EDITORIAL COMMENT
β3-Adrenoceptor Stimulation on Top of β1-Adrenoceptor Blockade"Stop or Encore?"*
Jean-Luc Balligand, MD, PhD*
Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium
* Reprint requests and correspondence: Dr. Jean-Luc Balligand, Director, Unit of Pharmacology and Therapeutics, Université catholique de Louvain, UCL-FATH 5349, Tour Vésale 5th Floor, 52 Avenue Mounier, 1200 Brussels, Belgium (Email: jl.balligand{at}uclouvain.be).
Key Words: nebivolol • beta3-adrenergic receptor • human heart • contractility • nitric oxide
Catecholamines released by the orthosympathetic system play a major role in the short- and long-term regulation of cardiac function. Although acute stimulation of adrenergic receptors (ARs) (mostly β1) increases all aspects of cardiac contractility and is generally considered as positive for heart function, their prolonged activation results in adverse remodeling of the myocardium, in part due to toxic effects on cardiomyocytes (and other cells composing cardiac muscle), as exemplified by the cardiac phenotype of mice with cardiac-specific overexpression of β1-AR (1). Accordingly, chronic overactivation of the orthosympathetic system in heart failure, albeit initially adaptive, is generally considered to be deleterious in the long term (2). This is amply supported by clinical evidence of the beneficial effect of β-adrenergic blockade in failing patients.
The mechanistic interpretation of this beneficial effect, however, is far from simple. Although the generic property to antagonize β1-AR activation (thereby preventing its long-term deleterious effects) is shared by all blockers with proven clinical efficacy, several characteristics have recently emerged as key factors to predict benefit (or absence thereof). These include polymorphisms at β-ARs (3–5) or G-protein receptor kinases regulating their desensitization (6), as well as ancillary pharmacodynamic properties of specific blockers.
Nebivolol belongs to the group of β-blockers with proven clinical benefit in a population of heart failure patients, as demonstrated in the SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) trial (7). It is endowed with high specificity for β1-AR antagonism (8). However, its pharmacodynamic properties extend beyond just β1-AR blockade. Early work has identified ancillary properties as serotonin 5-HT1A receptor or P2Y purinergic receptor (9) agonist—at least in the kidney vasculature—β2-AR agonist (10), or more recently, alpha-1-AR antagonist (11). Most of these properties, however, are based on observations in heterologous expression systems (against recombinant receptors) or animal tissues, raising doubt about their generalizability to the drug's effect on native human receptors in situ. In a previous study on small resistance coronary vessels from human specimens, C. Dessy in our laboratory had demonstrated vasodilating properties of nebivolol through activation of the third isotype of beta-adrenoceptors, β3-ARs (12).
β3-ARs have classically been considered as receptors mediating metabolic effects (e.g., lipolysis) in adipocytes, although their low expression and lipolytic activity in (at least normal) human white fat tissue has dampened enthusiasm for their exploitation as therapeutic targets of obesity (13). They raised renewed interest in the cardiovascular field after the discovery of their expression in human ventricular myocardium (14). Surprisingly, in this tissue, their activation with preferential agonists (in the presence of combined β1- and β2-AR blockade) produced effects functionally antipathetic to those classically ascribed to the other 2 isotypes, (i.e., a decrease in developed cardiac muscle tension). This has been independently confirmed with similar pharmacologic approaches in ventricular cardiac tissues and cells from a number of animal species (15,16). Accordingly, mice with deletion of the β3-AR gene display an enhanced inotropic response to nonspecific β-adrenoceptor agonists (17), which could be interpreted as unopposed stimulation of the residual β1- and β2-ARs. Mechanistically, this countervailing effect of β3-AR stimulation was shown to involve G-alpha-i coupling to a nitric oxide synthase (NOS) activity (18), resulting in NO-mediated attenuation of β1- and β2-adrenergic effects on cardiac muscle (Fig. 1).
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Figure 1 Putative Beneficial Effects of Combined Activation of β3-Adrenoceptors and Blockade of β1-Adrenoceptors on Cardiac Function
Nebivolol combines the properties of a β1-adrenoceptor (AR) antagonist (β1-blocker) and a β3-AR agonist. In human myocardium, β3-ARs are expressed both on endothelial cells of the coronary microvasculature and on cardiac myocytes. (Left) Activation of β3-ARs on coronary endothelium produces the activation of endothelial nitric oxide synthase (NOS) and the release of nitric oxide (NO) and of an endothelium-derived hyperpolarizing factor (EDHF), both of which contribute to increased vasodilation and coronary perfusion. In addition, NO may paracrinally promote cardiomyocyte relaxation and left ventricular (LV) diastolic filling, thereby enhancing diastolic reserve. (Right) In ventricular cardiomyocytes, nebivolol combines the effects of β1-AR blockade, which prevents the deleterious effects of chronic adrenergic stimulation on myocardial remodeling, and activation of β3-AR; the latter, through G-alpha-i coupling, (e)NOS activation and NO production may oppose the acute effects of adrenergic stimulation of contractility. Hypothetically, agonism on β3-ARs may contribute to additional protection against adverse remodeling under chronic adrenergic stress through sustained functional antagonism of the β1-AR/cyclic adenosine monophosphate (cAMP) pathway or other (yet undetermined) pathways. The combined effects on remodeling, ventricular perfusion and filling ultimately would result in improved LV function. Figure illustration by Rob Flewell.
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Other distinctive properties of β3-ARs deserve further consideration in the context of cardiac diseases. Contrary to β1-AR (and to a lesser extent β2-AR), the abundance of β3-AR messenger ribonucleic acid (and proteins) increases in ventricular myocardium from patients with heart failure from ischemic or dilated cardiomyopathies (19), as well as sepsis (20). Such paradoxical regulation is consistent with in vitro up-regulation of β3-ARs in rodent cardiomyocytes chronically exposed to catecholamines (21), as well as animal models of diabetes (22), a condition also associated with hyperadrenergism. Also, β3-ARs are more resistant (than β1- and β2-ARs) to homologous desensitization (23). Overall, this makes β3-ARs very attractive candidate targets for an efficient pharmacologic modulation in the diseased heart.
Building upon previous evidence for β3-AR agonism of nebivolol in human vessels (12), Rozec et al. (24) in this issue of the Journal tested the ability of the drug to activate similar receptors in human myocardium. Using ventricular biopsies from transplanted human hearts, they show a concentration-dependent attenuation of developed contraction force with nebivolol, which replicates similar effects of the preferential β3-AR agonist, BRL37344. This effect is maintained despite coincubation with the β1- and β2-AR blocker, nadolol, ruling out the implication of these 2 isotypes; conversely, it is strongly inhibited by coincubation with a β3-AR antagonist, L-748,337. As in previous studies on similar human material (18), this β3-AR effect is sensitive to NOS inhibition with L-NMMA, implicating a β3-AR–mediated activation of NO synthesis.
How do these findings bear on the clinical use of nebivolol? First, it should be remembered that the authors used human myocardium from transplanted hearts, studied in organ baths ex vivo. They have done an extensive characterization of this model in their earlier work (25), with contractile responsiveness consistent with inotropic modulation in classical cardiac preparations; they also carefully excluded rejecting hearts. However, their in vitro setting allows only limited prediction of the effect of similar agonists in vivo; in particular, loading conditions cannot be calibrated, and parameters such as relaxation cannot be studied accurately. Therefore, their observation of an attenuation of contractile tension with nebivolol may not necessarily translate into a negative inotropic effect in vivo. Indeed, a β3-AR–mediated blunting of the positive inotropic effect of catecholamines may abbreviate systolic contraction and increase the length of diastolic interval, which together with NO release in the myocardium may promote relaxation, diastolic filling, and subendocardial perfusion (26). The overall result would be an increased diastolic reserve and improved left ventricular function (Fig. 1).
The authors also selected myocardial samples from nonfailing hearts. Although this allows some degree of analysis of β3-AR effects in close to "normal" conditions, the conclusions may not necessarily apply to the failing heart; indeed, heart failure induces dramatic changes in excitation–contraction coupling, tissue remodeling, and alterations in some key intracellular signaling elements, including NOS expression, NOS coupling, and NO bioavailability due to increased oxidant stress. The latter, in particular, may obliterate some of the NO-dependent effects reported here. However, in a previous study by Moniotte et al. (19), the effect of β3-AR agonists was somewhat attenuated, but still present in biopsies from failing compared with nonfailing hearts, and was relatively less desensitized than the β1- and β2-AR positive inotropic effect. This would support a persistent attenuation of the β1- and β2-AR effects by β3-AR stimulation (including with nebivolol) in failing hearts. In addition, Dessy et al. (27) showed that the vasodilatory effect of β3-AR stimulation in human coronary microvessels (300-µm diameter) persisted despite deficient NO-mediated relaxation, due to alternative coupling to endothelium-derived hyperpolarizing factor (EDHF) vasorelaxing mechanisms. Finally, nebivolol is endowed with additional antioxidant properties in vitro (28), which may translate into additional protection against endothelial dysfunction (29) and tissue remodeling in vivo. Overall, there is a good probability that the combination of β1-AR blockade with β3-AR agonism by nebivolol may similarly be operative on the failing heart. This is supported by the results of an early clinical study with nebivolol on a limited number of patients with ischemic cardiomyopathy (30). The putative beneficial effect on diastolic reserve would have been particularly suited for the improvement of heart failure in elderly patients, as included in the SENIORS study, because of the high prevalence of heart failure with normal left ventricular (LV) ejection fraction (and altered diastole) in this population. Of interest, the effects observed in the present study were already apparent at nanomolar concentrations of nebivolol, which are probably close to therapeutic levels in vivo.
Several important questions remain and call for some "nuances" to the above paradigms. More careful analysis needs to be done on the electrophysiological effects of β3-AR stimulation in (animal or human) cardiac cells, in particular on the action potential and automaticity. Regional differences probably exist for these effects (e.g., between atria and ventricles). A recent study in human atrial cells showed an increase in ICa-L with increased contractile shortening in response to β3-AR stimulation (31), contrasting with the effects on ventricular muscle reported here (to the extent that isolated cell shortening can be compared with developed tension of whole, multicellular muscle tissue; the protocol for pharmacologic characterization of a β3-AR pathway also differs significantly between the 2 studies). Nevertheless, there are precedents for such differences at the atrial level, particularly for the effects of NO (32). The effect of β3-AR stimulation on heart rate is also difficult to predict; in vivo, infusion of β3-AR agonists resulted in cardiac acceleration, but this was mainly due to baroreflex tachycardia secondary to systemic vasodilatation (33). In the case of nebivolol, this would be counteracted by β1-AR blockade.
As importantly, the effect of long-term stimulation of cardiac β3-ARs on remodeling needs to be carefully examined. Chronic overexpression of β1-AR in transgenic mice results in the development of dilated cardiomyopathy, as mentioned previously (1). If β3-ARs antagonize the effects of β1-AR stimulation, as proposed in the preceding text, the prediction would be that long-term β3-AR stimulation would protect against adverse remodeling (Fig. 1). This is supported by observations on the phenotype of transgenic mice with cardiac-specific overexpression of β3-ARs under chronic catecholaminergic stress (34). Such a protective mechanism may also participate in the supplemental protection afforded by nebivolol (vs. metoprolol) in post-infarction remodeling (35).
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Footnotes
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This study was supported by the Fondation Jean Leducq, FP6-IP "EUGeneHeart" of the European Commission, the Politique Scientifique Fédérale (PAI-P6/55), the Communauté Française de Belgique (ARC 06/11-338), and Fonds National de la Recherche Scientifique.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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