SEARCH

SEARCH BY CITATION

Keywords:

  • Skeletal muscle;
  • muscle wasting;
  • human heart;
  • arrhythmias;
  • β2-adrenoceptor;
  • formoterol;
  • salmeterol

Abstract

  1. Top of page
  2. Abstract
  3. Acknowledgments
  4. References

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.

British Journal of Pharmacology (2006) 147, 583–586. doi:10.1038/sj.bjp.0706670

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)

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 (leqslant R: less-than-or-eq, slant2-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.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Acknowledgments
  4. References

Research was supported by grants from the National Health and Medical Research Council of Australia and The Prince Charles Hospital Foundation. Lu Chen is supported by an Endeavour International Postgraduate Research Scholarship (IPRS) at the University of Queensland.

References

  1. Top of page
  2. Abstract
  3. Acknowledgments
  4. References
  • ANKER, S.D. & COATS, J.S. (1999). Cardiac cachexia. A syndrome with impaired survival and immune and neuroendocrine activation. Chest, 115, 836847.
  • ANKER, S.D., PONIKOWSKI, P., VARNEY, S., CHUA, T.P., CLARK, A.L., WEBB-PEPLOE, K.M., HARRINGTON, D., KOX, W.J., POOLE-WILSON, P.A. & COATS, A.J.S. (1997). Wasting as independent risk factor for mortality in chronic heart failure. Lancet, 349, 10501053.
  • ARGILÉS, J.M., BUSQUETS, S., FELIPE, A. & LÓPEZ-SORIANO, F.J. (2005a). Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia. Int. J. Biochem. Cell. Biol., 37, 10841104.
  • ARGILÉS, J.M., BUSQUETS, S., FELIPE, A. & LÓPEZ-SORIANO, F.J. (2005b). The pivotal role of cytokines in muscle wasting during cancer. Int. J. Biochem. Cell. Biol., 37, 20362046.
  • BAKER, J.G. (2005). The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br. J. Pharmacol., 144, 317322.
  • BRODDE, O.-E. (1991). β1- and β2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol. Rev., 43, 203242.
  • BUSQUETS, S., FIGUERAS, M.T., FUSTER, G., ALMENDRO, V., MOORE-CARRASCO, R., AMETLLER, W., ARGILÉS, J.M. & LÓPEZ-SORIANO, F.J. (2004). Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. Cancer Res, 64, 67256731.
  • CAZZOLA, M., IMPERATORE, F., SALZILLO, A., DI PERNA, F., CALDERARO, F., IMPERATORE, A. & MATERA, M.G. (1998). Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest, 114, 411415.
  • DORN II, G.W., TEPE, N.M., LORENZ, J.N., KOCH, W.J. & LIGGETT, S.B. (1999). Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice. Proc. Natl. Acad.Sci. U.S.A., 96, 64006405.
  • ENGELHARDT, S., HEIN, L., WIESMANN, F. & LOHSE, M.J. (1999). Progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice. Proc. Natl. Acad. Sci. U.S.A., 96, 70597064.
  • FOWLER, M.B., TIMMIS, A.D., CRICK, J.P., VINCENT, R. & CHAMBERLAIN, D.A. (1982). Comparison of haemodynamic responses to dobutamine and salbutamol in cardiogenic shock after acute myocardial infarction. Br. Med. J., 284, 7376.
  • HALL, J.A., KAUMANN, A.J. & BROWN, M.J. (1990). Selective β1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through β2-adrenoceptors in human atrial myocardium. Circ. Res., 66, 16101623.
  • HALL, J.A., PETCH, M.C. & BROWN, M.J. (1989). Intracoronary injections of salbutamol demonstrate the presence of functional β2-adrenoceptors in the human heart. Circ. Res., 65, 546553.
  • HANSEN, M.J., GUALANO, R.C., BOZINOVSKI, S., VLAHOS, R. & ANDERSON, G.P. (2006). Therapeutic prospects to treat skeletal muscle wasting in COPD (chronic obstructive lung disease). Pharmacol. Ther., 109, 162172.
  • HINKLE, R.T., HODGE, K.M.B., CODY, B.S., SHELDON, R.J., KOBILKA, B.K. & ISFORT, R.J. (2002). Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the β2-adrenergic receptor. Muscle Nerve, 25, 729734.
  • HOFFMANN, C., LEITZ, M.R., OBERDORF-MAASS, S., LOHSE, M.J. & KLOTZ, K.-N. (2004). Comparative pharmacology of human β-adrenergic receptor subtypes – characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedeberg's Arch. Pharmacol., 369, 151159.
  • KAUMANN, A., BARTEL, S., MOLENAAR, P., SANDERS, L., BURRELL, K., VETTER, D., HEMPEL, P., KARCZEWSKI, P. & KRAUSE, E.-G. (1999). Activation of β2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failue. Circulation, 99, 6572.
  • KAUMANN, A.J., LYNHAM, J.A., SANDERS, L., BROWN, A.M. & MOLENAAR, P. (1995). Contribution of differential efficacy to the pharmacology of human β1- and β2-adrenoceptors. Pharmacol. Comm., 6, 215222.
  • KAUMANN, A.J. & MOLENAAR, P. (1997). Modulation of human cardiac function through 4 β-adrenoceptor populations. Naunyn-Schmiedeberg's Arch. Pharmacol., 355, 667681.
  • KAUMANN, A.J. & SANDERS, L. (1993). Both β1- and β2-adrenoceptors mediate catecholamine-evoked arrhythmias in isolated human right atrium. Naunyn-Schmiedeberg's Arch. Pharmacol., 348, 536540.
  • KAUMANN, A.J., SANDERS, L., LYNHAM, J.A., BARTEL, S., KUSCHEL, M., KARCZEWSKI, P. & KRAUSE, E.-G. (1996). β2-Adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium. Mol. Cell. Biochem., 163/164, 113123.
  • KILTS, J.D., GERHARDT, M.A., RICHARDSON, M.D., SREERAM, G., MACKENSEN, G.B., GROCOTT, H.P., WHITE, W.D., DAVIS, R.D., NEWMAN, M.F., REVES, J.G., SCHWINN, D.A. & KWATRA, M.M. (2000). β2-Adrenergic and several other G protein-coupled receptors in human atrial membranes activate both Gs and Gi. Circ. Res., 87, 705709.
  • KIM, Y.S., SAINZ, R.D., MOLENAAR, P. & SUMMERS, R.J. (1991). Characterization of β1- and β2-adrenoceptors in rat skeletal muscles. Biochem. Pharmacol., 42, 17831789.
  • KIM, Y.S., SAINZ, R.D., SUMMERS, R.J. & MOLENAAR, P. (1992). Cimaterol reduces β-adrenergic receptor density in rat skeletal muscles. J. Anim. Sci., 70, 115122.
  • KISSEL, J.T., MCDERMOTT, M.P., MENDELL, J.R., KING, W.M., PANDYA, S., GRIGGS, R.C. & TAWIL, R. (2001). Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology., 57, 14341440.
  • KISSEL, J.T., MCDERMOTT, M.P., NATARAJAN, R., MENDELL, J.R., PANDYA, S., KING, W.M., GRIGGS, R.C. & TAWIL, R. (1998). Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology, 50, 14021406.
  • KRAUSE, E.-G., BARTEL, S., VETTER, D., KARCZEWSKI, P., RUSSELL, F.D., KAUMANN, A.J. & MOLENAAR, P. (2004). Both β1- and β2-adrenoceptors mediate increases in contractile force and hastening of relaxation in human atrium. J. Mol. Cell. Cardiol., 37, 229.
  • LEMOINE, H., OVERLACK, C., KÖHL, A., WORTH, H & REINHARDT, D. (1992). Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: comparison of relaxation with receptor binding. Lung, 170, 163180.
  • LEMOINE, H., OVERLACK, C., WORTH, H. & REINHARDT, D. (1991). Increased muscarinic prestimulation of guinea-pig tracheal strips decreases potency and intrinsic activity (ISA) of synthetic β2-sympathomimetics. Comparison of relaxation with receptor binding and adenylate stimulation. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, R98.
  • LIGGETT, S.B., TEPE, N.M., LORENZ, J.N., CANNING, A.M., JANTZ, T.D., MITARIAI, S., YATANI, A. & DORN II, G.W. (2000). Early and delayed consequences of β2-adrenergic receptor overexpression in mouse hearts. Critical role for expression level. Circ. Res., 101, 17071714.
  • LOWE, M.D., ROWLAND, E., BROWN, M.J. & GRACE, A.A. (2001). β2 Adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium. Heart, 86, 4551.
  • METTAUER, B., ROULEAU, J.-L. & BURGESS, J.H. (1985). Detrimental arrhythmogenic and sustained beneficial hemodynamic effects of oral salbutamol in patients with chronic congestive heart failure. Am. Heart J., 109, 840847.
  • MOLENAAR, P., BARTEL, S., COCHRANE, A., VETTER, D., JALALI, H., POHLNER, P., BURRELL, K., KARCZEWSKI, P., KRAUSE, E.-G. & KAUMANN, A. (2000). Both β2- and β1-adrenergic receptors mediate hastened relaxation and phosphorylation of phospholamban and troponin I in ventricular myocardium of Fallot infants, consistent with selective coupling of β2-adrenergic receptors to Gs-protein. Circulation, 102, 18141821.
  • MOLENAAR, P. & PARSONAGE, W.A. (2005). Fundamental considerations of β-adrenoceptor subtypes in human heart failure. Trends Pharmacol. Sci., 26, 368375.
  • MORISCO, C., ZEBROWSKI, D.C., VATNER, D.E., VATNER, S.F. & SADOSHIMA, J. (2001). Adrenergic cardiac hypertrophy is mediated primarily by the β1-subtype in the rat heart. J. Mol. Cell. Cardiol., 33, 561573.
  • NAVEGANTES, L.C.C., RESANO, N.M.Z., MIGLIORINI, R.H. & KETTELHUT, I.C. (2001). Catecholamines inhibit Ca2+-dependent proteolysis in rat skeletal muscle through β2-adrenoceptors and cAMP. Am. J. Physiol. Endocrinol. Metab., 281, E449E454.
  • NEWHOUSE, M.T., CHAPMAN, K.R., MCCALLUM, A.L., ABBOUD, R.T., BOWIE, D.M., HODDER, R.V., PARÉ, P.D., MESIC-FUCHS, H. & MOLFINO, N.A. (1996). Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma. Chest, 110, 595603.
  • ROUX, F.J., GRANDORDY, B. & DOUGLAS, J.S. (1996). Functional and binding characteristics of long-acting β2-agonists in lung and heart. Am. J. Resp. Crit. Care. Med., 153, 14891495.
  • RYALL, J.G., SILLENCE, M.N. & LYNCH, G.S. (2006). Systemic administration of β2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses. Br. J. Pharmacol., 147, 587595 (this issue).
  • SALPETER, S.R. (2004). Cardiovascular safety of β2-adrenoceptor agonist use in patients with obstructive airway disease. A systematic review. Drugs Aging, 21, 405414.
  • SARSERO, D. & MOLENAAR, P. (1995). Effects of chronic infusion of (−)-isoprenaline on rat cardiac muscarinic (M2)-cholinoceptors and β1- and β2-adrenoceptors. J. Auton. Pharmacol., 15, 239255.
  • TESCHEMACHER, A. & LEMOINE, H. (1999). Kinetic analysis of drug–receptor interactions of long-acting β2 sympathomimetics in isolated receptor membranes: evidence against prolonged effects of salmeterol and formoterol on receptor-coupled adenylyl cyclase. J. Pharmacol. Exp. Ther., 28, 10841092.
  • TROFAST, J., ÖSTERBERG, K., KÄLLSTRÖM, B.-L. & WALDECK, B. (1991). Steric aspects of agonism and antagonism at β-adrenoceptors: synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers. Chirality, 3, 443450.
  • XIAO, R.-P. (2001). β-Adrenergic signaling in the heart: dual coupling of the β2-adrenergic receptor to Gs and Gi proteins. Sci. STKE, 104, re15.
  • XIAO, R.-P., ZHU, W., ZHANG, M., CHAKIR, K., BOND, R., LAKATTA, E.G. & CHENG, H. (2004). Subtype-specific β-adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol. Sci., 25, 358365.
  • ZHENG, M., ZHU, W., HAN, Q. & XIAO, R.-P. (2005). Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling. Pharmacol. Ther., 108, 257268.