Cardiac implications for the use of β₂-adrenoceptor agonists for the management of muscle wasting

Abstract

There are proposals for the implementation of β₂-adrenoceptor agonists for the management of muscle wasting diseases. The idea has been initiated by studies in animal models which show that β₂-adrenoceptor agonists cause hypertrophy of skeletal muscle. Their use in clinical practice will also need an understanding of possible effects of activation of human heart β₂-adrenoceptors. Consequences could include an increased probability of arrhythmias in susceptible patients.

Muscle wasting is a collection of complex clinical syndromes associated with many conditions including ageing (sarcopenia, Argilés et al., 2005a), cancer (cancer cachexia, Argilés et al., 2005b), chronic obstructive lung disease (Hansen et al., 2005), muscle dystrophies (Kissel et al., 1998; 2001) and chronic heart failure (Anker & Coats, 1999). The degree of muscle wasting is a predictor of mortality for cancer, chronic obstructive lung disease and chronic heart failure (Anker et al., 1997; Argilés et al., 2005a; Hansen et al., 2005). Mechanisms of muscle wasting possibly include proinflammatroy cytokines, tumour necrosis factor-α, interleukin-1, interleukin-6 and interferon-γ (Argilés et al., 2005a; Hansen et al., 2005) and these have been considered as therapeutic targets (Argilés et al., 2005b).

The potential use of β-adrenoceptor agonists for the management of muscle wasting has been raised (Kissel et al., 1998; 2001; Busquets et al., 2004; Ryall et al., 2006). Chronic administration of β-adrenoceptor agonists causes skeletal muscle hypertrophy in many animal species (Kim et al., 1992; Hinkle et al., 2002; Busquets et al., 2004; Ryall et al., 2006) and humans (Kissel et al., 2001). The successful implementation of β-adrenoceptor agonists for this purpose would include an ability to reverse muscle loss, promote muscle gain, strength and mobility without inducing adverse effects. With respect to the latter, some considerations are given for possible effects in the heart.

High doses of formoterol (2 mg kg⁻¹ body weight, i.p.) administered to rats or mice with induced cachectic cancer tumours resulted in a reversal of skeletal and heart muscle wasting (Busquets et al., 2004). Formoterol caused an inhibition of skeletal muscle proteolysis and increased protein synthesis (Busquets et al., 2004). Ryall et al. (2006) report the potential use of low-dose formoterol and salmeterol for pathologies of muscle wasting and weakness. Currently, both drugs are used for the management of asthma and are characterized by relatively high lipophilicity, high affinity for the β₂-adrenoceptor and consequently long duration of action (Teschemacher & Lemoine, 1999). In rats, subcutaneous administration of both salmeterol and formoterol caused skeletal and heart muscle hypertrophy. To avoid cardiac complications, it would be desirable to target therapeutic strategies to skeletal muscle. In the study of Ryal et al. (2006), formoterol exhibited ∼8–16-fold hypertrophic selectivity on the basis of pEC₅₀ values for skeletal versus heart muscle, while salmeterol was essentially nonselective for both muscle groups (⩽2-fold heart selective). The relative potencies of formoterol and salmeterol for causing skeletal and heart muscle hypertrophy by Ryall et al. are interesting in the context of previously determined affinities at β₁- and β₂-adrenoceptors. Salmeterol is 65–2818-fold selective for guinea-pig and human β₂- versus β₁-adrenoceptors on the basis of affinity (Roux et al., 1996; Hoffmann et al., 2004; Baker, 2005), and formoterol 60–346-fold β₂-adrenoceptor selective (guinea-pig β-adrenoceptors, Lemoine et al., 1991; 1992; Roux et al., 1996). Both agonists have the ability to form guanine nucleotide-sensitive high-affinity binding sites (H) at guinea-pig β₁- and β₂-adrenoceptors (Roux et al., 1996). The high-affinity guanine nucleotide-sensitive binding site (H) is presumably responsible for agonist effects. Salmeterol (117-fold) and formoterol (10-fold) are selective for guanine nucleotide-sensitive, high-affinity guinea-pig β₂- versus β₁-adrenoceptor binding sites (Roux et al., 1996). In functional studies, formoterol was ∼680–1700-fold selective for causing relaxation of 0.1 μM carbachol contracted guinea-pig tracheal strips (β₂>β₁-adrenoceptors) than for causing positive inotropic effects in guinea-pig left ventricular papillary muscle (β₁-adrenoceptors, Trofast et al., 1991).

In several experimental conditions, rodent hearts or cardiomyocytes are more susceptible to hypertrophy through β₁- than β₂-adrenoceptors. Isoprenaline caused hypertrophy of neonatal rat cardiomyocytes in vitro and adult rat heart in vivo which was blocked by the β₁-blocker betaxolol but not the β₂-blocker ICI 118551 (Morisco et al., 2001). Cardiac overexpression (5–15-fold) of human β₁-adrenoceptors in mice caused progressive myocyte hypertrophy, measurable within weeks of birth (Engelhardt et al., 1999). On the other hand, 60-fold cardiac overexpression of wild-type human β₂-adrenoceptors did not show any evidence of cardiac hypertrophy up to the age of 1 year but did at higher expression levels (Liggett et al., 2000). In mice, 30-fold overexpression of β₂-adrenoceptors prevented Gαq-protein overexpression (∼5-fold)-induced hypertrophy (DORN et al., 1999). This prompts the question which receptors (β₁-, β₂-) were responsible for salmeterol- and formoterol-induced hypertrophy in skeletal and heart muscle preparations in the study of Ryall et al.? Rat soleus muscle comprises 20 : 80% β₁- : β₂-adrenoceptors (Kim et al., 1991) and rat ventricle ∼73:27% β₁- : β₂-adrenoceptors (Sarsero & Molenaar, 1995). In rat soleus and EDL muscles in vitro, a high concentration of ICI 118 551 (10 μM) reversed 100 μM adrenaline- and 10 μM clenbuterol-mediated inhibition of proteolysis (Navegantes et al., 2001). The use of low concentrations of β₂-adrenoceptor selective agonists together with previous studies with selective blockers suggests that β₂-adrenoceptors mediate hypertrophy in skeletal muscle. Whether ‘break-through' of β₁-adrenoceptors by salmeterol and formoterol was partly or solely responsible for hypertrophy in the heart would need to be determined with selective β₁- and β₂-adrenoceptor blockers (Morisco et al., 2001).

Is the progression of this potential therapeutic strategy to humans feasible? The use of highly selective β₂-adrenoceptor agonists, possibly in conjunction with a selective β₁-blocker where possible, could ensure prevention of unintended β₁-adrenoceptor activation. This is particularly important for cardiovascular β₁-adrenoceptors, where chronic activation of β₁-adrenoceptors is contraindicated for prevalent cardiac and vascular disorders including hypertension, ischaemic heart disease, arrhythmias and heart failure where β-blockers are indicated in some cases. A pathological role of the β₁-adrenoceptor was confirmed in transgenic mice with 15-fold overexpression which exhibited an enhancement of heart function (dP/dt) followed by progressive deterioration involving hypertrophy and heart failure (Engelhardt et al., 1999). The importance of blocking β₁-adrenoceptors in heart failure to abrogate cardiotoxic β₁-adrenoceptor-mediated effects is well understood (Molenaar & Parsonage, 2005).

Assuming selective activation of β₂-adrenoceptors is achievable, progression of this potential therapeutic strategy from rats to humans requires consideration of the potential effects of chronic activation of β₂-adrenoceptors in human heart. Inhalational formulations of β₂-adrenoceptor agonists used for chronic management of airways diseases are designed for local application and systemic effects are unintended. Nevertheless, frequent use resulting in higher doses can result in cardiac events (Newhouse et al., 1996), while effects on muscle mass and function via this route have not been reported. Systemic administration of β₂-adrenoceptor agonists will result in widespread β₂-adrenoceptor activation including the heart. Preliminary studies are often carried out in rodents and therefore differences between rodent and human cardiac β₂-adrenoceptor systems should be noted. Briefly, evidence, mostly from Rui-Ping Xiao's laboratory, indicates dual coupling of β₂-adrenoceptors to stimulatory Gsα- and inhibitory Giα-proteins (reviewed most recently by Xiao, 2001; Xiao et al., 2004; Zheng et al., 2005). As is the case for β₁-adrenoceptor–Gsα-protein–cyclic AMP–PKA signalling in heart, coupling of the β₂-adrenoceptor to the same signalling pathway causes enhanced cell shortening and hastening of relaxation. Coupling of the β₂-adrenoceptor to pertussis toxin-sensitive Giα-protein and activation of phosphoinositide 3-kinase (PI3K) essentially opposes and bluntens the effects of β₂-adrenoceptor–Gsα-protein coupling. Prolonged stimulation also enables the β₂-adrenoceptor to couple to Giα-protein–PI3K–Akt (protein kinase B) pathways to exert an antiapoptotic effect. In human right atrium, it was demonstrated that the β-adrenoceptor agonist isoprenaline in the presence of CGP 20712A but not ICI 118 551 (all drugs 100 μM) were used to show Giα-protein coupling (Kilts et al., 2000). Additionally, pertussis toxin enhanced adenylyl cyclase activity in the presence of isoprenaline and CGP 20712A and isoprenaline in the presence of ICI 118 551 (all drugs 100 μM). However, the concentrations of drugs used in that study were particularly high and several studies investigating functional responses suggest predominant coupling to Gsα-proteins. In human atrium (Kaumann et al., 1996; Kaumann & Molenaar, 1997; Krause et al., 2004) and ventricle (Kaumann et al., 1999; Molenaar et al., 2000), activation of β₂-adrenoceptors caused increases in contractile force and hastening of relaxation associated with phosphorylation of phospholamban and troponin I, consistent with β₂-adrenoceptor coupling to Gsα-protein–cyclic AMP–PKA. In fact, the cardiostimulant effects mediated through activation of β₂-adrenoceptors were as great as or nearly as great as those mediated through activation of β₁-adrenoceptors. This observation has implications for the systemic use of β₂-adrenoceptor agonists for the purposes of inducing skeletal muscle growth in humans. Activation of human heart β₂-adrenoceptors causes increased rate, force (Fowler et al., 1982; Hall et al., 1989; Hall et al., 1990; Brodde, 1991; Kaumann et al., 1999; Molenaar et al., 2000) and induction of arrhythmias (Kaumann & Sanders, 1993; Kaumann et al., 1995). Salbutamol, a drug used for the management of asthma, causes an increase in contractile force in human right atrium in vitro (Hall et al., 1990) and causes tachycardia when administered directly into the right coronary artery (Hall et al., 1989). Salbutamol infusion into the right femoral vein causes an increase in dispersion of the QTend interval duration representing variations in ventricular repolarization and increase in repolarization heterogeneity (Lowe et al., 2001). This has been correlated with an increase in arrhythmia risk (Lowe et al., 2001). Thus, activation of ventricular β₂-adrenoceptors in susceptible individuals may cause an increase in triggered arrhythmias (Lowe et al., 2001). The clinical cardiovascular safety of β₂-adrenoceptor agonists has remained contentious. A recent meta-analysis of randomized controlled studies in patients with obstructive airways disease suggests that there may be increased risk of adverse cardiac events in this population (Salpeter, 2004). Orally administered salbutamol to 20 patients with advanced congestive heart failure was associated with ventricular tachycardia in six patients and atrial fibrillation in another (Mettauer et al., 1985). Such observations provide a caution that in certain large groups of patients with conditions associated with skeletal muscle wasting, obstructive airway disease and chronic heart failure, there may be particular risks associated with the administration of β₂-adrenoceptor agonists. Current clinical information concerning salmeterol and formoterol is restricted to inhalation administration. Both drugs are considered relatively safe with little evidence of cardiac adverse events except possibly in patients predisposed to arrhythmias (Cazzola et al., 1998). It was concluded from a review of multiple studies that inhaled salmeterol 100 μg could lead to changes in the ECG in a small number of patients from some but not all studies, suggesting ‘doubtful clinical meaning'.

β₂-Adrenoceptor agonists may have a role in the management of muscle wasting diseases in selected patients; however, their use may be contraindicated in some patients, particularly those predisposed to the occurrence of cardiac arrhythmias.

Abbreviations

CGP 20712A

2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl) 1H-imidazole-2-yl)-phenoxy) propyl) amino) ethoxy)-benzamide monomethane sulphonate

ICI 118

551 (erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butano-2-ol)