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European Journal of Heart Failure 2001 3(4):407-414; doi:10.1016/S1388-9842(01)00161-1
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© 2001 European Society of Cardiology

Up-regulation of ‘clearance’ receptors in patients with chronic heart failure: a possible explanation for the resistance to biological effects of cardiac natriuretic hormones

Maria Grazia Andreassi, Silvia Del Ry, Cataldo Palmieri, Aldo Clerico, Andrea Biagini and Daniela Giannessi*

CNR Institute of Clinical Physiology Area della Ricerca, Via Moruzzi, 1, 56100 Pisa, Italy

* Corresponding author. Tel.: +39-050-3152664; fax: +39-050-3152166. E-mail address: danielag{at}ifc.cnr.it (D. Giannessi).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: Three specific receptors for the cardiac natriuretic peptide system have been identified to date. Down-regulation of the biologically active binding sites (i.e. NPR-A and NPR-B) could explain the blunted response to cardiac natriuretic hormones observed in heart failure (HF), but not the increased metabolic clearance rate. Variations in the ratio between biological and clearance (NPR-C) receptors in target tissue may explain this increase.

Aim: The aim of this study was to investigate the regulation of NPR-C receptors on platelets, in patients with HF.

Methods: Eighteen patients with HF (NYHA class: I–II, n = 8; III–IV, n = 10) and 18 age-matched healthy subjects were studied. The affinity constant (Kd) and density (Bmax) of binding sites were derived by saturation assays on platelet suspensions using 125I-ANP as radioligand.

Results: Bmax increased as a function of the severity of disease: 21.3±3.3 fmol/109 cells in class III–IV, 11.7±2.2 in class I–II, and 11.6±1.1 in controls, respectively (P = 0.0179 for class III–IV vs. controls and P = 0.0451 vs. NYHA I–II).

Conclusions: The increase in density of ‘clearance’ receptors in severe HF is theoretically consistent with the reduction in cardiac natriuretic peptide biological activity, as well as the increase in metabolic clearance rate. This suggests that clearance receptor blockade may be of potential therapeutic value in HF.

Key Words: Natriuretic peptides • ANP • BNP • Heart failure • Clearance receptor • Platelets

Received April 26, 2000; Revised May 19, 2000; Accepted September 3, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Deficiencies in the cardiac natriuretic system could help explain the disturbed electrolyte and fluid homeostasis, which occurs in HF [1,2]. Cardiac natriuretic peptides (ANP and BNP) are increased in patients with HF, due to enhanced cardiac synthesis and secretion. The elevation of these peptides has diagnostic and prognostic importance, because it occurs in proportion to the progression of clinical symptoms and the deterioration of hemodynamics [3–9].

The activation of the cardiac natriuretic peptide system (ANP, BNP) in patients with left ventricular dysfunction has beneficial, compensatory actions to promote systemic arterial dilation, natriuresis, diuresis and renin inhibition [10,11].

Indeed, the effect of exogenous infusion of cardiac natriuretic peptides is markedly attenuated in experimental models and in patients with severe heart failure [9,11,12]. Furthermore, by using a tracer method, disturbed metabolism of ANP was observed in patients with different degrees of HF [1]. This altered degradation and distribution of ANP was characterized by an increase in metabolic clearance rate (on average, 2.5-fold) and hormone production (on average, sixfold) as well as by progressive reduction in distribution spaces when compared with normal subjects at the same sodium intake.

Three different subtypes of natriuretic peptide receptors (NPR) have so far been identified [13]. Two of these receptors (NPR-A and NPR-B) are generally considered to mediate all known biological actions of these hormones, activating a particulate guanylate cyclase with intracellular accumulation of cGMP. The third member of the natriuretic peptide receptor family, the NPR-C receptor, is independent of guanylate cyclase and seems to have a mainly clearance function. However, several studies suggest that this receptor may also have signalling activity in selected target tissue [14].

Down-regulation of the biologically active binding sites (NPR-A, NPR-B) could explain the blunted response to cardiac natriuretic hormones in HF, and the reduction in distribution spaces in patients with HF, but does not account for the increased metabolic clearance rate. However, variations in the ratio between biological and clearance receptors in target tissue could explain the increase in metabolic clearance rate observed in HF.

On the basis of this knowledge, new therapeutic strategies could emerge to potentiate the biological activity of these hormones in heart failure.

The aim of the present study was to evaluate the regulation of NPR-C receptors in heart failure. We performed a classical ligand binding study, with 125I-ANP as the radioligand, on isolated human platelets (cells known to have only NPR-C receptors), in order to evaluate the density and affinity of receptors, in patients with HF of differing severity.

The characterization of platelet ANP receptors was performed by competition experiments with c-ANP (selective ligand of NPR-C receptors) and by evaluation of cGMP production after treatment with ANP.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Experimental subjects
2.1.1. Patients
Eighteen patients (13 male and 5 female, age range: 29–73 years) with chronic cardiomyopathy, admitted to the clinical department of our institute, were enrolled in the study and divided into two groups according to their functional class. One patient had hypertrophic cardiomyopathy, 5 patients had coronary artery disease and 12 had idiopathic dilated cardiomyopathy. Myocardial contractility, cardiac dimension and function were assessed by two-dimensional echocardiography, radionuclide ventriculography and hemodynamic study. The main clinical parameters of the study population are presented in Table 1.


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  		Table 1 Clinical parameters of the HF patients

 
Patients were divided into two groups on the basis of their functional class, Group I comprised 8 patients with less severe disease (NYHA class: I–II and left ventricular ejection fraction ≥40%, mean±S.D.=61±2.0%); Group II consisted of 10 patients with more severe disease (NYHA class: III–IV and left ventricular ejection fraction <40%, mean±S.D.=24±2.4%). Patients with mild symptoms of disease (NYHA class I and II) were treated with a relative restriction of both physical activity and sodium intake (this was achieved using a personalized, well-controlled diet with a sodium intake of 100–140 mmol/day). Drug therapy included vasodilators (generally an angiotensin converting enzyme inhibitor and/or nitrates). Diuretics (generally a loop diuretic) were added for patients with more severe symptoms of heart failure (NYHA class III and IV). All patients had normal renal function (serum creatinine and electrolytes were measured at the start of the study). In addition, circulating levels of atrial natriuretic peptide (ANP) were measured at the start of study.

2.1.2. Control group
Eighteen age and sex-matched healthy subjects were used as a control group. All control subjects were free from acute disease and denied any history of serious disease, or use of any drug for at least 3 weeks prior to the study. All of the control group had normal values for the main plasma parameters and a sodium intake of between 100 and 200 mmol/day.

The study protocol was approved by the local ethics committee and written consent was obtained from all patients before the start of the study.

2.2. Plasma ANP assay
Blood samples (8–10 ml) were collected in ice-chilled polypropylene tubes containing EDTA (1 mg/ml of plasma) and aprotinin (500 KIU/ml of plasma) and immediately centrifuged at 4°C. Plasma ANP concentrations were measured (at least in duplicate) with a direct (without extraction) immunoradiometric assay (IRMA) (Shionoria ANP, Shionogi & Co., Ltd, Osaka, Japan), as previously described [15,16]. This method is a solid-phase sandwich IRMA, which uses two monoclonal antibodies prepared against two sterically remote epitopes of ANP molecule; the first antibody was coated on the beads and the second was radiolabelled with 125I. The assay sensitivity of this IRMA was 0.74±0.09 pmol/l, mean±S.E.M., n=12 and the working range (range of ANP concentration measured with a coefficient of variation lesser than 15%) was very wide, ranging from 2 to 700 pmol/l.

2.3. Washed platelet preparation
Peripheral venous blood (40 ml) was collected using ACD (6:1) as anticoagulant and centrifuged at 100xg for 10 min to obtain the platelet-rich plasma (PRP); the PRP was centrifuged at 1000xg for 10 min at 37°C. The pellet was resuspended in the binding assay buffer [50 mmol/l Tris–HCl, pH 7.4 containing 150 mmol/l NaCl, 0.1 mmol/l EDTA, 5 mmol/l MgCl2, 1 mmol/l PMSF, 1 µmol/l aprotinin, 1 µmol/l leupeptin, 0.1 µmol/l pepstatin, 0.1% (w/v) bacitracin, 0.1% (w/v) BSA] at a platelet concentration >5x1012 cells/l. Prostacyclin (2 mmol/l final concentration) was used throughout the procedure to minimize platelet aggregation.

2.4. Radioligand preparation
Human ANP [1–28] (Novabiochem, Switzerland) was iodinated with Na125I (sp.a. 17 Ci/mg, Sorin Biomedica SpA, Italy) by the lactoperoxidase method. 125I-ANP separation was carried out by reverse-phase HPLC (column Novapak C18, 4 µm, 3.5x300 mm, Waters Associates, Milford, MA, USA), eluted with linear gradient, from 20 to 50% of CH3CN in 0.1% trifluoracetic acid, for 60 min, flow rate of 1 ml/min [17].

The direct measurement of the specific activity of the radioligand, performed using a commercial enzyme immunoassay (Cayman Chemicals, Ann Arbor, MI, USA), confirmed the expected theoretical value of 2100 Ci/mmol.

2.5. Binding assay
In saturation experiments, 200 µl aliquots of platelet suspension corresponding to 300x106 cells/ml, were incubated with 5–7 increasing concentrations of 125I-ANP (3–300 pmol/l); non-specific binding was measured in the presence of a large excess of unlabelled ANP (100 nmol/l).

In competition experiments, platelets were incubated with a fixed concentration (50 pmol/l) of 125I-ANP and increasing doses (1 pmol/l–10 µmol/l) of unlabelled c-ANP (Sigma, St. Louis, MO, USA).

In both cases, the final incubation volume was 300 µl; the platelets were incubated at room temperature for 60 min under constant agitation. Separation of platelet-bound 125I-ANP from free radioactivity was performed by centrifugation at 2000xg for 10 min at 25°C. The supernatant was discarded, the pellet was resuspended in 1 ml of ice-cold Tris–HCl buffer, pH 7.4, and centrifuged again; the radioactivity in the platelet pellet was counted.

2.6. Cyclic GMP assay
Aliquots of platelets (250 µl) were pre-incubated with 0.1 mmol/l of isobutylmethylxanthine for 15 min at 37°C. Then the platelets were incubated with hANP (10–6, 10–7 mol/l) and sodium nitroprusside (SNP, 10–5 mol/l: known to increase platelet cGMP levels), the reaction was stopped by addition of EDTA (10 mmol/l) followed by immediate boiling for 2 min. The mixture was then cooled to 4°C, the precipitated protein was centrifuged in an Eppendorf microcentrifuge for 5 min. Cyclic GMP content in the supernatant was measured with a radioimmunological assay kit (Amersham International, UK).

2.7. Data analysis
The affinity constant (Kd) and the density of binding sites (Bmax) were obtained from saturation experiment data using an iterative curve fitting programme (KaleidaGraph). IC50 values for c-ANP were similarly derived from competition experiments.

2.8. Statistical analysis
Student's t-test for unpaired data was used to compare the Kd and Bmax values for the two groups of subjects studied. The data for the three sub-groups (Group I, Group II and control subjects) were analyzed by ANOVA, and the significant differences between the pairs of means were tested by the Scheffe's test. Since ANP values in healthy subjects are not normally distributed, a logarithmic transformation was used for statistical analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Plasma levels of atrial natriuretic peptide
The plasma levels of ANP found in our HF patients and in the control subjects are reported in Table 2. ANP levels were significantly increased in patients in Group II. (ANOVA: Group I vs. control subjects, P=0.29; Group II vs. control subjects, P=0.0002; Group II vs. Group I, P=0.053).


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  		Table 2 Mean (±S.E.M.) values of platelet binding parameters and plasma ANP

 
3.2. Clearance receptor characterization
In all subjects, binding of 125I-ANP to human intact platelets was a saturable process and resulted in linear Scatchard plots; a typical saturation curve is reported in Fig. 1, together with a data linearization by Scatchard analysis. The specificity of binding of 125I-ANP to platelets was studied by competitive displacement of radioligand by unlabelled c-ANP. The binding of 125I-ANP was completely inhibited, in a concentration-dependent manner, by c-ANP (selective ligand of NPR-C receptor) (Fig. 2).


Figure 1
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  		Fig. 1 Typical saturation curve for the binding of 125I-ANP to platelets and the corresponding Scatchard plot.

 


Figure 2
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  		Fig. 2 Inhibition curve of 125I-ANP specific binding by c-ANP; mean±S.E.M. of three different curves is reported.

 
The intracellular cGMP content was measured after hANP (10–6, 10–7 mol/l) and 10–5 mol/l SNP treatment (Fig. 3). Intracellular cGMP levels were not different from basal value (5.27±1.48 pmol/109 platelets) after addition of hANP (5.32±0.99 and 5.25±1.13, respectively, for the two doses tested; P=ns vs. control), but significantly higher after addition of SNP (16.57±2.46; P=0.0032 vs. control).


Figure 3
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  		Fig. 3 cGMP platelet generation after stimulation with hANP and SNP; mean value±S.E.M. of five different experiments are reported.

 
3.3. Receptor density and heart failure
Analysis of saturation data demonstrated a significant increase in density of ‘clearance’ NPR-C receptors in the platelets of HF patients, (Groups I and II combined), compared to the control group (16.9±2.3 vs. 11.7±1.1 fmol/109 cells, P=0.048), without significant variation of the affinity.

The receptor density increased with the severity of disease (Table 2); ANOVA analysis showed a significant increase in receptor density values for patients in Group II compared with the controls (P=0.0179) and compared to Group I (P=0.0451). There was no difference between the values for Group I and the controls (P=0.99).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Our results confirm the presence of cardiac natriuretic peptide receptors on human platelets. Complete inhibition of platelet binding was obtained by the specific ligand c-ANP, indicating the presence of only ‘clearance’ receptors. In addition, intracellular cGMP levels were not affected by h-ANP stimulation, indicating the lack of biologically active receptors on human platelets.

As far as the regulation of cardiac natriuretic peptide receptors in HF is concerned, to the best of our knowledge, this is the first study to show an up-regulation of clearance receptors in platelets of patients with chronic heart failure.

4.1. Comparison with previous studies
Plasma cardiac natriuretic peptide levels are greatly elevated in both human and experimental HF [3–9]. However, the biological actions of cardiac natriuretic peptides are severely attenuated in experimental models and in patients with HF, suggesting a resistance to the biological effects of the hormone [9,11,12]. It has been suggested that the blunted effect of cardiac natriuretic hormones could be due to increased activation of the renin–angiotensin–aldosterone system and the sympathetic nervous system [10,18]. It has also been suggested that cardiac natriuretic receptors could be down-regulated by high plasma levels of hormones [19–21]. However, published reports on cardiac natriuretic peptide receptor regulation in both experimental and human chronic heart failure are far from being unanimous [19,21–25]. At the platelet level, downregulation and no variation have been observed in patients with HF [21,22]. Differences in analytical procedure as well as in the clinical characteristics of the subjects studied could account for these differences. In our study, we used an age-matched control group, thus we can exclude a possible effect of age on the number of binding sites [22].

An additional complication is related to the hetereogeneity of the cardiac natriuretic peptide receptor population, since alterations in the proportions of these receptor subtypes in target tissue might have important physiological consequences. The NPR-C receptor contributes to the metabolic clearance of ANP [26,27] and does not stimulate cGMP generation [28]. Natriuretic cardiac hormones bind to cell-bound NPR-C, the receptor–ligand complex is internalized, and the peptides are hydrolyzed by lysosomes, while the receptor is recycled to the cell surface. Clearance receptors are located in a number of different tissues and cells, including vascular endothelial and smooth muscle cells, glomerular cells and pulmonary parenchyma [29–31]. Several studies have investigated the regulation of the NPR-C by exogenous ANP or by pathophysiological stimuli that promote increased circulating levels of endogenous ANP [32–34]. These studies suggest that increased concentrations of ANP promote down-regulation of ANP receptors and decreased internalization of the receptor–ligand complex. The biological role of atrial natriuretic factor ‘clearance’ receptor in congestive heart failure has not been fully defined, a down-regulation or an occupancy of the NPR-C receptor has been suggested in experimental canine heart failure [35]. In contrast, a selective increase in mRNA expression of NPR-C in human failing hearts has recently been documented [36]. It is important to note that our data closely agree with this last observation and are consistent with the modification of metabolic clearance rate and distribution spaces described in this situation. It is worth noting that an up-regulation of the clearance receptors in severe HF better relates to the increase in ANP clearance described in these patients.

The molecular mechanism underlying this potential increase in NPR-C is not known. Interestingly, some studies have shown that β-blockers appear to increase ANP, BNP and cGMP concentrations [37,38]. Moreover, it has been recently shown that β-adrenoreceptor agonists significantly decrease both receptor densities and mRNA levels of NPR-C receptor [39]. These observations suggest that the high concentrations of cathecolamines found in heart failure, may modulate the increase in NPR-C receptors.

4.2. Up-regulation of ‘clearance’ receptors in heart failure: a possible explanation for the resistance to cardiac natriuretic peptides
The increase in density of clearance receptors observed in patients with severe HF is theoretically consistent with the reduction in cardiac natriuretic peptide biological activity (and distribution spaces) as well as with the increase in metabolic clearance rate described in these patients [1,2]. In fact, clearance receptors are mainly distributed on the endothelial cell membrane, so that their increase causes an enhanced degradation of circulating molecules of cardiac natriuretic hormones (i.e. an increased metabolic clearance rate), which in turn could reduce the number of molecules available for biological receptors and consequently also the biological activity of the overall cardiac natriuretic hormone system.

Our data suggest that the resistance to biological effects of ANP may be due to variation in the ratio between biological and clearance receptors, i.e. an increase in clearance receptors (as observed in our study) and a parallel decrease in biological receptors, as found by other workers, both in human and animal models of HF [19,20,25]. It is generally thought that cardiac natriuretic hormones can be degraded in vivo by two different systems: clearance receptors and plasma neutral endopeptidases 21.11 (NEP) [40]. Several studies have recently indicated the inhibition of NEP as a new approach in the treatment of heart failure [41]. However, the clearance receptors and endopeptidases seem to have an equal role in natriuretic peptide metabolism in heart failure [42]. Therefore, these findings and our observations, concerning an up-regulation of clearance receptors, strongly suggest that clearance receptor blockade, with or without NEP inhibitors, may have greater potential therapeutic value in HF.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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