Allergology International. 2005;54:89-97 REVIEW ARTICLE Clinical Use of !2-adrenergic Receptor Agonists Based on Their Intrinsic Efficacy Hiroaki Kume1 ABSTRACT Clinical choice of β2-adrenergic receptor agonists (β2-agonists) is based on the parameter of receptor selectiv- ity, potency, and duration of action. The guidelines for asthma management describe nothing about intrinsic ef- ficacy concerning the use of β2-agonists. Since intrinsic efficacy refers to the ability to activate β2-adrenergic re- ceptors independent of agonist concentration, β2-adrenergic desensitization may be associated with intrinsic efficacy. However, little is currently known whether chronic administration of high intrinsic efficacy drugs inter- feres with the effects of β2-agonists as a reliever medication. In this review, the causal relationship between in- trinsic efficacy and desensitization to β2-agonists is examined in tracheal smooth muscle using isometric ten- sion records. Reasonable clinical use of these agonists based on these observations is discussed. When β2- agonists intrinsic efficacy was measured as relaxation response (the maximum inhibitory effects against 1 µM methacholine-induced contraction), their rank order was : isoproterenol = procaterol = formoterol > salbutamol > salmeterol >> tulobuterol. Next, the subsequent response to short-acting β2-agonists (procaterol, salbutamol) was examined after continuous exposure to long-acting β2-agonists (formoterol, salmeterol, tulobuterol). β2- adrenergic desensitization induced by these long-acting β2-agonists was enhanced in proportion to their intrin- sic efficacies. On the other hand, under the conditions of impairment of β2-adrenergic receptors, reduced re- sponsiveness to these short-acting β2-agonists was enhanced in inverse proportion to the intrinsic efficacy. Al- though the clinical relevance of these results is still unclear, our data may provide evidence that weak partial agonists are useful as a controller medication, whereas full or strong agonists are useful as a reliever medica- tion． KEY WORDS airway smooth muscle, bronchial asthma, desensitization, Gs, long-acting β2-agonists, Rho, β2-adrenergic receptors referred to as desensitization.2,3 Moreover, a decline INTRODUCTION in β2-agonist activity is observed after prolonged ex- β2-Adrenergic receptor agonists ( β2-agonists ) are posure to pro-inflammatory cytokines4-6 and lysophos- widely used clinically to relax airway smooth muscle pholipid7 that participate in the airway inflammation and are the principal bronchodilator agents used to of bronchial asthma. A postmortem study also has treat bronchial asthma . Regular administration of shown that the response to β2-agonists in vitro is at- short-acting β2-agonists may cause not only a deterio- tenuated in airway smooth muscle harvested from pa- ration of asthma control and an exacerbation of air- tients with fatal asthma.8 The impaired β2-adrenergic way hyperreactivity, but also an accelerative decline action is a characteristic feature of patients with this in lung function in patients with this disease.1 These disease , and is an important problem in both the undesirable dysfunctions may be due to reduced re- pathogenesis and therapy． sponsiveness to short-acting β2-agonists elicited by Rapid- and short-acting β2-agonists suppress bron- excessive exposure to these agents, a phenomenon choconstriction and related sympotoms of acute 1Division of Respiratory Medicine, Department of Medicine, Na- −8550, Japan. goya University Graduate School of Medicine, Nagoya, Japan. Email: [email protected]−u.ac.jp Correspondence: Hiroaki Kume, M.D., Ph.D., Division of Respira- Received 11 March 2004. tory Medicine, Department of Medicine, Nagoya University Gradu- !2005 Japanese Society of Allergology ate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466 Allergology International Vol 54, No1, 2005 www.js-allergol.gr.jp! 89 Kume H asthma exacerbations, but do not inhibit airway in- receptor phosphorylation, i.e., 1) second messenger- flammation and airway hyperreactivity . Treatment activated kinases such as the adenosine 3’, 5’-cyclic with anti-inflammatory agents is more effective than monophosphate ( cAMP ) -dependent kinase ( PKA ) that with bronchodilator agents for long-term man- and 2) the second messenger-independent G protein- agement of bronchial asthma . Although the anti- coupled receptor kinases such as the β2-adrenergic inflammatory effects of long-acting β2-agonists are receptor kinase (βARK) and G protein-coupled recep- still unclear in clinical use, the guidelines for asthma tor kinases ( GRKs ) . 18,19 Receptor phosphorylation prevention and management recommend daily ad- mediated by PKA occurs with low concentrations of β ministration of long-acting β2-agonists as a controller 2-agonists, leading to heterologous desensitization.20 medication . The regular use of long-acting β2- On the other hand, high concentrations of β2-agonists agonists in combination with inhaled glucocorti- are required for activaton of βARK and GRKs, leading costeroid is considered to be beneficial to these pa- to homologous desensitization.20 The former refers to tients according to the cross-talk between these two a reduced response to not only β2-agonists but also receptors. 9,10 However, a few reports have demon- other agents that elevate concentration of intracellu- strated that regular use of inhaled long-acting β2- lar cAMP bypassing β-adrenergic receptors, such as agonists results in desensitization of β2-adrenergic re- forskolin, theophylline, db-cAMP, and prostaglandin ceptors even though these agonists are added to in- (PG) E2. The latter refers to a specific reduced re- haled glucocorticosteroid therapy.11,12 Little is essen- sponse to β2-agonists while response to these other tially known whether prolonged activation of β2- agents remain intact． adrenergic receptors is not harmful． In airway smooth muscle cells, intracellular cAMP There are several parameters in characterizing the formation in response to isoproterenol is attenuated interaction of an agent with receptors, such as affin- after incubation with not only β2-agonists but also ity, potency, and efficacy. However, β2-agonists are other agents involving cAMP such as forskolin and just classified by onset and duration of action in the PGE2.21 An inhibition in cAMP formation is mediated guideline for asthma management. This current clas- by heterologous desensitization. However, in airway sification may be insufficient to establish safe admini- smooth muscle, relaxation induced by β2-agonists is stration of β2-agonists. Previously statistical correla- impaired after excessive exposure to these agonists, tion between regular use of β2-agonists and asthma whereas the reduced relaxation by β2-agonists does mortality or morbidity has been reported.13 This dete- not occur after excessive exposure to these cAMP in- rioration is considered to be due to desensitization of volving agents independent of β2-adrenergic recep- β2-adrenergic receptors mediated by excessive ad- tors.14,15 When desensitization of β-adrenergic recep- ministration of β2-agonists of higher intrinsic effica- tors is examined by measuring a biochemical re- cies, such as isoproterenol and fenoterol. We should sponse (cAMP formulation), heterologous desensiti- carefully reconsider how to use these agonists. In zation is observed. In contrast, when β2-adrenergic this review, the relationship between intrinsic efficacy desensitization is examined by measurering a physi- and desensitization to β2-agonists is examined in de- ologic response (smooth muscle relaxation in vitro), tail using airway smooth muscle, and in addition, rea- heterologous desensitization is not observed . sonable clinical use of these agents based on this ob- Interferon-γ inhibits the reduced relaxation by het- servation is discussed． erologous β2-adrenergic desensitization after expo- β β sure to TGF- 1, but does not recover the reduced MECHANISMS OF DESENSITIZATION OF 2- cAMP formation by TGF-β1.6 There is a discrepancy ADRENERGIC RECEPTORS IN AIRWAY between cAMP formulation and relaxation concern- SMOOTH MUSCLE ing the impairment of β2-adrenergic action. Hence, in It is well known that response to β2-agonists is mark- airway smooth muscle measurement of relaxation edly attenuated after continuous and repeated expo- needs to estimate accurately desensitization to β2- sure to the agonists in airway smooth muscle of hu- agonists． mans 14 and other animals. 15 Previous reports have Forskolin needs to produce a large amount of demonstrated the molecular mechanisms of desensi- cAMP to cause an equivalent relaxation that is tization of β2-adrenergic receptors in various tis- achieved with isoproterenol by producing a small sues. 16,17 After exposure to β2-agonists for a short amount of cAMP in airway smooth muscle.22 cAMP term (less than 30 min), the β2-agonist activity is formation in response to β2-agonists is not always as- markedly attenuated via the phosphorylation of β2- sociated with relaxation. Recently, it is generally con- adrenergic receptors, resulting in an uncoupling from sidered that β2-agonists have the effects mediated by the stimulatory GTP-binding (G) protein of adenylyl not only cAMP-dependent but also cAMP- cyclase, Gs. A longer-term exposure leads to down- independent processes. The discrepancy in causing regulation of surface receptor number via internaliza- heterologous desensitization may be due to these tion of the receptor and its subsequent degradation. cAMP-independent