Atrial natriuretic peptide: physiological release associated with natriuresis during water immersion in man

Thermoneutral water immersion produces a physiological increase of thoracic blood volume, raises central venous pressure and increases urinary sodium excretion by a hitherto ill-understood mechanism. We have investigated whether this enhanced sodium excretion could be mediated by the recently discovered natriuretic factor, atrial natriuretic peptide (ANP). During water immersion there was a highly significant (P less than 0.001) twofold increase of the mean plasma ANP concentration and a doubling of the mean urinary sodium excretion. Both were unchanged during the control experiments. These results are consistent with the hypotheses that ANP is released into plasma in response to central blood volume expansion and that it functions as a natriuretic hormone in normal man under physiological conditions.     

Atrial natriuretic peptide concentrations in umbilical cord plasma from pre-eclamptic women

Summary. Atrial natriuretic peptide (ANP) was measured in arterial and venous umbilical cord plasma at the time of delivery by cesarean section in pre-eclamptic (n= 7) and normal women (n= 6). In addition venous samples were obtained from pre-eclamptic (n= 7) and normal pregnant women (n= 7) near term. ANP plasma levels were higher in pregnant women with pre-eclampsia than in normal pregnant women (27·9±4·4 [mean±SEM] and 14·1 ±2·5 pmol 1^-1, respectively, P<0·05). Immediately after delivery plasma ANP in pre-eclamptic mothers was 66·7 ± 12·8 pmol 1^-1 compared to 13·9 ±2·2 pmol 1^-1 in normal mothers (P<0·01). However, in the pre-eclamptic group the levels of ANP in arterial and venous umbilical cord plasma (19·5 ±4·2 and 16·7±4·3 pmol 1^-1 respectively) were significantly (P<0·01) lower than ANP levels in arterial and venous cord plasma (39·6 ± 1·0 and 31·1±4·2 pmol 1^-1, respectively) from normal mothers. It is concluded that the increased ANP plasma level in pre-eclamptic women originates from a maternal source. In addition, since the ANP level is lower in cord plasma than in maternal plasma in pre-eclampsia, fetoplacental volume homeostasis may also be changed in pre-eclampsia.     

Atrial natriuretic peptide: physiological release associated with natriuresis during negative pressure breathing in man

1. Negative pressure breathing was one of the first physiological tools used to study the renal effects of redistribution of the blood volume from the peripheries to the thorax. The recent discovery of a putative natriuretic hormone (atrial natriuretic peptide, ANP) in cardiac atrial tissue has rekindled interest in the effect of the cardiovascular system on renal function. We have therefore studied the effects of this physiological manoeuvre on plasma ANP concentrations and renal responses. 2. Plasma concentrations of ANP, plasma renin activity and plasma aldosterone concentration were measured during an 80 min period of negative pressure breathing at -12 cmH2O pressure in six hydrated normal subjects. Identical control studies were performed in the same subjects at at least 1 week apart. 3. Negative pressure breathing resulted in a natriuresis and diuresis which were associated with a significant rise in plasma ANP concentration. The natriuresis occurred despite an increase in plasma renin activity and in plasma aldosterone concentration. 4. These findings, under specific carefully controlled conditions, support the previously contentious postulate that negative pressure breathing enhances sodium excretion, in addition to its well-recognized diuretic effect. They add further weight to the hypothesis that expansion of the central blood volume is an important stimulus to the release of ANP from the heart (acting by way of atrial distension), and suggest that changes of plasma ANP concentration may have induced the natriuresis which occurred in the face of a modest activation of the sodium-retaining renin-aldosterone system.     

Effect of posture on plasma immunoreactive atrial natriuretic peptide concentrations in man

The effect of changes of posture on plasma atrial natriuretic peptide concentrations and renal function was studied in normal human volunteers. Plasma atrial natriuretic peptide concentrations increased in the supine posture, reached a maximum value after 30-60 min, remained elevated for 4 h and decreased to baseline values on return to the upright posture. Inflation of antishock trousers, which apply positive pressure to the legs and lower abdomen, attenuated the fall in plasma atrial natriuretic peptide concentration in the upright position. In the supine posture there were increases in urine flow rate, sodium, lithium, fractional sodium and fractional lithium clearances. Fractional distal water and sodium excretion, and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, also increased. Heart rate and systolic and diastolic blood pressures decreased in the supine and increased on return to the upright posture. Inflation of antishock trousers prevented the increase in heart rate in the upright posture. The contribution of haemodynamic factors to the increase in plasma atrial natriuretic peptide concentrations in the supine position and the relationship between this increase and the associated changes in renal function are discussed. However, the contribution of atrial natriuretic peptide to these changes is uncertain.     

Atrial natriuretic peptide inhibits osmolality-induced arginine vasopressin release in man

1. Eight normal volunteers were infused with 5% saline (5 g of NaCl/100 ml) at a rate of 0.06 ml min-1 kg-1 for 120 min to increase plasma osmolality and plasma arginine vasopressin. Human atrial natriuretic peptide (alpha-hANP; 100 micrograms) or placebo was given in random order in a double-blind cross-over design for the last 20 min of the saline infusion. 2. Compared with the placebo infusion, atrial natriuretic peptide (ANP) produced a 43% greater sodium excretion and a 34% greater urinary volume in the subsequent hour. 3. Mean plasma immunoreactive ANP did not increase in response to changes in osmolality and rose to a peak of 118 pg/ml during the alpha-hANP infusion. alpha-hANP produced significant suppression of mean plasma arginine vasopressin over the 60 min after the infusions. 4. We conclude that ANP is not released in response to increased osmolality in vivo, and that it inhibits osmolality-induced arginine vasopressin release in man.     

Atrial natriuretic peptide: an endogenous factor enhancing sodium excretion in man

For many years experimental evidence has suggested the existence of a circulating factor able to enhance sodium excretion. Very recently peptides with natriuretic activity in experimental animals have been isolated from mammalian and human cardiac tissue. In order to determine whether this natriuretic activity has relevance to man we have studied the effects of an infusion of alpha-human atrial natriuretic peptide (alpha-h-ANP) in normal subjects. Sodium excretion trebled (P = less than 0.005) during the infusion of a calculated dose of 15 pmol of alpha-h-ANP min-1 kg-1 and there was an accompanying diuresis; radioimmunoassay of plasma alpha-h-ANP during the natriuresis indicated a mean peak incremental concentration of 203 +/- 78 (SEM) pmol/l. The infusion of a calculated dose of 1.5 pmol min-1 kg-1 did not affect sodium excretion. There were no haemodynamic changes and no side effects were noted.     

Diurnal change in plasma atrial natriuretic peptide concentrations

1. Diurnal changes in plasma concentrations of atrial natriuretic peptide (ANP), renin, angiotensin II, aldosterone, cortisol and antidiuretic hormone were investigated in seven normal volunteers studied under standardized conditions of dietary sodium, posture and physical activity. After completion of the diurnal study serial measurements of these variables were continued during, and on recovery from, a 2 day period of severe sodium depletion. 2. Clear diurnal variations in plasma concentrations of renin, angiotensin II, aldosterone, cortisol and antidiuretic hormone were observed. 3. Plasma ANP concentrations also varied significantly over 24 h. Values peaked about mid-day and a distinct trough in peptide concentrations occurred in the early evening. However, variations in plasma ANP values were of relatively small amplitude and not clearly independent of modest parallel shifts in sodium balance. 4. Changes in plasma ANP concentrations both within the diurnal study period and during sodium deprivation were closely and positively correlated with concomitant changes in cumulative sodium balance. 5. No simple parallel or reciprocal relationships between plasma concentrations of ANP, on the one hand, and concurrent plasma concentrations of other hormones or in the rate of urinary sodium excretion, on the other, were observed during the 25 h of the diurnal study.     

The plasma release of atrial natriuretic peptide in man

We studied plasma atrial natriuretic peptide (ANP) concentrations in seven normal subjects after the acute intravenous infusion of sodium chloride/potassium chloride solution (saline). Three separate infusions of 6, 12 and 18 ml of saline/kg body weight each significantly increased the circulating concentration of ANP without changes of plasma osmolality or electrolyte concentrations. The mean maximal rise of the plasma ANP concentration after the three saline infusions was significantly correlated (r = 0.74, P less than 0.001) with, but occurred 10-30 min later than, the maximal atrial pressure rise. These observations are in accord with the hypotheses that: (a) ANP is a circulating natriuretic factor; (b) atrial distension is an important stimulus to ANP release in man.     

Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume

Atrial natriuretic peptide (ANP) acts acutely to reduce plasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular permeability. Authors of a study in this issue of the JCI performed a knockout of the receptor for ANP in vascular endothelia in order to distinguish the effects of ANP-dependent increases in vascular permeability from those of other endocrine actions of ANP in the regulation of plasma volume. The knockout mice exhibited reduced vascular permeability to plasma protein, resulting in chronically increased plasma volume, arterial hypertension, and cardiac hypertrophy. Renal excretion and vasodilation did not account for these changes. Thus ANP-induced increases in endothelial permeability may be critical to the ability of ANP to lower arterial blood pressure.     

Effect of dietary sodium chloride and posture on plasma immunoreactive atrial natriuretic peptide concentrations in man

The effect of changes of dietary sodium chloride intake and posture on plasma atrial natriuretic peptide concentration and renal function was studied in 11 normal human volunteers. Plasma atrial natriuretic peptide concentration was higher in the upright posture on a high than it was on a medium or low salt diet. On the medium and high but not on the low salt diet the concentration increased significantly on adoption of the supine posture. Creatinine, sodium, lithium and fractional lithium clearances, fractional distal sodium excretion and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, were significantly higher on the high than on the low salt diet. The medium salt intake gave intermediate values. Heart rate while upright was significantly higher on the low than on either the medium or the high salt diets. Systolic blood pressure was unaffected by salt intake. Diastolic blood pressure in the supine position was significantly higher on the low than on the medium or high salt diets. Both plasma noradrenaline concentrations and plasma renin activity were significantly higher on the low than on the high salt diet. Values on the medium salt intake were intermediate. Plasma concentrations of both hormones were higher in the upright than in the supine posture on all three salt intakes. The data are consistent with the hypothesis that atrial natriuretic peptide contributes to the cardiovascular and renal adjustments to changes in dietary sodium chloride, and the possible role of the peptide is discussed.     

Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man

We have investigated the interaction between the recently discovered natriuretic factor alpha human atrial natriuretic peptide (alpha h-ANP) and the renin-angiotensin-aldosterone system in man. Angiotensin II infused with placebo produced a significant rise of plasma aldosterone concentration (mean +/- SEM increment 352 +/- 23 pmol/l, n = 7, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II largely abolished the aldosterone response (P less than 0.001). Diastolic blood pressure rose in response to the infusion of angiotensin II with placebo (mean increment 21.0 +/- 0.9 mmHg, P less than 0.001). Systolic blood pressure increased to a lesser degree (mean increment 12.5 +/- 0.7 mmHg, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II significantly blunted the diastolic pressor response (P less than 0.01). This ability of alpha h-ANP to blunt the pressor effect of angiotensin II may be important in the control of systemic blood pressure. The inhibition of angiotensin II-stimulated aldosterone release demonstrates that alpha h-ANP may not only be a circulating natriuretic factor in its own right but that it may also act as a modulator of a related endocrine system.     

Atrial natriuretic peptide and renal adaptation to contralateral nephrectomy in healthy man

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo) and arginine vasopression (AVP) in plasma were determined in 12 healthy renal transplant donors before and 5, 12, 26, 54 days after uninephrectomy (N_x) in order to study the possible role of these hormones in functional adaptation to acute reduction in renal mass. Glomerular and tubular function was studied by measurements of the clearances of ⁵¹Cr-EDTA, lithium, sodium, postassium, and albumin. ANP was 7.4±3.1 pmol l^-1 (mean±SD) before N and 8.7±6.1 pmol l^-1 at 5 days after Nx and remained at this level through the observation period. Aldo showed a non-significant transient fall at 5 days after Nx. AII and AVP remained normal after Nx. At 5 days after Nx glomerular filtration rate (GFR) of the remaining kidney had risen from 45±7 ml min-1 before Nx to 57± ml min^-1 (p<0·01), lithium clearance had risen from 13±2 ml min^-1 before Nx to 20±7 ml min^-1 (p<0.01), and sodium and water balance was normal. To conclude, plasma ANP, AII, Aldo and AVP do not appear to be responsible for the hyperfiltration and depression of fractional proximal sodium and water reabsorption observed in recently uninephrectomized man with normal sodium and water balance.     

Atrial natriuretic factor: comparability of venous and arterial plasma measurements in man at rest and during exercise

1. Simultaneously obtained arterial and venous plasma atrial natriuretic factor (ANF) concentrations were compared at supine rest and during graded dynamic leg exercise in 10 healthy male subjects (aged 33-51 years). 2. Arterial ANF concentrations ranged between 12 and 179 pg/ml and venous concentrations between 9 and 177 pg/ml. 3. A positive correlation between arterial and venous concentrations was found (r = 0.984). 4. Arterial ANF concentrations were higher than venous concentrations in all pairs of samples (n = 31), but the difference was small and changed little with exercise: the mean difference was 5 pg/ml at rest, 12 pg/ml during submaximal exercise and 6 pg/ml during maximal exercise. 5. The extraction ratios for ANF varied greatly, but were in general lower (P less than 0.05) during maximal exercise (median 0.07, range 0.01-0.32) than at rest (median 0.22, range 0.05-0.33). 6. It was concluded that the plasma ANF concentration in a peripheral arm vein is a good indicator of the systemic peptide concentration at rest as well as during dynamic leg exercise.     

Atrial natriuretic peptide and renal adaptation to contralateral nephrectomy in healthy man.

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo) and arginine vasopressin (AVP) in plasma were determined in 12 healthy renal transplant donors before and 5, 12, 26, 54 days after uninephrectomy (Nx) in order to study the possible role of these hormones in functional adaptation to acute reduction in renal mass. Glomerular and tubular function was studied by measurements of the clearances of 51Cr-EDTA, lithium, sodium, potassium, and albumin. ANP was 7.4 +/- 3.1 pmol l-1 (mean +/- SD) before Nx and 8.7 +/- 6.1 pmol l-1 at 5 days after Nx and remained at this level through the observation period. Aldo showed a non-significant transient fall at 5 days after Nx. AII and AVP remained normal after Nx. At 5 days after Nx glomerular filtration rate (GFR) of the remaining kidney had risen from 45 +/- 7 ml min-1 before Nx to 57 +/- 8 ml min-1 (p less than 0.01), lithium clearance had risen from 13 +/- 2 ml min-1 before Nx to 20 +/- 7 ml min-1 (p less than 0.01), and sodium and water balance was normal. To conclude, plasma ANP, AII, Aldo and AVP do not appear to be responsible for the hyperfiltration and depression of fractional proximal sodium and water reabsorption observed in recently uninephrectomized man with normal sodium and water balance.     

Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide.

Using a specific radioimmunoassay for human brain natriuretic peptide (hBNP) with a monoclonal antibody, we have investigated its synthesis, secretion, and clearance in comparison with those of atrial natriuretic peptide (ANP) in normal subjects and patients with congestive heart failure (CHF). Mean BNP-like immunoreactivity (-LI) levels in normal atrium and ventricle were 250 and 18 pmol/g, respectively. The plasma BNP-LI level in normal subjects was 0.90 +/- 0.07 fmol/ml, which was 16% of the ANP-LI level. In contrast, the plasma BNP-LI level markedly increased in patients with CHF in proportion to its severity, and surpassed the ANP-LI level in severe cases. There was a significant step-up of the plasma BNP-LI level in the coronary sinus (CS) compared with that in the aortic root (Ao) and the difference between these BNP-LI levels, delta(CS-Ao)BNP, also increased with the severity of CHF. In addition, the step-up of the BNP-LI level in the anterior interventricular vein [delta(AIV-Ao)BNP] was comparable to delta(CS-Ao)BNP, indicating that BNP is secreted mainly from the ventricle. Predominant BNP synthesis in the ventricle was also confirmed by Northern blot analysis. Catheterization and pharmacokinetic studies revealed that hBNP is cleared from the circulation more slowly than alpha-hANP; this was in part attributed to lower (about 7%) binding affinity of hBNP to clearance receptors than that of alpha-hANP. A predominant molecular form of BNP-LI in the heart and plasma was a 3-kD form corresponding to hBNP. These results indicate that BNP is a novel cardiac hormone secreted predominantly from the ventricle, and that the synthesis, secretion and clearance of BNP differ from those of ANP, suggesting discrete physiological and pathophysiological roles of BNP in a dual natriuretic peptide system.     

Atrial natriuretic peptide in human cerebrospinal fluid

We measured immunoreactive atrial natriuretic peptide (ANP) levels in cerebrospinal fluid (CSF) collected from patients with various neurologic disorders requiring diagnostic lumbar puncture. ANP was present in all of the CSF samples from 45 patients (1.7 +/- 0.6 pmol/L, mean +/- SD). CSF ANP levels were not related to the underlying central nervous diseases of the patients, to the presence or the absence of consciousness disturbance, or to CSF osmolalities in individual patients. In 35 patients, the mean ANP concentration in CSF corresponded to 27% of that in plasma, and there was no significant correlation between ANP concentrations in each paired sample. When ANP in pooled CSF was extracted by anti-ANP-agarose and analyzed by reverse-phase high performance liquid chromatography (HPLC), multiple peaks of ANP were found. One of the major ANP peaks was identified as ANP-(103-126) on the basis of its retention time on HPLC and the specificity of the antiserum used in the radioimmunoassay; however, none of other peaks coeluted with ANP-(99-126), ANP-(101-126), ANP-(102-126), ANP-(103-125), or ANP-(105-126). We conclude from these results that ANP is present in human CSF that is differently processed from ANP in the cardiac atrium.     

Atrial natriuretic factor increases after a protein meal in man

1. The renal function changes induced by dietary protein are thought to result from the activity of hormonal factors that remain as yet undefined. Since a meat meal and high dose atrial natriuretic factor (ANF) infusions have similar effects on glomerular filtration rate, natriuresis and kaliuresis, we decided to investigate the possibility that a protein meal could stimulate ANF activity. 2. We studied 10 normal volunteers who had a fixed protein and sodium intake for 7 days before the experiments. The subjects received a meat meal (1-1.5 g of protein/kg) and, on a separate occasion, a carbohydrate meal that had a similar caloric, sodium and potassium content. Diuresis was stimulated with water ingestion, and urine collections were obtained before the meals (baseline) and after the meals for a period of 3 h. Blood samples were obtained 30 min and 5 min before the meals and every hour for 3 h in the period after the meal. 3. The protein meal, but not the carbohydrate meal, was associated with parallel increments in plasma immunoreactive ANF (i-ANF), natriuresis, kaliuresis and glomerular filtration rate (estimated from creatinine clearances) which reached peak values 2-3 h after the meal. The mean increment of plasma i-ANF after the protein meal represented a twofold increase over baseline levels. 4. We conclude that ANF may participate in the physiological response to an oral protein load.     

C-type natriuretic peptide does not affect plasma and urinary adrenomedullin in man

To investigate whether C-type natriuretic peptide (CNP) at pathophysiological plasma levels stimulates the release of adrenomedullin (ADM) in man, six healthy subjects (three men and three women, mean age 35 ± 3 years, range 33–40 years) received an intravenous infusion of synthetic human CNP-22 (2 pmol kg^?1 min for 2 h), in a single-blind, placebo-controlled, random order, cross-over study, with measurements of the plasma levels of cyclic guanosine monophosphate (cGMP), ADM, renin and atrial natriuretic peptide (ANP), arterial pressure, heart rate, renal blood flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and the urinary excretion rates of cGMP, ADM and sodium. Infusion of CNP induced increases in its own levels (from 1·17 ± 0·11 up to 21·13 ± 1·41 pmol l^?1) without modifying the plasma levels of cGMP, ADM, renin and ANP, the urinary excretion rate of ADM and cGMP, renal haemodynamics and sodium excretion. These data indicate that circulating CNP is not involved in the regulation of ADM release, renal haemodynamics and sodium excretion in man.