Plasma concentrations of atrial natriuretic peptide in various diseases

Using a radioimmunoassay for atrial natriuretic peptide (ANP) we studied plasma concentrations of immunoreactive ANP in order to investigate the pathophysiological role of ANP in patients with various diseases. Plasma ANP levels were elevated in patients with congestive heart failure (394 +/- 260 pg/ml, n = 8) and chronic renal failure (219 +/- 86 pg/ml, n = 11). In patients undergoing hemodialysis plasma ANP levels were markedly high and decreased after hemodialysis from 433 +/- 166 pg/ml to 204 +/- 92 pg/ml (n = 11). ANP was removed from blood to dialysate (21 +/- 13 pg/ml of dialysate, n = 6, dialysate flow: 500 ml/min). Plasma ANP level was conversely correlated with creatinine clearance (r = -0.812, p less than 0.001) in patients with renal diseases (n = 29). In patients with atrial fibrillation, pace maker implantation, lung disease, chronic glomerulonephritis, nephrotic syndrome, essential hypertension, liver disease and cerebrovascular disease, plasma ANP levels were not significantly different from those in normal subjects (70 +/- 32 pg/ml, n = 28). These results suggest that ANP may be a circulating hormone playing pathophysiological roles in congestive heart failure and chronic renal failure.     

Contrasting cardiac regional responses of A-type and B-type natriuretic peptide to experimental chronic heart failure

OBJECTIVE: The aim of this study was to examine the regional myocardial variation in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) synthesis during development of congestive heart failure (CHF). METHODS: Heart failure was induced by left atrial rapid pacing for 3 weeks in pigs. The gene expression of ANP and BNP was measured by northern blot analysis and the peptide concentration in myocardial tissue and plasma by radioimmunoassay (RIA). RESULTS: At the end of the pacing period pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) increased, and cardiac output (CO) decreased compared to sham-operated controls (PCWP: 17.6 +/- 1.9 vs. 3.1 +/- 0.9 mmHg) (RAP: 10.4 +/- 1.7 vs. 2.2 +/- 0.6 mmHg) (CO: 3.5 +/- 0.4 vs. 5.3 +/- 0.3 l/min), indicating a state of moderate to severe CHF. The gene expression and tissue concentration of BNP was low in sham pigs, but was strongly increased in all cardiac regions, and especially in the left ventricle, during CHF. In contrast, ANP was mainly produced in the atria both in normal and heart failure conditions. The relative increases in mRNA levels, tissue concentrations and circulating peptide concentrations were more profound for BNP than for ANP. CONCLUSIONS: In response to CHF induction, ANP and BNP respond differently across the cardiac regions. Strong expression of the BNP gene was only found in the heart failure state, while ANP was clearly expressed also in the normal state. These findings support the concept of BNP being superior to ANP as a biochemical marker of CHF.     

Evaluation of a direct assay for atrial natriuretic peptide

A direct radioimmunoassay for the assessment of human atrial natriuretic peptide (ANP) in plasma, using a highly specific antibody and a well-defined monoiodotyrosyl-tracer was developed and evaluated by concurrent application of an extraction method. Sensitivity was 13.4 pg/ml; intra- and interassay variations were 3.1 and 5.5%, respectively; recovery averaged 99%; normal values ranged from 15-111 pg/ml (mean +/- SD = 59 +/- 25 pg/ml, n = 41). The results, including the effect of exercise, of the two methods correlated well. Pooling ANP values in normal subjects and patients with congestive heart failure gave a good correlation (p less than 0.01). However, due to processes in unextracted plasma, in the lower range the results from the direct method were erratic. Velocity and duration of centrifugation changed the number of platelets, but no effect on ANP levels, whether assessed by the direct or by the extraction method, was observed. Although the direct method is considerably less laborious than the extracted method its lack of reliability disqualifies it for most purposes.     

Immunoreactive N-terminal pro-atrial natriuretic peptide in human plasma: plasma levels and comparisons with alpha-human atrial natriuretic peptide in normal subjects, patients with essential hypertension, cardiac transplant and chronic renal failure

1. Plasma levels of immunoreactive N-terminal pro-atrial natriuretic peptide (N-terminal ANP) have been measured in 25 normal subjects, 29 patients with essential hypertension, six cardiac transplant recipients, seven patients with dialysis-independent chronic renal failure and 11 patients with haemodialysis-dependent chronic renal failure. Plasma was extracted on Sep-Pak cartridges and N-terminal ANP immunoreactivity was measured using an antibody directed against pro-ANP (1-30). 2. Plasma levels of N-terminal ANP (means +/- SEM) were 235.3 +/- 19.2 pg/ml in normal subjects and were significantly raised in patients with essential hypertension (363.6 +/- 36.3 pg/ml), in cardiac transplant recipients (1240.0 +/- 196.2 pg/ml), in patients with chronic renal failure not requiring dialysis (1636.6 +/- 488.4 pg/ml) and patients with chronic renal failure on maintenance haemodialysis (10336.1 +/- 2043.7 pg/ml). 3. There were positive and significant correlations between the plasma levels of N-terminal ANP and alpha-human ANP (alpha-hANP) with individual correlation coefficients of 0.68 within the normal subjects, 0.47 in patients with essential hypertension, 0.78 in patients with dialysis-independent chronic renal failure and 0.68 in patients with haemodialysis-dependent chronic renal failure (P less than 0.05 in every case).(ABSTRACT TRUNCATED AT 250 WORDS)     

The circulating levels of cardiac natriuretic hormones in healthy adults: effects of age and sex.

In order to study the relationships between sex hormones, aging, and circulating levels of cardiac natriuretic peptides and to define reference values for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) assays, we measured the plasma levels of cardiac natriuretic peptides in a large group of healthy adults divided according to age and sex. We studied 216 healthy subjects of both sexes (109 men and 107 women) with age ranging from 20 to 77 years (mean 43.2+/-14.8 years). All subjects were non-obese and had normal arterial blood pressure; they were free from acute diseases, including asymptomatic heart disease. Highly sensitive and specific IRMA methods were used to measure plasma ANP and BNP. The mean ANP value in healthy adult subjects of both sexes was 17.8+/-10.9 pg/ml with no significant difference between men (16.7+/-10.0 pg/ml) and women (18.8+/-11.7 pg/ml). The mean BNP value in healthy adult subjects of both sexes was 9.9+/-9.0 pg/ml with a significant difference (p<0.0001) between men (7.7+/-7.1 pg/ml) and women (12.2+/-10.2 pg/ml). There was a weak linear relationship between age and either ANP (r=0.350, p<0.0001) or BNP (r=0.254, p=0.0002) values. When the circulating levels of cardiac natriuretic hormones, and age and sex were analyzed by multiple stepwise regression analysis, both age and sex significantly and independently contributed to the regression. Our study indicates independent positive effects of aging and female sex hormones on ANP and BNP levels in healthy adult subjects. These effects should be taken into account in the calculation of appropriate reference values for cardiac natriuretic hormones.     

Decreased density of binding sites for atrial natriuretic peptide on platelets of patients with severe congestive heart failure

1. Binding sites for atrial natriuretic peptide (ANP) with a specificity similar to that of vascular ANP receptors have been demonstrated previously in human platelets. The density of these binding sites for ANP on platelets is decreased after increased dietary sodium intake, when plasma ANP levels increase. ANP-binding sites were investigated in patients with severe congestive heart failure (CHF), a condition in which there is an increase in the concentration of ANP in plasma. 2. In 24 patients with a clinical diagnosis of functional class III-IV CHF, plasma ANP (90.3 +/- 13.4 fmol/ml, mean +/- SEM) was significantly higher (P less than 0.001) than in 16 age-matched patients without cardiac disease (15.4 +/- 2.0 fmol/ml). The density of ANP-binding sites on platelets was significantly lower (P less than 0.01) in the 24 CHF patients (6.3 +/- 0.8 fmol/10(9) cells) than in the non-cardiac patients (11.8 +/- 1.4 fmol/10(9) cells). There was no significant difference in affinity of the ANP-binding sites between both groups. There was a significant non-linear inverse correlation of the density of ANP-binding sites on platelets with plasma ANP concentration. These results could not be explained by prior receptor occupancy secondary to the elevated concentration of circulating ANP. 3. In conclusion, ANP-binding sites on platelets are decreased in patients with severe CHF and with significantly elevated concentration of ANP in plasma.     

Relationship between atrial natriuretic polypeptide and cyclic 3'5'-guanosine monophosphate in human plasma

To examine the interrelationship between human atrial natriuretic polypeptide (hANP) and cyclic 3'5'-guanosine monophosphate (cyclic GMP), plasma concentrations of these compounds were determined in 61 disease-free humans, as controls, and in 35 patients with congestive heart failure. Levels of plasma hANP (199.6 +/- 53.7 pg/ml) and cyclic GMP (12.6 +/- 1.7 pmol/ml) in patients with congestive heart failure were significantly higher than in the control subjects (hANP 57.1 +/- 2.8 pg/ml, cyclic GMP 5.2 +/- 0.3 pmol/ml). Although plasma hANP concentrations in the patients with congestive heart failure tended to increase with the severity of cardiac dysfunction, there was no significant correlation between the levels of plasma hANP and the grade of heart failure, classified according to the New York Heart Association. However, a significant correlation was found between plasma hANP and cyclic GMP concentrations in both the healthy subjects and the patients with congestive heart failure, and a weak positive correlation between plasma hANP and cyclic 3'5'-adenosine monophosphate (cyclic AMP) concentration in the patients with congestive heart failure. Thus, changes in plasma cyclic GMP concentration depend to some extent on the plasma concentrations of hANP.     

Increased plasma concentrations of endothelin in congestive heart failure in humans.

Congestive heart failure is characterized by decreased cardiac output and increased peripheral vascular resistance. Endothelin, a peptide found in plasma, is a potent vasoconstrictor. We hypothesized that plasma concentrations of endothelin are increased in humans with congestive heart failure. Plasma samples were obtained from 71 healthy control subjects and 56 patients with congestive heart failure. The mean plasma concentration of endothelin, measured by radioimmunoassay, was 7.1 +/- 0.1 pg/ml in the 71 normal control subjects but 12.6 +/- 0.6 pg/ml in the 56 patients with heart failure (P = 0.001). To evaluate the relationship between circulating endothelin and clinical stage of congestive heart failure, we categorized patients into two groups--those with mild heart failure (New York Heart Association class I or II) and those with severe heart failure (class III or IV). Circulating endothelin in the 24 patients with mild disease was 11.1 +/- 0.7 pg/ml, significantly higher than in normal subjects (P < 0.001). Endothelin in the 32 patients with severe heart failure was 13.8 +/- 0.9 pg/ml, a level significantly higher than that in the group with mild disease (P = 0.029). In the 56 patients with congestive heart failure, a negative correlation was found between plasma concentration of endothelin and left ventricular ejection fraction (r = -0.279; P = 0.037). These data demonstrate that the plasma concentration of endothelin is increased in humans with congestive heart failure and that the level correlates with the severity of disease. Endothelin may have a role in the increased vascular resistance in patients with chronic congestive heart failure.     

Identification of atrial natriuretic factor within ventricular tissue in hamsters and humans with congestive heart failure.

In normal mammals, atrial natriuretic factor (ANF) is present within atrial myocardial cells but is absent from ventricular myocardium. In primitive organisms ANF is present within both atria and ventricle, suggesting that the ventricle may participate both in the synthesis and release of the hormone. The current study was designed to test the hypothesis that ventricular ANF develops as a homeostatic response to intravascular volume overload. Studies were performed on cardiac tissue obtained from (i) normal and cardiomyopathic hamsters, (ii) autopsied humans with and without cardiac disease, and (iii) living humans with congestive heart failure (CHF) undergoing diagnostic right ventricular endomyocardial biopsy. The myocardium was examined for the presence of immunoreactive ANF using a two-stage immunohistochemical technique, with nonimmune rabbit sera used as a negative control. There was unequivocal evidence of focal subendocardial deposits of immunoreactive ANF present in both of the ventricles of all six cardiomyopathic hamsters, four of five autopsied human subjects with CHF, and five of seven biopsied humans. No immunoreactive ANF was observed within the ventricular myocardium of control hamsters or normal humans. Utilizing crude tissue homogenates and radioimmunoassay techniques, the quantity of ANF was determined in cardiac atria, ventricles, and noncardiac skeletal muscle. Heart failure is characterized by a reduction in atrial ANF and an increase in ventricular ANF. This study demonstrates immunoreactive ANF is present within the ventricular myocardium in cardiomyopathic hamsters and humans with CHF, and suggests that the ventricle may be capable of responding to chronic volume overload by producing ANF.     

Effect of endopeptidase 24.11 inhibition in conscious cardiomyopathic hamsters

An elevated plasma concentration of atrial natriuretic peptide (ANP) is characteristic of congestive heart failure (CHF) in both humans and animals. One strategy for facilitating the biological actions of this circulating hormone is to inhibit its metabolism. Neutral endopeptidase 24.11, an enzyme known to degrade ANP, has been implicated in the metabolic clearance of this hormone. Inhibition of endopeptidase 24.11 may produce increases in the local concentrations of ANP in organs rich in the enzyme, such as the kidney, thereby enhancing local actions, e.g. natriuresis. Exogenous administration of ANP to CHF patients produces limited natriuresis, perhaps because of the associated fall in arterial pressure. This approach of blocking endopeptidase 24.11 activity in CHF could offset the general effects of exogenous administration of ANP and result in enhanced natriuresis. We therefore undertook studies to determine if thiorphan, an endopeptidase 24.11 inhibitor, would increase circulating ANP levels and enhance natriuresis in conscious cardiomyopathic hamsters with CHF. Cardiomyopathic hamsters had significantly lower (P less than .05) basal mean arterial pressures in comparison to normal hamsters (90 +/- 2 vs. 135 +/- 3 mm Hg). Treatment with thiorphan (10 mg/kg i.v. bolus followed by 10 mg/kg/hr i.v. infusion) did not change arterial pressure in either group and produced a 3-fold increase in urinary sodium excretion in the cardiomyopathic group but not in the normal hamsters. This natriuretic response in the cardiomyopathic hamsters was associated with a doubling of the plasma concentration of ANP. These results indicate that inhibition of endopeptidase 24.11 increases natriuresis and circulating ANP concentrations in this model of CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular cloning of hamster brain and atrial natriuretic peptide cDNAs. Cardiomyopathic hamsters are useful models for brain and atrial natriuretic peptides.

Brain and atrial natriuretic peptides (BNP and ANP) are cardiac hormones with diuretic, natriuretic, and vasodilatory activities. Cardiomyopathic hamsters are widely used animal models of heart failure. Due to the structural divergence of BNP among species, examination on pathophysiological roles of BNP using cardiomyopathic hamsters is so far impossible. We therefore isolated hamster BNP and ANP cDNAs, and investigated synthesis and secretion of these peptides in normal and cardiomyopathic hamsters. The COOH-terminal 32-residue peptide of cloned hamster preproBNP with 122 amino acids, preceded by a single arginine residue, supposedly represents hamster BNP showing < 50% homology to rat BNP. Alpha-hamster ANP, 28-residue peptide, is identical to alpha-rat ANP. In hamsters, BNP and ANP occur mainly in the ventricle and the atrium, respectively. The 32-wk-old hypertrophic cardiomyopathic BIO14.6 strain exhibited ventricular hypertrophy. The 32-wk-old dilated cardiomyopathic BIO53.58 strain remained at the stage without apparent heart failure. In BIO14.6 and BIO53.58 strains at this age, ventricular BNP and ANP gene expressions are augmented, and the plasma BNP concentration is elevated to 136 and 108 fmol/ml, respectively, three times greater than the elevated plasma ANP concentration, which well mimics changes of the plasma BNP and ANP concentrations in human heart failure. Cardiomyopathic hamsters, therefore, are useful models to investigate the implication of BNP in human cardiovascular diseases.     

Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice

Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal ANP are good research indices of the severity of heart failure. The stability of these peptides at room temperature has become an important factor in assessing their use as indicators of cardiac function in routine clinical practice. Inhibitors such as aprotinin are routinely added in the blood collection process, but may provide no benefit in sample collection and routine clinical practice. We assessed the stability of BNP, ANP and N-terminal ANP in blood samples collected in either the presence or the absence of the protease inhibitor aprotinin. Blood, either with or without aprotinin, was processed immediately (initial; 0 h) and after blood samples had been left for 3 h, 2 days or 3 days at room temperature. These times were chosen to reflect processing in a hospital outpatient clinic (2-3 h), or when posted from general practice (2-3 days). Initial plasma BNP, ANP and N-terminal ANP levels in the absence of aprotinin were 28.2+/-5.4, 44.2+/-7.9 and 1997+/-608 pg/ml respectively, and were not significantly different from initial values in the presence of aprotinin (29.0+/-5.9, 45.2+/-8.0 and 2009+/-579 pg/ml respectively). After 3 h at room temperature, there was a significant fall in ANP in the absence of aprotinin (36. 7+/-7.9 pg/ml; P<0.005), but not in the presence of aprotinin (41. 2+/-7.6 pg/ml). Both BNP and N-terminal ANP were unchanged in either the absence (BNP, 27.6+/-5.5 pg/ml; N-terminal ANP, 2099+/-613 pg/ml) or the presence (BNP, 29.4+/-5.6 pg/ml; N-terminal ANP, 1988+/-600 pg/ml) of aprotinin. After 2 days at room temperature, ANP had fallen significantly in both the absence (16.9+/-3.4 pg/ml) and the presence (24.0+/-5.0 pg/ml) of aprotinin compared with initial values, and there was a significant difference in ANP levels in the absence and presence of aprotinin (P<0.001). ANP levels had decreased further after 3 days at room temperature, to 11.9+/-3.4 pg/ml (no aprotinin) and 20.3+/-5.0 pg/ml (aprotinin added); these values were significantly different (P=0.002). In contrast, there was no change in the levels of BNP or N-terminal ANP after 2 or 3 days at room temperature, in either the absence or the presence of aprotinin. These studies indicate that aprotinin adds little benefit to the stability of cardiac peptides at room temperature. Blood samples for BNP and N-terminal ANP measurement used as a test of heart function in hospital clinics and by general practitioners in the community could be taken into blood tubes containing only EDTA as anticoagulant and without the additional step of adding the routinely used inhibitor aprotinin.     

Plasma bradykinin levels in human chronic congestive heart failure

Induction of congestive heart failure by high-frequency pacing has been reported to increase plasma levels of immunoreactive kinins in dogs. In the present study, we evaluated plasma bradykinin levels in human heart failure. Utilizing a recently developed method, we specifically measured plasma levels of bradykinin-(1-9) nonapeptide in 21 patients with chronic congestive heart failure [New York Heart Association (NYHA) stages III and IV). At the same time, we measured plasma atrial natriuretic peptide levels and plasma renin activity, and, as a marker of inflammation, plasma levels of tumour necrosis factor. In addition, 18 healthy subjects matched for gender and age served as normal controls. Plasma bradykinin concentrations were not higher in patients with chronic congestive heart failure (median 2.1 fmol/ml) than in healthy subjects (2.6 fmol/ml). In contrast, plasma atrial natriuretic peptide levels were clearly higher (patients, 63 fmol/ml; controls, 24 fmol/ml; P<0.0001), despite diuretic treatment and in the presence of high plasma renin activity (patients, 13.0 ng x h(-1) x ml(-1); controls, 0.3 ng x h(-1) x ml(-1); P<0.0001). Tumour necrosis factor was elevated in heart failure patients in NYHA class IV only (27 pg/ml, compared with 21 pg/ml in controls; P=0.013). Bradykinin, atrial natriuretic peptide and plasma renin activity levels were not correlated with the severity of the disease, as assessed by NYHA classification. These results indicate that a rather selective cytokine activation, without concomitant stimulation of the kallikrein-kinin system, occurs in human chronic congestive heart failure.     

Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.

Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.     

Mechanism of opioid-induced atrial natriuretic peptide release in conscious rats

To examine the role of atrial stretch and vasopressin in opiate-induced atrial natriuretic peptide (ANP) release, we studied the effects of a mu receptor agonist fentanyl on plasma immunoreactive ANP (IR-ANP) and hemodynamics (mean arterial pressure, heart rate and right atrial pressure) in the conscious, chronically cannulated Wistar, Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Infusion of fentanyl (3 and 10 micrograms/kg i.v.) produced an immediate decrease in heart rate in conscious Wistar rats, whereas mean arterial pressure did not change significantly. Heart rate returned to control levels within 2 min of the injection, except after the largest dose of fentanyl when heart rate remained decreased for 5 min. Administration of 10 micrograms/kg of fentanyl caused a marked increase in right atrial pressure (3.9 +/- 0.3 mm Hg, n = 9, P less than .001) associated with 3.5-fold increase in the plasma IR-ANP concentration (168 +/- 17 pg/ml vs. 567 +/- 116 pg/ml, n = 9, P less than .01). In contrast, right atrial pressure decreased by 0.8 +/- 0.3 mm Hg (P less than .05) in response to infusion of 3 micrograms/kg of fentanyl with a slight increase (34%) in plasma IR-ANP. One microgram per kilogram i.v. of fentanyl had no effect on hemodynamic variables and plasma IR-ANP levels. Infusion of V1 antagonist (5 micrograms/kg/min for 25 min) did not affect basal or fentanyl-stimulated changes in hemodynamics or plasma IR-ANP concentration in Wistar rats. Infusion of fentanyl (3 and 10 micrograms/kg) in the LE and DI rats produced similar short-lasting heart rate reductions as seen in Wistar rats. Furthermore, injection of 10 micrograms/kg of fentanyl decreased blood pressure and increased plasma IR-ANP and right atrial pressure in both strains. The analysis of changes in plasma IR-ANP and right atrial pressure in response to fentanyl showed that for a given increase in right atrial pressure, a smaller amount of IR-ANP was released in the DI than in the LE rats. These results demonstrate that at higher fentanyl doses, the increased ANP release is mediated primarily by elevation of right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide in human essential hypertension

We measured the circulating levels of atrial natriuretic peptide (ANP) in 62 patients with untreated uncomplicated essential hypertension and in 30 normotensive subjects. In the hypertensive patients, mean systolic and diastolic blood pressures were 148 and 101 mm Hg, respectively, and the mean heart rate was 73 beats/min. ANP concentrations were not elevated in the hypertensive group but were actually decreased slightly over those of the control group (27.4 +/- 1.8 pg/ml versus 35.3 +/- 2.4 pg/ml [P less than 0.02]). No relationship was found between ANP levels and diastolic blood pressure, plasma renin activity, urinary sodium excretion, or serum creatinine level. In 8 of the 62 patients with essential hypertension, 6 weeks of treatment with a dihydropyridine calcium channel blocker, nitrendipine, significantly reduced plasma ANP levels from 28.6 +/- 4.3 pg/ml to 18.7 +/- 1.8 pg/ml (P less than 0.05). In 17 additional patients treated with the hypotensive agent ketanserin, ANP levels were not significantly reduced after treatment. Thus, this study demonstrates that circulating plasma ANP levels are not increased but are slightly decreased in patients with uncomplicated essential hypertension in comparison with normotensive subjects. Furthermore, antihypertensive treatment with a calcium channel antagonist reduced plasma levels of ANP.     

Changes in the plasma levels of atrial natriuretic peptides during mineralocorticoid escape in man

Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay in eight normal healthy volunteers before and during mineralocorticoid escape. Mean plasma ANP on a fixed sodium intake before fludrocortisone was 6.5 +/- SEM 1.1 pg/ml. Within 24 h of fludrocortisone administration there was a significant increase in plasma ANP which continued to increase daily reaching a plateau by day 4 (14.9 +/- 2.4 pg/ml) to day 7 (15.1 +/- 2.6 pg/ml). The rise in plasma ANP was closely related to the amount of sodium retained during the fludrocortisone treatment and the sodium 'escape' occurred by days 4 to 7. These results support the concept that ANP could play an important hormonal role in over-coming the sodium-retaining effects of mineralocorticoids in man.     

A functional role for endogenous atrial natriuretic peptide in a canine model of early left ventricular dysfunction.

Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.     

Increased secretion of atrial natriuretic polypeptide from the left ventricle in patients with dilated cardiomyopathy.

To examine whether atrial natriuretic polypeptide (ANP) is released from the left ventricle in patients with dilated cardiomyopathy (DCM) we measured plasma ANP level in the aortic root (Ao), the anterior interventricular vein (AIV), the great cardiac vein (GCV), and the coronary sinus (CS) in 11 patients with DCM and 18 control subjects. Plasma ANP levels in Ao, AIV, GCV, and CS were 454 +/- 360, 915 +/- 584, 1,308 +/- 926, and 1,884 +/- 1,194 pg/ml, respectively, in the patients with DCM and 108 +/- 42, 127 +/- 55, 461 +/- 224, and 682 +/- 341 pg/ml, respectively, in the control subjects. There was no significant difference in the plasma ANP levels between Ao and AIV in the control subjects. On the contrary, there was a significant (P less than 0.001) step-up in plasma ANP levels between Ao and AIV in patients with DCM. Thus, the difference in ANP levels between Ao and AIV was significantly increased in patients with DCM as compared with the control subjects (461 +/- 248 vs. 19 +/- 59 pg/ml, P less than 0.001). The difference in ANP levels between Ao and CS was also significantly increased in patients with DCM as compared with the control subjects (1,429 +/- 890 vs. 577 +/- 318 pg/ml, P less than 0.001). We conclude that ANP is released in increased amounts into the circulation from the left ventricle as well as from the heart as a whole in patients with DCM.     

Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling.

OBJECTIVES: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.