Current indications of plasma atrial natriuretic peptide measurements in human diseases

The discovery of atrial natriuretic peptide (ANP) has modified our current understanding of the regulation of sodium metabolism. This peptide, of which the second messenger is cyclic guanosine monophosphate (cyclic GMP), is released by the atrial myocytes in response to increased atrial stretch and has for essential function to diminish the venous return to the heart. Radioimmunoassays have demonstrated that plasma ANP and cyclic GMP levels are increased in various diseases such as congestive heart failure (CHF), renal insufficiency, and, to a lesser extent, diabetes mellitus and liver cirrhosis with ascites. Plasma ANP is of prognostic value in CHF and reflects the effective central volemia in renal failure so that its assay as well as that of plasma cyclic GMP seem of interest in these diseases. Further studies are needed to assess the pathophysiological significance of ANP in diabetes mellitus and cirrhosis, and to define the indications of the treatment by enkephalinase inhibitors which increase endogenous ANP levels by lowering the catabolism of this hormone.     

Evaluation of atrial natriuretic peptide and brain natriuretic peptide in atrial granules of rats with experimental congestive heart failure.

The natriuretic peptides are believed to play an important role in the pathophysiology of congestive heart failure (CHF). We utilized a quantitative cytomorphometric method, using double immunocytochemical labeling, to assess the characteristics of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in atrial granules in an experimental model of rats with CHF induced by aortocaval fistula. Rats with CHF were further divided into decompensated (sodium-retaining) and compensated (sodium-excreting) subgroups and compared with a sham-operated control group. A total of 947 granules in myocytes in the right atrium were analyzed, using electron microscopy and a computerized analysis system. Decompensated CHF was associated with alterations in the modal nature of granule content packing, as depicted by moving bin analysis, and in the granule density of both peptides. In control rats, the mean density of gold particles attached to both peptides was 347.0 +/- 103.6 and 306.3 +/- 89.9 gold particles/microm2 for ANP and BNP, respectively. Similar mean density was revealed in the compensated rats (390.6 +/- 81.0 and 351.3 +/- 62.1 gold particles/microm2 for ANP and BNP, respectively). However, in rats with decompensated CHF, a significant decrease in the mean density of gold particles was observed (141.6 +/- 67.3 and 158.0 +/- 71.2 gold particles/microm2 for ANP and BNP, respectively; p<0.05 compared with compensated rats, for both ANP and BNP). The ANP:BNP ratio did not differ between groups. These findings indicate that the development of decompensated CHF in rats with aortocaval fistula is associated with a marked decrease in the density of both peptides in atrial granules, as well as in alterations in the quantal nature of granule formation. The data further suggest that both peptides, ANP and BNP, may be regulated in the atrium by a common secretory mechanism in CHF.     

Human cardiac plasma concentrations of atrial natriuretic peptide quantified by radioreceptor assay

The presence of high affinity receptors for atrial natriuretic peptide in bovine adrenal cortex has enabled the development of a sensitive, specific and rapid radioreceptor assay for this peptide in human plasma. In 18 normal subjects, venous plasma atrial natriuretic peptide concentration ranged from 6 to 65 pM. This plasma concentration was two-fold higher in right atrium as compared to venous blood in 12 patients investigated by cardiac catheterisation, confirming that the right atrium is the site of release of atrial natriuretic peptide into circulation. There was a further step up in plasma atrial natriuretic peptide concentration between pulmonary arterial and aortic plasma. This finding indicates that released hormone in man may undergo further activation in the lungs, or that there may be direct release from the left atrium.     

Lack of diurnal rhythm in plasma atrial natriuretic peptide.

The occurrence of a circadian rhythm in the concentration of circulating atrial natriuretic peptide (ANP) is not clearly established. To investigate diurnal changes, plasma levels of ANP were measured at 10-min intervals for 24 hours in six normal volunteers. The subjects were studied once during a normal sleep-wake cycle and once during a cycle with a shifted sleep period. They received continuous enteral nutrition from 8 hours preceding the experiment until the end of the experiment, throughout this time the subjects remained in a supine position. The mean ANP levels did not differ significantly between the sleep periods and the periods spent awake in either of the protocols, which provides evidence of a lack of a sleep-related influence of ANP. A significant linearity of the mean ANP profile was observed, smoothing out the transient and randomly occurring fluctuations in individual ANP concentration. These results lead to the conclusion that ANP secretion is neither under the control of endogenous circadian rhythmicity nor is it affected by sleep-regulatory mechanisms.     

Presence of immunoreactive atrial natriuretic peptides in pericardial fluid of human subjects with congenital heart diseases

The epicardial release of immunoreactive atrial natriuretic peptides (ir-ANPs) in inside-out perfused rabbit atria has been reported. In order to determine the presence of ir-ANPs in pericardial fluid and to evaluate their biochemical characteristics, we measured the concentration of ir-ANPs in pericardial fluid obtained from the patients with congenital heart diseases during open heart surgery. Serial dilution curves made with the extrats of pericardial fluid using Sep-Pak C18 cartridges were parallel with standard curve. The concentration of ir-ANPs in pericardial fluid was significantly lower than the corresponding plasma concentration. On gel permeation and reverse-phase high performance liquid chromatography, the ir-ANPs in pericardial fluid, plasma and atrial appendage showed both high and low molecular weights. The major peak of ir-ANPs in plasma was observed at the corresponding fraction to the alpha-human ANP and considerable amount of high molecular weight form of ir-ANPs was observed in pericardial fluid. However, the major peak of ir-ANPs in atrial appendage was observed at the corresponding fraction to the rat pro-ANP. The data suggest that ir-ANPs exist both high and low molecular weight forms in pericardial fluid.     

Attenuated diuretic and natriuretic effects of atrial natriuretic peptide in rats with heart failure

Plasma levels of atrial natriuretic peptide (ANP) and renal responses to ANP were examined in rats with chronic cardiac failure produced by coronary artery ligation and in sham-operated controls. Plasma ANP levels were elevated in the rats with severe cardiac failure as compared with the controls (P less than 0.001). ANP injections at the doses of 1, 5, 25 and 50 micrograms/kg increased water and sodium excretion significantly at all but the lowest dose in the controls; only the two largest doses caused clear diuresis and natriuresis in the heart failure group. The diuretic and natriuretic effects of ANP were significantly weaker at the doses of 5 and 25 micrograms/kg in the rats with heart failure as compared with the controls. We conclude, that natriuretic and diuretic effects of ANP are attenuated in this chronic heart failure mode.     

Elevated plasma atrial natriuretic peptide in rats with myocardial infarcts

We measured atrial natriuretic peptide (ANP) plasma levels in rats with experimental heart failure caused by left coronary artery ligation. ANP levels were clearly higher in infarcted rats (409 +/- 59 pg/ml; mean +/- S.E.M.) than in sham-operated controls (39 +/- 6 pg/ml). Moreover, plasma ANP levels increased progressively with the severity of cardiac dysfunction and size of infarct. Increased release of ANP in post-infarction heart failure appears to be a meaningful compensatory response to control rising preload. Our results are in keeping with evidence from human studies showing increased plasma concentration of ANP in patients with congestive heart failure. This model is a useful tool to further explore the role of ANP in heart failure.     

Cardiac atrial natriuretic peptide concentrations in experimental obese mice

Obesity is usually associated with expansion of blood volume. Therefore, we studied whether obesity affects cardiac and plasma atrial natriuretic peptide (ANP) levels in experimental animal model. Mice made obese with gold thioglucose developed cardiac hypertrophy associated with increases in ANP in atrial tissue and plasma. There were significant (p less than 0.01) correlations between the cardiac ANP concentration and body weight or cardiac weight. These data suggest that enhanced synthesis of atrial ANP in obese mice can be mainly ascribed to increased blood volume associated with cardiac hypertrophy.     

Plasma atrial natriuretic peptide levels in children with cardiac diseases: correlation with cGMP levels and haemodynamic parameters

In children with various forms of cardiac diseases (aged 2 months to 16 years) significantly higher plasma atrial natriuretic peptide (ANP; range 36-680, median 247 pg/ml) and cyclic 3'5'-guanosine monophosphate (cGMP; range 0.2-46, median 8.2 pmol/ml) levels were found than in control children (p less than 0.0001). In control children (aged 4 months to 17 years) plasma ANP and cGMP levels were measured in the range of 2.4-98 pg/ml and of 0.2-2.8 pmol/ml, respectively. There was a linear correlation between the two parameters in children with cardiac diseases (r = 0.62, p less than 0.01). Children with elevated mean right atrial pressure (i.e., greater than 6 mm Hg) showed significantly higher plasma ANP levels than children with normal atrial pressure (p less than 0.01). However, there was only a weak linear correlation between mean right atrial pressure and plasma ANP levels (r = 0.48, p less than 0.01). Plasma ANP levels from right atrium, pulmonary artery, left atrium and left ventricle were significantly higher than those from vena cava (p less than 0.05). Analysis of ANP-like immunoreactive material by high performance liquid chromatography suggested that alpha-ANP is the major form of circulating ANP in blood of children with cardiac diseases.     

Plasma levels of human atrial natriuretic peptide in patients with hypertensive diseases

Three types of antihuman atrial natriuretic peptide antiserum were obtained. From the study of cross-reactivity to human atrial natriuretic peptide fragments, it was suggested that antisera-1, -2, and -3 are mostly specific to 1-28, 5-25, and the ring structure, respectively. The estimated values of this hormone were significantly lower in the order of antisera-1, -2, and -3. Moreover, high performance liquid chromatographic study showed that various types of fragments of atrial natriuretic peptide exist in human plasma. These findings suggested that the highly specific antiserum to 1-28 human atrial natriuretic peptide such as antiserum-1 should be used to estimate the 1-28 human atrial natriuretic peptide levels in human plasma. From the study by using antiserum-1, it was concluded that the plasma human atrial natriuretic peptide increased in essential hypertensives, and in patients with primary aldosteronism, chronic renal failure, and malignant hypertension. Regarding the pathophysiological significance of increased plasma atrial natriuretic peptide, it is unlikely that this plays an important role in the etiology of essential hypertension or other hypertensive diseases, because the plasma level of this hormone is elevated in these patients. The increase of plasma atrial natriuretic peptide level in these patients should be considered to be a secondary or compensatory reaction to high blood pressure.     

Acute stress increases plasma concentrations of atrial natriuretic peptides

5 min exposure of inbred Maudsley Reactive male rats to intermittent foot-shock resulted in an approximate doubling of plasma atrial natriuretic peptides ANP (Control grp mean = 62.12 +/- 8.74; Stressed grp mean = 128.70 +/- 26.63 pg/ml) and 25 min exposure resulted in a three-fold increase (Stressed grp mean = 187.88 +/- 39.24 pg/ml). In the second experiment exposure of genetically heterogeneous Wistar male rats to 15 min of intermittent foot-shock produced a 10-fold increase in plasma ANP (Control grp mean = 45.76 +/- 6.05; Stressed grp mean = 471.20 +/- 58.49 pg/ml). The magnitude of the increase in plasma ANP produced by acute stress is as large as the increase caused by volume expansion and administration of various pharmacological agents and therefore delineation of biological role of ANP must take account of its potential role as a stress-hormone.     

Atrial natriuretic peptide concentrations in pre-eclampsia.

The concentration of plasma immunoreactive atrial natriuretic peptide is positively associated with right atrial and pulmonary capillary wedge pressure, suggesting that blood volume and hence atrial pressure govern its release. Expansion of plasma volume is a central physiological adjustment in normal pregnancy. Conversely, pregnancies complicated by pre-eclampsia are associated with a reduction in plasma volume and central venous pressure. A study was therefore undertaken to test the hypothesis that plasma atrial natriuretic peptide concentrations are low in pre-eclampsia owing to deficient secretion. Concentrations of the peptide were measured by a specific radioimmunoassay. The mean plasma immunoreactive atrial natriuretic peptide concentration in healthy pregnant women (n = 22; third trimester) was higher (56 (1 SD 29) ng/l) than in 25 young, non-pregnant controls (37 (19) ng/l). Concentrations in patients suffering from mild pre-eclampsia (n = 9) were higher (127 (60) ng/l) than in normal pregnant women, and in patients with severe pre-eclampsia (n = 6) concentrations were higher still (392 (225) ng/l). Despite failure of plasma volume expansion and low central venous and pulmonary capillary wedge pressures in pre-eclampsia this condition is associated with greatly increased plasma concentrations of plasma immunoreactive atrial natriuretic peptide, which increase still further with the severity of the disease. These findings are clear evidence that atrial pressure may not be the principal determinant of the release of the natriuretic peptide in pre-eclampsia.     

Nocturnal fluctuations of plasma atrial natriuretic peptide in normotensive and hypertensive men

Plasma levels of immunoreactive atrial natriuretic peptides (ANP) were measured at 10-min intervals during night-sleep in 4 normotensive and in 4 moderate, essential hypertensive subjects. The mean ANP levels ranged from 24.3 to 27.9 pg.ml-1 for the normal subjects. These mean levels were not significantly different in the hypertensive subjects (range: 26.3 to 37.2 pg.ml-1). Fluctuations, often of small amplitude, were observed around this mean, without any defined periodicity. Changes in plasma ANP were not associated with changes in heart rate. Analysis of the ANP profiles and the concomitant sleep stage patterns did not reveal any temporal relationship between ANP fluctuations and specific sleep stages or waking periods. The ANP profiles did not differ between the groups, which indicates no abnormality in ANP secretion in moderate essential hypertension.     

C-receptor ligand blocks pulmonary clearance of atrial natriuretic peptide in isolated rat lungs.

Pulmonary clearance of atrial natriuretic peptide (ANP) was measured by indicator dilution technique in isolated perfused rat lungs with and without ANP clearance receptor (C-receptor) blockade. Approximately 50% of a bolus injection of 125I-ANP was removed during a single pass through the lungs compared with the intravascular marker 14C-dextran. Pulmonary clearance of 125I-ANP was suppressed in a dose-dependent fashion by unlabeled ANP. C-receptor blockade suppressed pulmonary clearance of 125I-ANP to the same degree as unlabeled ANP. High-performance liquid chromatography analysis of the pulmonary venous effluent from lungs treated with C-receptor ligand demonstrated intact 125I-ANP. We conclude that virtually all of the pulmonary vascular uptake of 125I-ANP during a single pass through isolated lungs is secondary to removal by ANP C-receptors.     

Plasma and atrial levels of atrial natriuretic peptide (ANP) in pulmonary hypertensive rats

Immunoreactive atrial natriuretic peptide (IR-ANP) was measured in plasma and atrium of normal and monocrotaline induced pulmonary hypertensive rats (PH rats). In these animals, there was right ventricular hypertrophy and right ventricular systolic pressure was elevated. Fourteen days after a single dose of monocrotaline (40 mg/kg), plasma IR-ANP concentrations were significantly elevated (964.3 +/- 63.0 pg/ml vs. 521.0 +/- 81.9 pg/ml in controls, p less than 0.001). Tissue levels of IR-ANP in the right atrium in PH rats was significantly lower than those in the controls (45.1 +/- 3.9 ng/mg vs. 240.5 +/- 10.4 ng/mg, p less than 0.001), while there was no significant difference in tissue levels of atrial IR-ANP in the left atrium between the two groups. Thus, development of pulmonary hypertension led to an increase in release of ANP from the right atrium.     

Effects of angiotensin II, arginine-vasopressin, endothelin and catecholamines on plasma atrial natriuretic peptide concentrations in the conscious newborn calf.

The effects of epinephrine (E), norepinephrine (NE), angiotensin II (AII), arginine-vasopressin (AVP) and endothelin on plasma ANP levels were studied according to a latin square design in six 12-21 days-old conscious Jersey calves weighing 30 +/- 4 kg. The animals chronically-instrumented with a carotid catheter for blood pressure recording, received at 11.00 a.m. an i.v. right jugular continuous infusion for 30 min of two different sub-pressor or pressor dose-levels of each substance; E: 0.6 and 5.5 nmol/min per kg body wt; NE: 0.6 and 6 nmol/min per kg body wt; AII: 9.6 and 96 pmol/min per kg body wt; AVP: 0.6 and 69 pmol/min per kg body wt; and endothelin: 1.2 and 12 pmol/min per kg body wt). Control animals received, in the same way, the same volume (2 ml/kg body wt) of NaCl 0.9%. In Jersey calves, basal plasma atrial naturetic peptide (ANP) levels were around 5 pmol/l. Marked increases in this parameter were produced by all substances when given at the highest dose-level. The maximal rise of 600% was observed with AII; however on a molar basis, endothelin appeared more potent than AII and at the same dose-level, E appeared more effective than NE to increase circulating ANP (17.8 +/- 0.3 vs 9.5 +/- 0.1 respectively at time 70 min; P less than 0.01). The time-course of plasma ANP levels was positively correlated (P less than 0.01) by linear regression with the increase in blood pressure when pressor agents were given at the highest dose.(ABSTRACT TRUNCATED AT 250 WORDS)