CLINICAL RESEARCH: CARDIAC PHARMACOLOGY
Nebivolol, a Vasodilating Selective β1-Blocker, Is a β3-Adrenoceptor Agonist in the Nonfailing Transplanted Human Heart
Bertrand Rozec, MD, PhD*, , , ,||,
Mortéza Erfanian, BS*,,,,
Karine Laurent, BS*,,,,
Jean-Noël Trochu, MD, PhD*,,, and
Chantal Gauthier, PhD*,,,,*
* INSERM, UMR915, l'institut du thorax, Nantes, France
CNRS, ERL3147, Nantes, France
Université de Nantes, Nantes, France
CHU Nantes, l'institut du thorax, Nantes, France
|| Department of Anaesthesiology, CHU Nantes, Nantes, France
Manuscript received May 27, 2008;
revised manuscript received November 20, 2008,
accepted November 24, 2008.
* Reprint requests and correspondence: Dr. Chantal Gauthier, INSERM UMR915, l'institut du thorax, Faculty of Medicine, 1, Rue Gaston Veil, BP 53508, 44035 Nantes, France (Email: chantal.gauthier{at}nantes.inserm.fr).
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Abstract
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Objectives: The present study was to assess whether nebivolol could activate β3-adrenergic receptors (ARs) in the human heart.
Background: Nebivolol is a third-generation β-blocker used in the treatment of heart failure. It associates selective β1-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of β3-ARs, but no data are available in the heart.
Methods: The effect of nebivolol (0.1 nmol/l to 10 µmol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer.
Results: Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 µmol/l: –55 ± 4%, n = 6), which was similar to that obtained with a preferential β3-AR agonist, BRL 37344 (maximum effect obtained at 1 µmol/l: –45 ± 2%, n = 12). The nebivolol effect was not modified by 10 µmol/l nadolol, a β1,2-AR antagonist, but was significantly reduced in the presence of 1 µmol/l L-748,337, a selective β3-AR antagonist, and after pre-treatment with 100 µmol/l NG-monomethyl-L-arginine, an NOS inhibitor.
Conclusions: Our study demonstrated that nebivolol activated β3-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials.
Key Words: nebivolol • β-adrenergic receptor • human heart • contractility • nitric oxide
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Abbreviations and Acronyms
| | AR = adrenergic receptor | | eNOS = endothelial nitric oxide synthase | | L-NMMA = NG-monomethyl-L-arginine | | NO = nitric oxide | | NOS = nitric oxide synthase |
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In the heart, at least 3 populations of β-adrenergic receptors (ARs) potentially modulate the cardiac function. The effects of β1- and β2-ARs are well established both in humans and other mammals. Their stimulation produces positive chronotropic and inotropic effects. The first characterization of β3-AR was performed in the human heart in 1996 (1). β3-AR stimulation produces a negative inotropic effect opposite to that induced by β1- and β2-ARs, involving the nitric oxide synthase (NOS) pathway (2). The presence of β3-AR in ventricles from nonfailing human hearts has been confirmed by the detection of transcripts by reverse-transcriptase polymerase chain reaction assays (1) and proteins by western blotting and immunohistochemistry (3). In the normal heart, it has been suggested that β3-AR stimulation might play a role of a "safety valve" during intense adrenergic stimulation.
Chronic heart failure is associated with a progressive activation of the sympathetic nervous system, albeit a failing heart has a diminished positive inotropic response to β-AR stimulation due, at least in part, to a selective down-regulation of β1-AR and desensitization of β1- and β2-ARs (4). Conversely, all studies agree that β3-ARs are up-regulated in heart failure as demonstrated in humans (3), in cardiomyocytes from dogs with pacing-induced cardiac heart failure (5), and in rats (6). It is admitted that at first, the increased cardiac adrenergic drive is beneficial, but is ultimately damaging to the myocardium. Based on those data and on several clinical studies (MERIT-HF [Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure], CIBIS-II [Cardiac Insufficiency Bisoprolol Study II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and SENIORS [Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure]) (7–10), the new guidelines for management of chronic congestive heart failure include broader, stronger recommendations for β-blocker therapy (11). Nevertheless, complete mechanisms underlying the beneficial effects of β-blockers remain to be extensively studied. β-blockers used in clinical trials belong either to second generation compounds (cardioselective β-blockers: metoprolol, bisoprolol) or to more recently developed vasodilating β-blockers (carvedilol, nebivolol). β-blockers with vasodilatory properties may be superior compared to nonvasodilatory β-blockers in treating heart failure because arteriolar dilation would reduce afterload to the failing heart (12). The mechanisms that mediate the beneficial effects of nebivolol in patients with chronic heart failure remain controversial, albeit the β1- and β3-ARs have been shown to be involved. However, the involvement of β3-AR in the beneficial effect of nebivolol has been only described in vessels. Nebivolol induces a vasodilation in rat thoracic aorta (13) and human coronary artery (14) through activation of the nitric oxide (NO) pathway. Conversely, very few works focused on the cardiac β3-AR targets of nebivolol and they were performed in mice (15). Thus, the aim of our study was: 1) to determine and characterize the involvement of human cardiac β3-AR in the effects of nebivolol; and 2) to compare the pharmacological profile of nebivolol to that of a preferential β3-AR agonist, BRL 37344.
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Methods
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Human ventricular biopsies.
All protocols were approved by the local ethics committee. Fifty-two human endomyocardial biopsies were obtained from the right interventricular septum of cardiac transplant patients (41 men and 5 women) after their informed consent. Biopsies were systematically performed in the follow-up of the heart transplant patients. Under local anesthesia, a biotome was introduced percutaneously through the right jugular vein to the right ventricle using X-ray guidance; 6 biopsies were taken from the right ventricular septum, and 1 biopsy out of 6 was used for the present study. None of the patients showed evidence of cardiac rejection, and no adverse event related to the procedure was reported. All received immunosuppressive therapy (tacrolimus, prednisolone, mycophenolate mofetil, or cyclosporine). In addition, some of them received cardiovascular treatment (calcium antagonist, β-adrenoceptor antagonist,  -adrenoceptor antagonist, diuretic, digoxin) (Table 1). In order to follow the rejection, biopsies are harvested at different times after the transplantation. Thus, in some cases (n = 4) of our study, several biopsies were obtained from the same patient.
Endomyocardial biopsies are small (wet weight being about 3 to 7 mg) with various shapes depending on forceps insertion in the right ventricular septum. The parallel arrangement of myocardial fibers in septal endomyocardial biopsies is not present. These characteristics (size and fiber orientation) contrast with human epicardial and papillary muscle preparations classically used in contractile force measurement. These latter samples are frequently obtained from explanted heart.
Isometric force of contraction measurements.
The experiments were performed as previously described (16). Briefly, tissues were placed in a transport solution containing (in mmol/l) 120 NaCl, 5 KCl, 1 CaCl2, 1.1 MgCl2, 0.33 NaH2PO4, 5 glucose, and 10 Hepes (pH being adjusted to 7.4 with NaOH) and quickly conveyed to the laboratory. Preparations were then placed in an experimental chamber and superfused at a flow rate of 5 ml/min with oxygenated (95% O2, 5% CO2) Tyrode's solution (37 ± 0.5°C) composed as follows (in mmol/l): 120 NaCl, 5 KCl, 2.7 CaCl2, 1.1 MgCl2, 0.33 NaH2PO4, 5 glucose, and 27 NaHCO3. Tissues were subjected to field stimulation at a frequency of 0.6 Hz. Preparations were equilibrated for 60 min and subjected to field stimulation at pacing cycle length of 1,700 ms using square-wave pulses of 1- to 2-ms duration, and amplitude was twice the diastolic threshold. Mechanical tension was recorded using a mechanoelectric force transducer (Akers, AE 801, SensoNor, Horten, Norway). After a 60-min equilibration period, endomyocardial biopsies were stretched stepwise (10-µm increments) to a length at which contraction force was maximal. The cumulative concentration-response curves of agonists were then determined by superfusion with successive increasing concentrations of the drugs. For all concentrations, tension was measured at steady state using a digital storage oscilloscope (model 400, Gould, Les Ullis, France), a strip chart recorder (model 8188, Gould), and a digital tape recorder (model DTR-1200, Biologic, Claix, France).
Drugs.
Nadolol was obtained from Sigma Chemical Co. (St. Louis, Missouri). NG-monomethyl-L-arginine, monoacetate (L-NMMA) was purchased from Calbiochem (La Jolla, California). Nebivolol racemate was a generous gift from Menarini Research (Firenze, Italy). BRL 37344 (4-[-(2-hydroxy-[3-chlorophenyl]ethyl-amino)propyl] phenoxyacetate) was obtained from Research Biochemicals Int. (Natick, Massachusetts). L-748,337 was a generous gift from Merck (Rahway, New Jersey). All drugs were prepared as stock solutions in distilled water, with the exception of: 1) nadolol, which was dissolved in hydrochloric acid before being neutralized to pH 7.4 with NaOH 1 N; and 2) L-748,337, which was dissolved in dimethyl sulphoxide (Sigma Chemical Co., St. Louis, Missouri). The final concentration of the solvent in the organ bath was <0.1% vv–1. We have verified that the solvent had no effect on tension developed by human endomyocardial biopsies at the maximal concentration used (data not shown).
Data analysis.
The results of functional studies are expressed as mean ± SEM of n experiments. The statistical significance of the drug effect was assessed by 1-way analysis of variance for repeated measurement followed when appropriate by a Bonferroni test. Comparison of the concentration-response curves between 2 experimental protocols was performed by 2-way analysis of variance for repeated measurement followed when appropriate by a Bonferroni test. A value of p < 0.05 was considered significant.
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Results
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Comparison of nebivolol and BRL 37344 effects on human endomyocardial biopsy.
Nebivolol induced a concentration-dependent negative inotropic effect at concentrations ranging from 0.1 nmol/l to 10 µmol/l (Fig. 1C). One µmol/l of nebivolol decreased peak tension by 55 ± 4.1% (p < 0.01, n = 6) below the control level. A similar negative inotropic effect was obtained with a preferential β3-AR agonist, BRL 37344, in the same range of concentrations. The maximum effect induced by BRL 37344 was obtained at a concentration of 1 µmol/l, which decreased peak tension by 45.1 ± 2% (p < 0.01, n = 12) (Fig. 1C) below the control level. At higher concentrations, the negative inotropic effect induced by BRL 37344 was reduced due to a nonselective effect. Thus, for the following experiments, we constructed concentration-response curves to BRL 37344 for concentrations ranging from 0.1 nmol/l to 1 µmol/l.
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Figure 1 Comparison of Nebivolol and BRL 37344 Effects on Basal Contractility of Human Endomyocardial Biopsies
(A) Superimposed twitches obtained from one representative experiment in the absence (CTRL) and the presence of 1 µmol/l of nebivolol. (B) Superimposed twitches obtained from 1 representative experiment in the absence (CTRL) and the presence of 1 µmol/l of BRL 37344. (C) Concentration-response curves of nebivolol and BRL 37344 on contractility developed by human endomyocardial biopsies. For all curves, values are the mean ± SEM of n experiments. Response is expressed as the percentage of peak tension measured in control (CTRL). Significant statistical difference: **p < 0.01 versus CTRL nebivolol (n = 6); ##p < 0.01 versus CTRL BRL 37344 (n = 12). There was no significant difference between BRL 37344 (n = 12) and nebivolol (n = 6) (p = 0.59).
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β-AR targets of nebivolol.
To determine the specificity of the β-AR targets of nebivolol, a concentration-response curve to nebivolol was also plotted in the presence of several β-AR antagonists. After 20 min of pre-treatment, nadolol, a β1- and β2-adrenoceptor antagonist, had no effect on the basal peak tension of endomyocardial biopsies. The concentration-response curve to nebivolol was not modified by 10 µmol/l nadolol, perfused before and during all the experiments (Fig. 2A). In the same way, the concentration-response curve to BRL 37344 was not modified by nadolol (Fig. 2B).
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Figure 2 Negative Inotropic Effect of Nebivolol and BRL 37344 in the Presence of Nadolol, a β1-/β2-AR Antagonist, on Human Endomyocardial Biopsies
Nadolol (10 µmol/l) was perfused alone until a steady state was reached (15 to 20 min), and was defined as control. Cumulative concentrations of (A) nebivolol or (B) BRL 37344 were then perfused in the presence of the antagonist. For all curves, values are the mean ± SEM of n experiments. Response is expressed as the percentage of peak tension measured at baseline. There was no significant difference either between nebivolol + 10 µmol/l nadolol (n = 6) and nebivolol alone (n = 6) or between BRL 37344 + 10 µmol/l nadolol (n = 6) and BRL 37344 alone (n = 12).
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In another set of experiments, the concentration-response curve to nebivolol was performed in the presence of L-748,337, a selective antagonist of human β3-AR. Twenty minutes of pre-treatment of human endomyocardial biopsies with 1 µmol/l L-748,337 did not modify peak tension compared with control samples. L-748,337 was also perfused during all experiment. In such conditions, the concentration-dependent negative inotropic effects induced by nebivolol were blunted (Fig. 3A). The maximal decrease induced by 10 µmol/l nebivolol was only 19.58 ± 3.97% (p < 0.01 vs. nebivolol alone; n = 6). Similarly, the concentration-response curve to BRL 37344 was strongly reduced in the presence of 1 µmol/l L-748,337 (Fig. 3B). In this condition, peak tension only decreased by 15.67 ± 5.60% from control values (p < 0.01 vs. BRL 37344 alone; n = 6).
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Figure 3 Negative Inotropic Effect of Nebivolol and BRL 37344 in the Presence of L-748,337, a Selective β3-AR Antagonist, on Human Endomyocardial Biopsies
L-748,337 (1 µmol/l) was perfused alone until a steady state was reached (15 to 20 min), and was defined as control. Cumulative concentrations of (A) nebivolol (n = 6) or (B) BRL 37344 (n = 6) were then perfused in the presence of the antagonist. For all curves, values are the means ± SEM of n experiments. Response is expressed as the percentage of peak tension measured at baseline. **p < 0.01, which indicates significant statistical differences from nebivolol alone (n = 6) or BRL 37344 alone (n = 12).
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Involvement of the NO pathway in the negative inotropic effect of nebivolol.
As the NO pathway has been previously described in the effect of nebivolol, we have determined whether the NOS inhibitor, L-NMMA, modified the contractile response to nebivolol. L-NMMA had no significant effect on the basal peak tension of human endomyocardial biopsies after 20-min pre-treatment. A 20-min pre-treatment of endomyocardial biopsies with 100 µmol/l L-NMMA strongly reduced the negative inotropic effect induced by nebivolol (Fig. 4A); 10 µmol/l nebivolol decreased peak tension by only 21.50 ± 9.7% (n = 6) from control values (p < 0.01 vs. nebivolol alone). As illustrated in Figure 4B, the concentration-response curve to BRL 37344 was reduced by 100 µmol/l L-NMMA in a similar manner. In these conditions, 1 µmol/l BRL 37344 decreased peak tension by only 21.41 ± 5.01% (p < 0.01 vs. BRL 37344 alone, n = 4).
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Figure 4 Negative Inotropic Effect of Nebivolol and BRL 37344 in the Presence of L-NMMA, a Nonselective NOS Inhibitor, on Human Endomyocardial Biopsies
NG-monomethyl-L-arginine (L-NMMA) (100 µmol/l) was perfused alone until a steady state was reached (15 to 20 min), and was defined as control. Cumulative concentrations of (A) nebivolol (n = 6) or (B) BRL 37344 (n = 4) were then perfused in the presence of the antagonist. For all curves, values are the means ± SEM of n experiments. Response is expressed as the percentage of peak tension measured at baseline. **p < 0.01, which indicates significant statistical differences from nebivolol alone (n = 6) or BRL 37344 alone (n = 12).
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Discussion
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Our study demonstrated for the first time that nebivolol, a third-generation β-blocker, activated β3-AR in human heart. Nebivolol by activation of cardiac β3-AR produced like BRL 37344, a preferential β3-AR agonist, a concentration-dependent negative inotropic effect through activation of the NO pathway.
In the present work, using a pharmacological approach, we demonstrated that nebivolol decreased cardiac contractility in human endomyocardial biopsies. It is important to note that all biopsies used in our study were obtained in nonfailing, nonrejecting transplanted hearts. The mechanical effects of nebivolol were not modified by a pre-treatment with nadolol, a potent β1- and β2-AR antagonist possessing no β3-AR antagonist properties (17,18), indicating that this effect was not mediated by β1- or β2-AR. By contrast, L-748,337, a selective antagonist of human β3-AR (19), strongly reduced the negative inotropic effects induced by nebivolol. It is important to note that in humans, after the standard dose of 5 mg, nebivolol has a Cmax of 1.48 ng/ml equivalent to 3.3 nmol/l (20). This concentration still produced a 15% to 20% reduction of cardiac peak tension less marked than the decrease produced at micromolar concentration. To strengthen the action of nebivolol on cardiac β3-AR, we have compared the effects of nebivolol to those induced by BRL 37344, a preferential β3-AR agonist. Both compounds produced a similar concentration-dependent negative inotropic effect. The contractile effects of BRL 37344 were not modified by nadolol but blunted by L-748,337. Our results obtained with BRL 37344 corroborated previous data from our group performed in human endomyocardial biopsies (1). In our previous study, we have used another β3-AR antagonist, bupranolol, a nonselective β-AR antagonist, which was less efficient than L-748,337 to antagonize the BRL 37344 effects (1).
Our study is the first to describe nebivolol's effect on human ventricular contractility in basal conditions. Previous studies have reported the lack of inverse agonistic (21) or intrinsic sympathomimetic (22) activity of nebivolol in the human heart. Unfortunately, none of those studies has evaluated the inotropic effects induced by nebivolol under basal conditions or without cyclic adenosine monophosphate-dependent pre-stimulation (with isoproterenol or forskolin). In addition, it is important to mention that our samples were harvested from nonischemic heart and were used after a short time of transportation to the laboratory, whereas in other functional studies, left ventricular myocardium tissues were obtained from explanted failing hearts or explanted hearts that could not be used for transplantation. In both cases, even in the latter one, ischemia could modify functional responses. In human atria, β3-AR has been also described (23). However, nebivolol produced no effect on contractility (21), whereas BRL 37344 produced an increase of contractility. This last positive inotropic effect was abolished in the presence of nadolol, indicating that BRL 37344 induced this effect through activation of β1-/β2-AR (24). These results suggest that regional differences may exist regarding the functional roles of β3-AR in the human heart. Those discrepancies could be explained by: 1) a different signaling coupling in human atrium and ventricle; and/or 2) a differential β3-AR expression level in atria and ventricle. The results of the present work demonstrating an agonistic effect of nebivolol on β3-AR are in accordance with previous works performed in vessels. Indeed, nebivolol stimulated β3-AR in rat aorta (13,25), in human umbilical vein endothelial cells (26), and in human and rodent coronary arteries (14).
In this study, we demonstrated that the negative inotropic effect induced by nebivolol and BRL 37344 was strongly reduced in the presence of an NOS inhibitor, L-NMMA, suggesting an involvement of the NO pathway in this effect. These results corroborate those obtained in vessels, in which nebivolol, like preferential β3-AR agonists, produced an endothelium-dependent vasodilation through activation of the NO pathway (13,14). This pathway played a major role in the modulation of contractile function (27). It was demonstrated in various models that NO attenuates the β1-/β2-adrenergic increase in inotropy and chronotropy and reinforces the pre- and post-synaptic vagal control of cardiac contraction. By doing so, the NOS protects the heart against excessive stimulation by catecholamines, just as an "endogenous β-blocker." In addition, recently it was suggested that β3-AR could be considered by its cellular localization in cardiomyocyte and its coupling to NOS as a local feedback control loop by counteracting cyclic adenosine monophosphate generation obtained via β1-/β2-AR stimulation (28). However, the NOS isoforms involved in the negative inotropic effect induced by nebivolol or β3-AR agonists remain to be determined. Indeed, some studies reported endothelial nitric oxide synthase (eNOS) activation by β3-AR agonists (2,3), whereas recently a potential activation of the neuronal NOS was suggested in diabetic rat myocardium (29). Surprisingly, a recent study using nebivolol described a new putative β3-AR pathway in mice, involving the inducible NOS even in the absence of cardiovascular pathology (15). In our previous works, we demonstrated on human endomyocardial biopsies the presence of abundant eNOS but not inducible NOS protein in sections (2). Brixius et al. (30) suggested by immunostaining experiments that eNOS activation by a preferential β3-AR agonist, BRL 37344, differs between right atrial and left ventricular human myocardium: the translocation of eNOS was predominant in atrium and phosphorylation of eNOS in the left ventricle. Moreover, the same group suggests by immunohistochemical stainings that nebivolol did not activate eNOS in nonfailing human myocardium and even suppressed eNOS activity in the failing heart (31). Then, future works will have to be performed to clarify the role of different NOS isoforms in the mechanical effects induced by β3-AR agonists and/or nebivolol.
The use of human endomyocardial biopsies harvested from the denervated heart of patients receiving immunosuppressive drugs constitutes an important limitation in our study. Indeed, both conditions could induce modification in cardiac gene expression and thus directly influence or not influence the β-AR system. Nevertheless, as heart failure and rejection would have hampered proper interpretation, these 2 conditions were not present in our study.
Several large randomized trials and meta-analyses have provided clear evidence that β-blockers reduce the risk of death about 30% in chronic heart failure patients (32). Metoprolol, bisoprolol, and carvedilol have been successfully evaluated respectively in the MERIT-HF, CIBIS-II, and COPERNICUS trials (7–9). Recently, nebivolol was evaluated in the SENIORS trial, which concluded that nebivolol was effective and well tolerated in elderly heart failure patients (10). Our results demonstrate in human heart that nebivolol possesses β3-AR agonistic properties in addition to well-described, selective β1-AR antagonistic properties (22). Both simultaneous action of nebivolol on β1- and β3-ARs could play a major role in cardiac pathologies in which the β1- and β3-AR expressions are modified. It is the case in the human failing left ventricle, which is characterized by opposite changes occurring in β1- and β3-AR (2- to 3-fold increase in β3-ARs) abundance, with an imbalance between their inotropic influences. In this context, taking into account this original and specific pharmacological β-AR profile, nebivolol can be of particular interest in heart failure and may account for additive beneficial effects through several mechanisms. In particular, the stimulation of β3-AR could participate in the myocardium protection: 1) by a reduction of the activation of L-type calcium channels (33) and, thus, of calcium overload; 2) by a better diastolic function due to increased NO production; and finally, 3) by the vasodilating effects, because arteriolar dilation would reduce afterload and increase coronary blood flow.
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Conclusions
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This study gives more insight into the pharmacological properties of nebivolol, a β-blocker of the third generation, by demonstrating the affinity of nebivolol for β3-ARs in the human heart. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration, as previously described in clinical trials.
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Acknowledgments
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The authors thank the Department of Cardiology (Nantes University Hospital) for providing the human endomyocardial biopsies.
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Footnotes
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This work was supported by grants from Menarini International, "Fédération Française de Cardiologie," "Fondation de France," and "Fondation Langlois."
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References
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