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.     

Opioid-mediated inhibition of oxytocin during insulin-induced hypoglycemic stimulation of vasopressin in man

We have investigated the importance of endogenous opioids in the differential control of neurohypophysial peptide secretion. The effect of the opioid antagonist naloxone on the vasopressin and oxytocin responses to insulin-induced hypoglycemia was studied in 14 male subjects. Either saline (N = 8) or naloxone (4 mg bolus + 6 mg/h, N = 6) was infused iv during the study. After 60 min infusion soluble insulin 0.15 U/kg was injected. Naloxone infusion for 60 min did not alter basal plasma AVP or OT levels. Insulin-induced hypoglycemia led to a significant rise in plasma AVP in both saline and naloxone-infused subjects (P less than 0.05), which was maximal 45 min after insulin. There was no significant difference in the plasma AVP response to hypoglycemia between the 2 groups. Saline-infused subjects did not show any change in plasma OT in response to hypoglycemia whilst during concurrent naloxone infusion there was a significant rise in OT from 1.9 +/- 0.4 pmol/l before insulin to 3.2 +/- 1.3 pmol/l at 45 min (P less than 0.05). We conclude that there is opioid-mediated inhibition of OT which prevents its release when AVP is secreted in response to insulin-induced hypoglycemia.     

Effects of plasma volume and osmolality on secretion of atrial natriuretic peptide and vasopressin in man

To clarify the role of blood volume and osmolality in the mediation of the release of atrial natriuretic peptide (ANP) and to examine the relationship between plasma ANP and plasma AVP levels in man, the effects of hypertonic saline and hypertonic mannitol infusion, and of water load on plasma levels of ANP and AVP were studied. Infusion of 5% saline to 7 healthy men at a rate of 0.05 ml.min-1.kg-1 for 2 h resulted in a parallel rise in plasma sodium, osmolality, plasma ANP and plasma AVP, indicating that plasma hyperosmolality stimulates secretion of both ANP and AVP. Infusion of 20% mannitol to 6 healthy men at the same rate resulted in a parallel increase in plasma osmolality, plasma ANP and AVP, whereas plasma sodium decreased, indicating that plasma hyperosmolality stimulates secretion of both ANP and AVP. Water load (20 ml/kg) into 7 healthy men produced a prompt and parallel fall in plasma sodium, plasma osmolality and plasma AVP. In contrast, plasma ANP and plasma volume, calculated from the changes in hematocrit, increased concomitantly, which indicates that expanded plasma volume stimulates secretion of plasma ANP. These results suggest that secretion of ANP in man is regulated principally by plasma volume, which may be modulated by a change in plasma osmolality. AVP secretion, on the other hand, is controlled mainly by osmotic change and secondarily by plasma volume.     

α-HUMAN ATRIAL NATRIURETIC POLYPEPTIDE REDUCES THE PLASMA ARGININE VASOPRESSIN CONCENTRATION IN HUMAN SUBJECTS

The synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) was infused into six normotensive, euvolaemic, healthy volunteers to examine the effect on the plasma arginine vasopressin (AVP) concentration. The intravenous administration of alpha-hANP (0.1 microgram/kg/min, 20 min) led to a remarkable reduction in mean blood pressure (-10 mmHg, P less than 0.05), and there was an increase in pulse rate (+10 bpm, P less than 0.05), in each subject. The urinary volume, sodium excretion and cyclic 3',5'-guanosine monophosphate (cyclic-GMP) excretion were increased to 3.5 (P less than 0.05), 2.5 (P less than 0.05) eight-fold (P less than 0.01), respectively, during the alpha-hANP infusion. The dose and duration of the synthetic alpha-hANP in the present study was sufficient to induce these cardiovascular and renal effects. The plasma AVP concentrations decreased from 0.39 +/- 0.09 pg/ml to the undetectable level during the alpha-hANP administration. After infusion, the plasma concentrations of the AVP promptly returned to preinfusion levels (0.46 +/- 0.14 pg/ml). However, there was no significant change in plasma AVP concentration during placebo infusion. The marked suppression in plasma AVP concentration may account for the remarkable diuresis, in addition of the direct renal effects of the synthetic alpha-hANP.     

Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.     

Studies of the factors modulating antidiuretic hormone excretion in man in response to the osmolar stimulus: effects of oestrogen and angiotensin II

The aim of this study was to assess the influence of hormones known to regulate fluid and electrolyte balance on the release of antidiuretic hormone induced by raising serum osmolality. The stimulus provoked by the infusion of a 2.5% NaCl solution induces an increase of urinary [arginine-8]-vasopressin from 1.12 to 2.64 ng/h in men and from 1.65 to 7.27 ng/h in women as has been previously reported. These results were compared to those obtained in males infused with angiotensin II (AII) before and during a hypertonic sodium load and in males infused with hypertonic saline on the fourth day of administration of ethinyl-oestradiol. During the combined infusion of AII and then hypertonic saline, the mean hourly urinary excretion of AVP increased from 2.8 to 5.67 ng/h. Within each group the increase of urinary AVP was highly significant. The rise of urinary AVP during AII infusion was significantly different from the rise observed both in untreated males and untreated females, lying in between. The mean hourly excretion rate of AVP increased before and after hypertonic saline loading from 2.65 to 5.3 ng/h in males pre-treated with ethinyl-oestradiol. The significant difference observed between males and females is reduced when males treated with oestrogen were compared to female subjects. In each group plasma renin activity decreased to low values during the salt-loading test. During oestrogen treatment PRA and plasma renin substrate rose, while urinary aldosterone remained almost unchanged.(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.     

Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations

Whether atrial natriuretic hormone (ANH) has biological effects at physiological plasma levels in man is not known. Accordingly, we investigated the effects of a 3-h low dose infusion of human ANF (0.75 pmol/kg.min; i.e. 0.0023 micrograms/kg.min) in six normal men, whose sodium intake was normal while sitting, in a single blind, random order, placebo-controlled study. The ANF infusions induced changes in plasma ANH concentrations entirely within the range for normal subjects. The small increases in plasma ANH values were associated with a significant rise in urinary excretion of sodium, magnesium, calcium, and cGMP. PRA and plasma aldosterone concentrations uniformly decreased to 50% and 64% of placebo values, respectively. Systolic and mean arterial pressures fell significantly from preinfusion values during the ANH infusions. These findings constitute strong evidence that ANH is a hormone of physiological significance in the regulation of body fluid volumes in normal man.     

The efficacy of DDAVP is related to the circadian rhythm of urine output in patients with persisting nocturnal enuresis

OBJECTIVE: Desmopressin may be a useful treatment in some, but not all, patients with nocturnal enuresis. We have evaluated a relation between nocturnal urine output in patients with primary monosymptomatic nocturnal enuresis and the treatment response to synthetic vasopressin. DESIGN: Adolescent or adult enuretics and normal subjects were enrolled in the study and admitted to hospital for a 24 hour investigation of the diurnal variation in urine output, plasma vasopressin (AVP) and plasma atrial natriuretic peptide (ANP). The enuretics were characterized prior to investigation as either 1-desamino-8-D-arginine vasopressin (DDAVP) responders or non-responders. During admission the fluid intake was restricted to 25 ml/kg per day. PATIENTS: Twenty-four patients (15-37 years) with primary monosymptomatic nocturnal enuresis and 9 normal subjects (24-31 years). MEASUREMENTS: Circulating levels of AVP, ANP, plasma electrolytes and plasma osmolality were measured (1400, 2000, 2300, 0200, 0500 and 0800 hours) together with urine volume, urine osmolality and urine electrolytes during daytime and nighttime. Tubular reabsorptive capacity for water, osmoles and creatinine were assessed as well as urinary and fractional excretion rates of sodium and potassium. RESULTS: Controls and DDAVP non-responders had a significant decrease in urine output at night concomitant with a significant plasma AVP amplitude in peak/nadir values although both groups lacked a significant nocturnal increase in AVP. In contrast, in DDAVP responders there was no circadian variation in urine output and thus a nocturnal polyuria together with no oscillation in plasma AVP. The DDAVP responding group had a nocturnal urine production significantly larger than the two other groups. However, the mean 24 hour AVP levels were similar in all groups. The excessive urine production at night in DDAVP responders was accompanied by nocturnal natriuresis due to an increased fractional excretion of sodium. In contrast, nocturnal antidiuresis in controls and DDAVP non-responding enuretics coincided with diminished sodium excretion. Average ANP levels were elevated in both enuretic groups compared to normals, whereas a circadian variation was detected only in the latter. CONCLUSION: It is concluded that DDAVP responsiveness is linked to the nocturnal urine production and that no pathophysiological role can be ascribed to AVP or ANP in DDAVP refractory adolescent and adult enuretics. Moreover, it is suggested that an abnormal tubular handling of sodium may contribute to the nocturnal polyuria seen in DDAVP responders.     

A radioimmunoassay for plasma arginine-vasopressin in man and dog: application to physiological and pathological states.

A radioimmunoassay has been developed for plasma arginine-vasopressin in man and dog. The mean recovery of added arginine-vasopressin (AVP) was 60 +/-6.9 (S.D.)% and the lower threshold of detection 2.0 pmol/1. A close correlation was found between concurrent radioimmunoassay and bioassay values. The mean concentration found in peripheral venous blood in healthy men after overnight fasting was 5.3 pmol/1 (range 4.6-6.2 pmol/1.) In man, significant increases in plasma AVP occurred after dehydration (5-9-9-5 pmol/1) and significant decreases after oral water-loading (5.9-9.5 pmol/1). During i.v. infusion of graded doses of synthetic AVP in normal men, plasma levels were closely correlated with infusion rate. On stopping the infusion, plasma vasopressin fell exponentially with a half-life of between 7 and 8 min. In man, plasma AVP was unaffected by tilting head-up for 2 h, or by a non-hypotensive bleeding of 500 ml in 10 min. In the dog, haemorrhage of 5 ml/kg and over caused proportionate increases in AVP in the circulation. In normal men, plasma vasopressin was significantly correlated with concurrent urinary osmolality. Five patients with oat-cell bronchial carcinoma and hyponatraemia showed a marked increase of plasma vasopressin. Five patients with diabetes insipidus had significantly reduced, but detectable, levels of plasma AVP. The plasma concentration in these patients did not increase after water restriction.     

Effects of high sodium diet on dopaminergic mechanism in normal and hypertensive subjects

To investigate the effects of dietary sodium on the peripheral dopaminergic mechanism, changes of unconjugated plasma dopamine(DA) and its related humoral factors were studied in 8 patients with essential hypertension(EH) and 8 age-matched normal controls(N) while they were receiving ordinary meals (Na, 130-180 mEq daily) followed by higher sodium (250-300 mEq daily) diets for a week. Plasma and urinary DA, norepinephrine(NE) and epinephrine(E) were measured by the highly sensitive COMT-mediated radioenzymatic procedure, which permits an accurate estimation of plasma DA as low as 5-6 pg/ml. Under high sodium diets, blood pressure and heart rate were not changed significantly in N and EH subjects. Urinary NE and E tended to decrease, while urinary DA increased significantly in both groups of subjects (p less than 0.05). There was a significant correlation between urinary sodium and DA (r = 0.590, p less than 0.001), but plasma DA failed to correlate significantly to urinary sodium or DA in all subjects. Plasma NE and E tended to decrease in both N and EH subjects, while plasma DA increased significantly (p less than 0.05) in EH from 7.2 +/- 0.8 pg/ml [mean +/- SEM] to 9.3 +/- 1.0 and slightly in N from 9.1 +/- 1.8 to 11.2 +/- 1.3. Plasma renin activity(PRA) and plasma aldosterone(PAC) were invariably decreased in all subjects, while plasma prolactin(PRL) remained unchanged. A significant correlation was observed between plasma DA and NE under ordinary meals (r = 0.733, p less than 0.01), but this correlation disappeared under high sodium diets. Plasma DA showed an inverse correlation to PAC (r = 0.351, p less than 0.05) under both dietary conditions. Upright posture induced a significant rise (p less than 0.05) in NE, E, DA, PRA and PAC with ordinary meals, but the responses of NE and PAC were apparently attenuated with high sodium diets. An intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, provoked a slight rise in plasma NE and DA with ordinary meals, of which responses were further enhanced with high sodium diets. MCP induced a definite rise in PAC and PRL in all subjects under both dietary conditions (p less than 0.01), while plasma E and PRA remained unchanged after MCP challenge. The results lend support to the view that unconjugated plasma DA could be a useful marker of peripheral dopaminergic activity, which might be a physiological regulator responsible for the suppression of aldosterone secretion and sympathetic nerve activity observed during high sodium intake.     

Presence of oxytocin and arginine vasopressin in human ovary, oviduct, and follicular fluid

Oxytocin and arginine vasopressin (AVP) immunoreactivity in human ovary, oviduct, and follicular fluid were measured and found to coelute with the authentic peptides using both gel filtration column chromatography and reverse phase thin layer chromatography. In ovarian tissue, mean oxytocin and AVP concentrations were 0.48 and 0.24 ng/mg protein, respectively. These values are approximately 4000-fold higher than peripheral plasma levels. The concentration of oxytocin in the corpus luteum was approximately 6-fold greater (3.12 ng/mg protein) than that in ovarian tissue with no corpus luteum. In contrast, no significant difference in the concentration of AVP was found between corpus luteal and the remaining ovarian tissues. Follicular fluid contained 299 and 131 pg/ml oxytocin and AVP, respectively. These levels were 30-fold greater than the serum level of either peptide, suggesting ovarian synthesis of the neurohypophyseal hormones. In addition, immunoreactive oxytocin and AVP were detected in the oviducts (1.01 and 0.24 ng/mg protein, respectively); however, neither peptide was detectable in myometrial tissue (less than 0.02 ng/mg protein). Our results demonstrate the presence of high concentrations of oxytocin and AVP in human ovarian and oviductal tissues as well as follicular fluid and suggest that neurohypophyseal peptides have a paracrine role in the regulation of ovarian or oviductal functions.     

Role of vasopressin in regulation of sodium excretion

It has been proposed that arginine vasopressin (AVP) contributes to the regulation of renal sodium excretion by direct intrarenal actions, by neural-hormonal interactions, and via secondary effects of fluid volume retention. The present studies were designed to determine the extent to which the natriuretic effects of AVP are secondary to volume expansion. Three groups of dogs were studied: the first was infused with AVP for 2 weeks in amounts that increased plasma levels from 3 to 15 pg/mL, while water intake was maintained constant by intravenous (iv) water infusion. The second group received the same amount of AVP and was permitted to drink ad libitum. The third group was infused with the same amount of AVP, while total body weight and volume were maintained at a constant level by use of an electronically servo-controlled water infusion system. The results showed a large increase in total body weight (+1.5 kg) and arterial pressure (mean arterial pressure (MAP); +40 mm Hg) in dogs receiving a fixed water intake. This was accompanied by a continuing natriuresis over a 2-week period and severe hyponatremia (115 mEq/L). Dogs allowed ad libitum drinking retained much less fluid (+0.5 kg). MAP was not significantly elevated, and natriuresis did not occur in this group, but hyponatremia was observed (130 mEq/L), and plasma renin activity (PRA) was suppressed. Servo-controlled dogs exhibited no change in MAP, plasma sodium, or PRA, and only a small (-15 mEq) natriuresis occurred on day 1 of AVP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of endogenous opioids in neurohypophysial function of man

Studies were carried out in normal human subjects to determine the effect of two narcotic antagonists, oxilorphan and butorphanol, on antidiuretic hormone (ADH) release. Oxilorphan given to eight subjects on ad libitum fluid intake resulted in a transient but significant increase in 24-h free water clearance and a decrease in urine osmolality. These changes were not accompanied by an increase in creatinine or solute excretion, and urinary ADH levels did not rise even though plasma osmolality rose significantly from 289.4 +/- 0.9 to 292.9 +/- 0.8 mosmol/kg. Treatment with oxilorphan did not interfere with the response to ADH infusion in water-loaded subjects. Both oxilorphan and butorphanol significantly elevated the plasma osmolality at which ADH release became evident after the infusion of hypertonic saline in water-loaded subjects. Oxilorphan suppressed urinary ADH excretion at the time of the osmotic threshold for ADH release in spite of the greater plasma osmolality. The data indicate that the narcotic antagonists are capable of inhibiting ADH release in man during ad libitum fluid intake and in response to an osmotic stimulus by elevating the osmotic threshold for ADH release. It is concluded that narcotic antagonist inhibition of endogenous opioid action provides further evidence supporting a role for the brain opiates in the normal regulation of neurohypophysial hormone release in man.     

Release of oxytocin and vasopressin by intracerebroventricular vasoactive intestinal polypeptide

Vasoactive intestinal polypeptide (VIP)ergic nerves innervate both the neurohypophysis and the hypothalamus. To test the hypothesis that VIP is a releasing factor for neurohypophyseal hormones, rats were given intracerebroventricular (icv) infusions of VIP in doses varying from 0.3 pmol/kg.min to 3 nmol/kg.min for 5 min (0.001-10 micrograms/rat). Serial blood samples were drawn from the vena cava for measurement of oxytocin (OT), vasopressin (AVP), and VIP by RIA. After the VIP infusions mean plasma OT and AVP levels rose in a dose-dependent manner; the rise was significant for both hormones at the dose of 300 pmol/kg.min. Peak levels after infusion of 3 nmol/kg.min were greater for OT than AVP [96.1 +/- 14.7 vs. 33.9 +/- 9 microU/ml (mean +/- SE); n = 6]. In addition, the concentration of plasma OT increased more promptly than that of AVP. Plasma OT was significantly raised over control values at 5 min, whereas plasma AVP was not increased until 15 min after the VIP infusion began. The concentration of VIP in peripheral plasma rose somewhat after icv infusions (maximum, 300 pmol/liter 30 min after 10 micrograms/rat), but the rise was only 5% of that observed after systemic infusions of equimolar doses of VIP (maximum, 6000 pmol/liter 5 min after 10 micrograms/rat). Peak plasma OT levels after administration of 3 nmol/kg.min VIP were significantly higher after icv than after systemic infusion of the same dose of VIP reported previously. Intravenous injection of 0.5 ml VIP antiserum with a binding capacity of VIP of 2.3 micrograms/ml before the icv administration of VIP (1 microgram/rat) did not prevent the VIP-induced rise in plasma OT and AVP. These observations suggest a central site of action for VIP in OT and AVP release, probably in the hypothalamus. The results are in harmony with the hypothesis that endogenous VIP is a physiological regulator of OT and AVP release in rats.     

RESPONSES OF NEUROHYPOPHYSIAL PEPTIDES TO HYPERTONIC SALINE AND INSULIN-INDUCED HYPOGLYCAEMIA IN MAN

In order to investigate the possible role of oxytocin in osmoregulation and its response to stress, plasma immunoreactive oxytocin was measured during hypertonic saline infusion and insulin-induced hypoglycaemia in a group of normal subjects, four patients with idiopathic diabetes insipidus and one patient with DIDMOAD syndrome (the syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and deafness). The results were compared with those of plasma immunoreactive vasopressin to the same stimuli. As expected, there was a rise in plasma vasopressin in the normal subjects to both tests: this was absent in the patients with diabetes insipidus. Plasma oxytocin did not rise during hypertonic saline infusion in either group of subjects. The response of oxytocin to insulin-induced hypoglycaemia (0.15 U/kg soluble insulin) in normal subjects was much more variable. One highly symptomatic volunteer showed a marked rise in oxytocin. Two subjects also showed a rise when retested with 0.19 U/kg soluble insulin. There was no response of oxytocin to a standard-dose insulin test in the patients with diabetes insipidus. The data suggest that, in man, oxytocin is not involved in osmoregulation but that it may be secreted in response to marked hypoglycaemia.     

The role of the renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal human subjects.

To examine the role of angiotensin II in the maintenance of blood pressure and the control of aldosterone secretion in man, eight normal subjects were studied on a tilt table in sodium replete and sodium depleted states prior to and subsequent to the intravenous infusion of an angiotensin converting enzyme inhibitor (CEI). In both the sodium replete or sodium depleted state, upright tilting resulted in an increase in heart rate and a narrowing of pulse pressure. None of the sodium replete or depleted subjects fainted. Tilting was accompanied by a rise in plasma renin activity with an associated rise in plasma aldosterone concentration. When converting enzyme inhibitor was administered, which blocked the generation of angiotensin II, sodium replete subjects were able to compensate for an upright tilt, despite the absence of angiotensin II, without significant hemodynamic change when compared to control state. In sodium depleted subjects, after the administration of converting enzyme inhibitor, there was a sharp and significant decrease in systolic and diastolic blood pressure associated with a significant rise in heart rate. All but one sodium depleted subject fainted within seven minutes. Both plasma aldosterone concentration and plasma renin activity rose on tilting in both sodium replete and sodium depleted subjects. After the administration of converting enzyme inhibitor, plasma aldosterone failed to rise in association with a rise in plasma renin activity. In supine subjects, after the administration of converting enzyme inhibitor, plasma renin activity rose but plasma aldosterone concentration fell. In sodium depleted subjects, after the administration of CEI, aldosterone fell to a level significantly lower than that in supine controls and to a level no different from the supine sodium replete subject. These results indicate that angiotensin II is essential for blood pressure maintenance in sodium depleted individuals, that angiotensin II exerts a direct feedback control on renin secretion, and that angiotensin II is the primary stimulus to aldosterone secretion in response to both sodium depletion and to posture.     

Plasma substance P levels in normotensive and hypertensive subjects

Since substance P is a potent natriuretic, diuretic, and vasodilatory peptide, a radioimmunoassay for substance P was developed, and its levels measured in the plasma of normal subjects and patients with essential hypertension. The plasma substance P levels were 186+/-14 pg/ml in normal subjects and 164+/-3 pg/ml in hypertensive patients. When the sodium content of their diet was reduced to 10 mEq/day, substance P levels failed to change, but plasma renin activity and urinary kallikrein increased. An acute saline infusion also failed to alter plasma substance P levels. Assuming an upright posture increased plasma renin activity, but not substance P, in both groups of subjects. Thus, it appears that substance P is not involved in the control of blood pressure, kallikrein excretion or renin release in man.     

Simultaneous radioimmunoassay for plasma arginine-vasopressin and oxytocin using DEAE Sephadex A 25 extraction

A sensitive and specific radioimmunoassay method for simultaneous measurement of plasma arginine vasopressin (AVP) and oxytocin (OT) has been developed utilizing an extraction technique on DEAE Sephadex A25. This procedure resulted in mean recoveries of 70.7% (AVP) and 65.4% (OT) in the peptide range of 5 to 100 pg/4 ml. The sensitivity of the assay is 0.5 pg/tube for AVP and 2 pg/tube for OT. The lower limit of detection for plasma extracts was 1.2 pg AVP/ml and 5 pg OT/ml plasma. Employing this method in normal human non smokers and ad libitum fluid the basal levels (mean +/- SE) of plasma AVP are 3.5 +/- 0.2 pg/ml in males and 4.6 +/- 0.4 pg/ml in females and the basal concentrations of plasma OT are 5.1 +/- 0.3 pg/ml in males and 5.4 +/- 0.3 pg/ml in females. Dehydration and water loading produced significant changes in plasma AVP and OT concentrations and a significant correlation exists between plasma AVP and plasma (r = 0.96, p less than 0.001) and urinary (r = 0.84, p less than 0.01) osmolality, but not between plasma OT concentrations and plasma (r = 0.11, NS) and urinary (r = 0.27, NS) osmolality. These results suggest that a wide range of physiological and pathophysiological changes in plasma AVP and OT can be simultaneously measured by the extraction procedure and the radioimmunoassay described.     

Effects of acute water load, hypertonic saline infusion, and furosemide administration on atrial natriuretic peptide and vasopressin release in humans

A new specific RIA for alpha-human atrial natriuretic hormone (alpha hANP) was used to determine whether changes in plasma volume elicited by acute water loading, hypertonic saline infusion, and furosemide administration caused changes in ANP release and resultant changes in renal and cardiovascular function in normal subjects. In addition, changes in plasma arginine vasopressin (AVP), PRA, and aldosterone concentrations were studied simultaneously. Mean plasma alpha hANP and AVP levels were 51.3 +/- 16.0 (+/- SE) and 3.1 +/- 0.6 pg/ml, respectively, in the basal state. Plasma alpha hANP rose to 77.8 +/- 27.6 in response to a 4.5% increase in plasma volume induced by water loading, increased further to 134.1 +/- 28.9 in response to a 23% volume increase induced by hypertonic saline, and fell to 70.2 +/- 15.8 pg/ml in response to a decrease in plasma volume after furosemide treatment (P less than 0.01-0.05). On the other hand, plasma AVP fell to 1.8 +/- 0.1 pg/ml after the water load, rose to 4.1 +/- 0.6 after hypertonic saline, and rose further to 5.8 +/- 0.8 pg/ml after furosemide (P less than 0.01-0.05). Water and hypertonic saline loading decreased PRA, but plasma aldosterone concentrations did not change; subsequent furosemide administration increased both (P less than 0.01-0.05). Arterial pressure and heart rate did not change significantly. Increases in urinary Na excretion and osmolar clearances were associated with a rise in plasma alpha hANP after water loading and hypertonic saline infusion (P less than 0.01-0.05), but changes in urine flow were mainly associated with alterations in AVP release. associated with alterations in AVP release.