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. 2011 Feb;162(4):817–822. doi: 10.1111/j.1476-5381.2010.01005.x

Are there functional β3-adrenoceptors in the human heart?

Martin C Michel 1, Sian E Harding 2, Richard A Bond 3
PMCID: PMC3042193  PMID: 20735409

Abstract

β3-Adrenoceptor mRNA is expressed in the human heart, but corresponding receptor protein has not yet consistently been demonstrated. Furthermore, their physiological role remains highly controversial. For example, in human atria these receptors apparently do not promote cAMP formation. Evidence presented in this issue of the BJP suggests that a previously reported β3-adrenoceptor-mediated stimulation of Ca2+ channels at room temperature is absent at physiological temperatures, and that β3-adrenoceptors have no effect on atrial contraction. Drugs classified as β3-adrenoceptor agonists cause contraction in human atria but in most cases this involves β1- and/or β2-adrenoceptors. In contrast, in human ventricles β3-adrenoceptor agonists can exhibit negative inotropic effects, potentially involving Pertussis toxin-sensitive G-proteins and activation of a NO synthase. However, firmer pharmacological evidence is required that these effects indeed occur via β3-adrenoceptors. Whether the expected future use of β3-adrenoceptor agonists in the treatment of urinary bladder dysfunction is associated with adverse events related to cardiac function remains to be determined from clinical studies.

LINKED ARTICLE

This article is a commentary on Christ et al., pp. 823–839 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00996.x

Keywords: β3-adrenoceptors; heart, human; inotropy; calcium current

β-Adrenoceptors are important regulators of human cardiac function and the roles of β1- and β2-adrenoceptors in this regard are well defined (Brodde and Michel, 1999). Although the existence of a third β-adrenoceptor subtype, the β3-adrenoceptor, was formally recognized based on its cloning more than 20 years ago (Emorine et al., 1989), its existence as a functional receptor in the human heart remains controversial, as highlighted by a paper in this issue of the BJP (Christ et al., 2011). A major part of this controversy may relate to the lack of selectivity of pharmacological tools, such as the agonist BRL 37344 or the antagonist SR 59230, used to probe the involvement of this subtype in a given response (Vrydag and Michel, 2007). Furthermore, interpretation of the data is further clouded by the existence of an atypical low affinity state of the β1-adrenoceptor, which is activated by some compounds used to probe β3-adrenoceptor function, for example CGP 12177 (Kaumann and Molenaar, 2008). Against this background we will review, briefly, the current evidence for and against functional β3-adrenoceptors in the human heart. For reasons of scope, animal studies will not be covered here but have been reviewed previously (Rozec and Gauthier, 2006; Galindo-Tovar et al., 2009).

Cardiac β3-adrenoceptor message and protein expression

β3-Adrenoceptor mRNA has been detected repeatedly in the human heart (Krief et al., 1993; Gauthier et al., 1996) although with much lower abundance than that of β1- or β2-adrenoceptors (Moniotte et al., 2001b). In contrast to β1-adrenoceptor mRNA, β3-adrenoceptor mRNA was reported not to be down-regulated in heart failure patients (Moniotte et al., 2001b), potentially shifting the relative role of the two subtypes in disease states. Whether β3-adrenoceptor protein is also expressed in the human heart is less clear as no suitable radioligand exists (Vrydag and Michel, 2007). Antibody-based detection of β3-adrenoceptor protein has been reported in one study with a validated antibody (Chamberlain et al., 1999). Two other studies using a different non-validated antibody have also detected β3-adrenoceptor protein in immunohistochemistry and/or immunoblotting (Moniotte et al., 2001a; Napp et al., 2009). However, the latter findings are more difficult to interpret as recent data demonstrate that many β-adrenoceptor subtype antibodies lack selectivity for their cognate receptor (Hamdani and van der Velden, 2009; Pradidarcheep et al., 2009).

Lack of suitable ligands for functional studies

The uncertainty regarding expression of β3-adrenoceptor protein places the burden of proof on functional studies. Most of these studies have relied on agonists such as BRL 37344, CGP 12177, CL 316243 or SR 58611 or antagonists such as SR 59230 and L-748337. However, interpretation of the results of these studies is hampered by the lack of widely available, truly selective or highly preferential β3-adrenoceptor ligands (see Table 1). For example, BRL 37344 has little selectivity for β3- over β1- and/or β2-adrenoceptors and also displays several non-adrenoceptor effects (Vrydag and Michel, 2007; Ngala et al., 2009; Baker, 2010). Within a single experiment, it may cause some of its effects via β3- but others via β1/β2-adrenoceptors (Mori et al., 2010). CGP 12177 is a potent antagonist at β1- and β2-adrenoceptors, a low potency agonist at the atypical site of β1-adrenoceptors and a partial agonist at β3-adrenoceptors (Kaumann and Molenaar, 2008). CL 316243 preferentially works on rodent receptors and has only a 10-fold selectivity for human β3- over β2-adrenoceptors (Baker, 2005). SR 58611 is less well characterized for its selectivity for human subtypes but at least some of its effects apparently are not sensitive to β3-adrenoceptor antagonism (Brahmadevara et al., 2003). Among antagonists, SR 59230 is widely used but has little selectivity for the β3-subtype (Vrydag and Michel, 2007; Baker, 2010). Moreover, it can be an agonist for some β3-adrenoceptor responses (Michel and Alewijnse, 2007; Evans et al., 2010). L-748337 has the greatest selectivity for human β3- versus β1- and β2-adrenoceptors (Ki 4 vs. 390 and 204 nM respectively) (Candelore et al., 1999). A more recent study reports an even greater β3-selectivity (Ki 9 vs. 3631 and 3388 nM respectively) but also detected a second low affinity site on β3- but not β1- or β2-adrenoceptor-expressing cells (Baker, 2010). The lack of suitable pharmacological ligands needs to be taken into consideration in the interpretation of the functional data discussed below, particularly as several studies have relied on a single agonist or antagonist concentration.

Table 1.

Affinity of frequently used drugs at cloned human β1-, β2- and β3-adrenoceptors expressed in Chinese hamster ovary cells

β1-adrenoceptor β2-adrenoceptor β3-adrenoceptor Reference
BRL 37344 4.4–5.2 5.1–6.5 6.4–6.5 Hoffmann et al., 2004; Baker, 2010
CGP 12177 8.3–9.2 8.4–9.4 7.0–7.1 Hoffmann et al., 2004; Baker, 2005
CL 316243 <3 4.1 5.1 Baker, 2005
L-748337 5.4–6.4 6.5–6.7 8.0–8.4 Candelore et al., 1999; Baker, 2010
SR 58611 <4.5 6.3 8.5 Bianchetti and Manara, 1990
nadolol 7.2 8.6 6.2 Baker, 2005)
SR 59230 7.5–7.8 7.2–8.5 6.9–7.4 Hoffmann et al., 2004; Baker, 2010
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Data are pKi values in radioligand binding studies (except for SR 58611 which are pEC50 data for guinea pig atrium, rat uterus and rat colon).

Evidence for cardiac β3-adrenoceptors from functional studies

cAMP studies

Stimulation of cAMP formation is the prototypical signalling response of β-adrenoceptors. However, adenylyl cyclase stimulation by noradrenaline and adrenaline in human right atrium was entirely mediated by β1- and β2-adrenoceptors (Gille et al., 1985). Confirming these findings, the cAMP accumulation in atrial strips in response to isoprenaline was fully suppressed by 100 nM propranolol (Ikezono et al., 1987).

Ca2+channel studies

Cardiac β-adrenoceptors can also couple to activation of L-type Ca2+ channels and such activation has been demonstrated in isolated human atrial myocytes for three agonists which can activate β3-adrenoceptors, that is, BRL 37344, CGP 12177, and SR 58611 (Skeberdis et al., 2008). Such responses were blocked by 1 µM of the β3-antagonist L 748337, but this concentration may also inhibit β1-/β2-adrenoceptors (Table 1). Of note, these electrophysiological experiments had been carried out at room temperature, and Christ et al. confirm these observations for BRL 37344 and SR 58611 (Christ et al., 2011). On the other hand, the Ca2+ current activation by CGP 12177 at room temperature was not antagonized by 1 µM L-748337 in their hands but rather by 1–10 µM (-)-bupranolol, suggesting mediation via the atypical site of the β1-adrenoceptor. Importantly, when the channel recordings were performed at 37°C, CGP 12177 no longer affected Ca2+-channel function except for a small, bupranolol-sensitive effect when signals were amplified by the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Taken together these findings demonstrate β3-adrenoceptor stimulation of Ca2+-channels in human atrium at lower temperatures, incompatible with mammalian life, but not at a physiological temperature. BRL 37344 was also reported to cause Ca2+ elevations as assessed by the fluorescent indicator dye Fura-2 (Pott et al., 2003), but unfortunately the temperature at which this was measured was not reported. Interestingly, Christ et al., (2011) speculate that the preferential β3-adrenoceptor function at lower temperatures may relate to its phylogenetic role in brown adipose tissue and the shivering response (Arch, 2008). How these effects on Ca2+-channel function relate to a reported reduction of action potential duration in endomyocardial biopsies by BRL 37344 (Gauthier et al., 1996) remains unclear, particularly as the temperature at which these experiments were performed was not reported.

Cardiac contractility studies

Most data on possible human cardiac β3-adrenoceptor function relate to the control of contractility. Unless specifically stated otherwise, all of these experiments were performed at about 37°C. While the endogenous catecholamines noradrenaline and adrenaline and the prototypical β-adrenoceptor agonist isoprenaline cause positive inotropy in both atria and ventricles (Brodde and Michel, 1999), the proposed effects of β3-adrenoceptor agonists differ markedly between atria and ventricles.

Atrial contractility

In human atrial preparations, noradrenaline- and adrenaline-induced contractions were antagonized by propranolol with a potency consistent with mediation by β1/β2-adrenoceptors (Gille et al., 1985). Similarly, responses to isoprenaline were also attenuated by 100 nM propranolol, although not completely suppressed (Ikezono et al., 1987). BRL 37344 was reported to cause contraction of human atrium (partial agonism relative to isoprenaline) in most (Arch and Kaumann, 1993; Sennitt et al., 1998; Pott et al., 2003; Skeberdis et al., 2008; Christ et al., 2011) but not all studies (Kaumann et al., 1997). These responses were typically blocked by propranolol and/or other antagonists with potencies compatible with β1/β2-adrenoceptors (Arch and Kaumann, 1993; Sennitt et al., 1998; Pott et al., 2003; Christ et al., 2011), although one study failed to observe inhibition by 200 nM nadolol (Skeberdis et al., 2008). Interestingly, the contractile effects of the β3-adrenoceptor agonists, in contrast to those of isoprenaline, were no longer observed at 25°C, that is, the temperature where those compounds promote Ca2+ currents, indicating a dissociation between Ca2+ currents and contraction (Christ et al., 2011). While these data suggest that positive inotropic effects of BRL 37344 occur primarily if not exclusively via β1/β2-adrenoceptors, this agonist can also activate NO synthase and promote NO release in human right atrium by a propranolol-resistant mechanism (Pott et al., 2003; Brixius et al., 2004). As shown in many studies, CGP 12177 causes inotropic effects in the human atrium via the atypical site of the β1-adrenoceptor (for review see Kaumann and Molenaar, 2008), but one study failed to observe the expected inhibition of this response by 200 nM nadolol (Skeberdis et al., 2008). Bucindolol may also cause small inotropic responses via the atypical site of the β1-adrenoceptor (Bundkirchen et al., 2002). β3-Adrenoceptor agonists such as RO 363 (Molenaar et al., 1997) or a range of agonists from the phenylethanolamine and aryloxypropanolamine class (Sennitt et al., 1998) also cause their positive inotropic effects via β1/β2-adrenoceptors. With regard to SR 58611, one study has reported positive inotropic effects which were insensitive to 200 nM nadolol (Skeberdis et al., 2008), whereas two other studies did not observe inotropic effects of this β3-agonist (Kaumann et al., 1997; Christ et al., 2011). The β1-antagonist and putative β3-agonist nebivolol caused small negative inotropic effects when studied in the combined presence of 1 µM propranolol, a NO synthase inhibitor and a low concentration of forskolin (Bundkirchen et al., 2002). Finally, a lack of inotropic effects in the human atrium has also been reported for the β3-agonists ZD 2079 and CL 316243 as well as for SR 59230 (Kaumann et al., 1997), the latter being an antagonist in most systems but having agonist properties for some cellular response (Michel and Alewijnse, 2007; Evans et al., 2010). In conclusion, the majority of studies indicate that positive inotropic responses to β3-adrenoceptor agonists in human right atrium are not mediated by β3-adrenoceptors but rather by β1-(including atypical β1) and β2-adrenoceptors. Moreover, these effects are typically small and therefore may not be sufficiently robust to be detected consistently.

Ventricular contractility

A very different situation exists in human ventricles. As in the atria, the endogenous catecholamines noradrenaline and adrenaline cause positive inotropic effects via β1/β2-adrenoceptors (Brodde and Michel, 1999). While one study has reported positive inotropic effects of CGP 12177 or cyanopindolol in the presence of 200 nM propranolol in ventricular trabeculae when effects were enhanced by isobutylmethylxanthine (Kaumann et al., 1997), two other studies reported negative inotropic effects of CGP 12177 in endomyocardial biopsies (Gauthier et al., 1996; 1999;). In the latter studies and one additional report from that group (Rozec et al., 2009), BRL 37344, SR 58611, CL 316243 and nebivolol also exhibited negative inotropic effects which were not affected by 10 µM nadolol or 1 µM metoprolol whereas some inhibition was observed with 1 µM bupranolol or L 748337. The negative inotropic effects of BRL 37344 were sensitive to Pertussis toxin treatment. Negative inotropic effects of BRL 37344 (Napp et al., 2009) or marginal negative inotropic effects of BRL 37344, SR 58611A and CL 316243 causing changes amounting to only 2.5% of basal force (Kaumann and Molenaar, 1997), were also reported by other investigators. Of interest, BRL 37344 can cause NO release in human ventricles (Brixius et al., 2004) and the negative inotropic effects of both BRL 37344 and nebivolol were abolished in the presence of a NO synthase inhibitor (Napp et al., 2009; Rozec et al., 2009), in line with data from several other mammalian species (Moens et al., 2010). The physiological relevance of ventricular β3-adrenoceptors is difficult to judge but with cloned subtypes the response to β3-preferring agonists is typically small relative to that to isoprenaline unless high expression levels of the receptor are used (Hoffmann et al., 2004; Baker, 2010). This makes it difficult to estimate how relevant such negative inotropic effects may be in vivo in the presence of endogenous catecholamines.

Conclusions

In conclusion, the physiological relevance of β3-adrenoceptor-mediated activation of L-type Ca2+-channels in the human heart at room temperature remains unclear as it apparently is absent at physiological temperature. Contractile effects of CGP 12177 in human atrium appear to be mediated by the atypical site of the β1-adrenoceptor, and most other β3-adrenoceptor agonists may also act via β1/β2-adrenoceptors. In contrast, β3-adrenoceptor agonists may cause negative inotropic effects in the human ventricle but the involvement of a β3-adrenoceptor in these effects is not fully clear. Unlike the β1- and β2-adrenoceptors, little information is available on the spatial nature of β3-adrenoceptor signalling, or even whether NO release is a direct effect on the ventricular myocyte or indirect through stimulation of neighbouring microvascular endothelial cells. Possibly the effects of β3-adrenoceptors on contraction are subsidiary, and their main role is a metabolic, or another undetermined, effect. Two challenges for future research arise from these data. Firstly, the involvement of β3-adrenoceptors in human cardiac (particularly ventricular) responses to β3-adrenoceptor agonists needs to be established more firmly using quantitative pharmacology, that is, full concentration–response curves to agonists in the presence of multiple concentrations of subtype-preferential antagonists. Secondly, it remains to be explored whether selective β3-adrenoceptor agonists such as mirabegron (Vrydag et al., 2009) when used clinically for the treatment of the overactive bladder syndrome will be associated with cardiac adverse events. Limited data from two clinical studies with mirabegron (Chapple et al., 2008; 2010;) or solabegron (Grudell et al., 2008) have not pointed towards such adverse events until now but a definitive judgement has to await further studies.

Conflict of interest

Work in this field in the laboratory of MCM is supported by Astellas. RAB and SEH report no conflict of interest.

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