response obtained at 8 μg was highly reproducible such that the coefficient of variation for duplicate estimations of plasma renin (twelve duplicates) ranged from 1.7 to 4%. The rate of renin release from the kidney is known to be under adrenergic control (Vander, 1965; Wathen et al., 1965; Allison et al., 1970; Ueda et al., 1973) and recent studies in animals and man have indicated that an intrarenal beta-adrenoreceptor mediates this release (Tobert et al., 1973; Inoue, 1973; Vandongen et al., 1973; Sabto et al., 1975). Isoprenaline is the archetypal beta-adrenergic agonist with equal effects upon both beta₁ and beta₂ receptors (Lands et al., 1967). We have previously shown that minute bolus injections of this agent provokes renin release in normal people (Davies et al., 1975). However, there appears to have been no systematic investigation of a dose-response relationship for the release of renin provoked by isoprenaline in man. The aim of this study was to attempt to define such a relationship and, mindful of the possible application of this technique to studies of the adrenergic control of renin release in patients, we have documented the reproducibility of this response.     

INFLUENCE OF PRESYNCOPE AND POSTURAL CHANGE UPON PLASMA ARGININE VASOPRESSIN CONCENTRATION IN HYDRATED AND DEHYDRATED MAN

Plasma arginine vasopressin concentrations were measured in five healthy volunteers during postural change under conditions of dehydration and normal hydration. A rise in plasma arginine vasopressin was observed only after dehydration and standing for 40 min. Five further volunteers who developed presyncopal symptoms during orthostasis had exceedingly high plasma arginine vasopressin levels. Changes in plasma arginine vasopressin concentration occurred with no significant alterations in plasma osmolality.     

IN VIVO AND IN VITRO STUDIES ON THE EFFECT OF METOCLOPRAMIDE ON ALDOSTERONE SECRETION

Metoclopramide, a dopamine antagonist drug, elevated plasma aldosterone and prolactin levels without significantly affecting plasma renin activity, ACTH or potassium. Studies with isolated perfused rat zona glomerulosa cells showed that metoclopramide could directly stimulate aldosterone release and that this action was blocked by dopamine. These results suggest that dopamine may play an important inhibitory role in the control of aldosterone secretion.     

DEVELOPMENT OF A CYTOCHEMICAL ASSAY FOR PLASMA VASOPRESSIN: APPLICATION TO STUDIES ON WATER LOADING NORMAL MAN

A cytochemical assay has been developed to measure human plasma arginine vasopressin. It is based on the stimulation of Na+-K+, ATPase activity located in the outer medulla of the rat kidney, and is capable of detecting very low plasma arginine vasopressin concentrations, limit of detection 0.01 pmol/l. Specificity for vasopressin stimulation of the enzyme is conferred on the assay by the use of specific vasopressin antiserum. Index of precision of the assay is 0.21. Degradation of arginine vasopressin in plasma in inhibited by phenanthroline. Samples may be stored up to 8 weeks at -70 degrees C. Intra- and inter-assay coefficients of variation were 22% (n = 8) and 104% (n = 12), respectively. A sustained water load in eight healthy male adults caused a fall in plasma osmolality from a basal of 286.5 +/- 2.0 (mean +/- SEM) to 279.2 +/- 2.4 mmol/kg after the load (P less than 0.001), which was associated with a reduction in urine osmolality from 867 +/- 54 to 69 +/- 3 mmol/kg. Plasma immunoreactive arginine vasopressin fell from 1.3 +/- 0.3 pmol/l to become undetectable (less than 0.3 pmol/l), but plasma cytochemical arginine vasopressin decreased from 0.96 +/- 0.14 to 0.07 +/- 0.02 pmol/l. There was a curvilinear relationship between plasma osmolality and plasma cytochemical arginine vasopressin, which militated against the concept of an osmotic threshold for vasopressin release.     

EFFECT OF FLUPHENAZINE ON PITUITARY FUNCTION IN MAN

The growth hormone (hGH) and prolactin (hPRL) response to insulin induced hypoglycaemia was studied in six alcoholics on two occasions before and after treatment with a single intramuscular injection of fluphenazine (Modecate). On both occasions blood samples were taken at intervals before and after the intravenous injection of soluble insulin (0.1 u/kg body weight). The patients were investigated on the first occasion, 2-7 days after cessation of drinking and they all demonstrated an adequate hGH response. They then received an injection of fluphenazine (Modecate 12.5 mg) and were reinvestigated 1 week later. The hGH response to hypoglycaemia was significantly impaired after treatment with fluphenazine. Basal hPRL concentrations were significantly increased and increased concentrations of hPRL in response to hypoglycaemia occurred after treatment. We conclude that a single injection of fluphenazine (Modecate 12.5 mg) has a marked effect on hypothalamic-pituitary mechanisms controlling hGH and hPRL release.     

PLASMA VASOPRESSIN IN HYPERCALCAEMIC STATES

Plasma vasopressin was measured by radioimmunoassay in eight normal subjects and in six patients with hypercalcaemia. Vasopressin levels were significantly elevated in the hypercalcaemic patients, although urine osmolalities were lower than in controls. This finding is consistent with a renal resistance to the action of endogenous vasopressin in hypercalcaemia.