Clinical Use of Β2-Adrenergic Receptor Agonists Based on Their Intrinsic Efficacy

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Provided by Elsevier - Publisher Connector 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 efficacy concerning the use of β2-agonists. Since intrinsic efficacy refers to the ability to activate β2-adrenergic receptors 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 intrinsic efficacy and desensitization to β2-agonists is examined in tracheal smooth muscle using isometric tension 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 intrinsic efficacies. On the other hand, under the conditions of impairment of β2-adrenergic receptors, reduced responsiveness 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 medication．

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 pathways. Large conductance Ca Two types of protein kinases are responsible for the 2+-activated K+ (KCa) channels, which are densely dis-

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Agonists CTX Lyso-PC (VDC channels)

β2

AC ? + K Ca2+ βARK cAMP Rho (KCa channels) GRKs

Rho-kinase Protein kinaseA Ca2+ mobilization

2+ ? Ca sensitization

Receptor phosphoryation Desensitization

: activation : inhibition

Fig. 1 Schema of mechanisms underlying desensitization of β2-adrenergic receptors measured as a physiologic response (relaxation response) in airway smooth muscle. The reduced respon-

siveness to β2-agonists is not mediated by cAMP-dependent processes. The Gs/KCa channel stimulatory linkage and the Rho/Rho-kinase pathway activated by cAMP-independent processes 2+ are involved in this homologous β2-adrenergic desensitization. The former causes Ca mobilization, and the latter causes Ca2+ sensitization. CTX: cholera toxin, Lyso-PC: lysophosphatidylcholine, VDC channels: voltage-dependent Ca2+ channels.

tributed on the surface of the membrane,23 are partly by homologous desensitization, not by heterologous involved in the membrane hyperpolarization and re- desensitization (Fig. 1). The reduced responsiveness laxation induced by these agonists.24 These channels to β2-agonists is not affected even when the tissues are activated independently by the two pathways as are exposed to β2-agonists for an extended period in follows : 1) cAMP-dependent channel phosphoryla- the presence of Rp-cAMP, a permeable inhibitor of tion via PKA25 and 2) cAMP-independent channel ac- PKA, also indicating that the cAMP!PKA processes tivation via the α-subunit of Gs.26 The Gs!KCa channel are not involved in β2-adrenergic desensitization stimulatory linkage is partly involved in the cAMP- measured as a physiologic response.14,15 The recep- independent relaxation by β-agonists . Since β2- tor!Gs processes play an important functional role in agonists have two pathways, these agonists are much not only the β2-aderenergic action but also the β2- more potent in relaxation of airway smooth muscle adrenergic desensitization in airway smooth muscle. than other agents involving cAMP that bypass β2- β2-agonists are more potent in causing both relaxa- adrenergic receptors.22 tion and desensitization than other agents involving β β cAMP bypassing 2-adrenergic receptors. This char- INVOLVEMENT OF Gs IN 2-ADRENERGIC acteristic is due to cAMP-independent pathways such DESENSITIZATION IN AIRWAY SMOOTH as the Gs!KCa stimulatory linkage . 14,15,22,26 Hence , MUSCLE measurement of cAMP formation without examina- After excessive exposure to β2-agonists, the inhibition of relaxation response is not appropriate to an as- tory effects of agents involving cAMP independently sessment of β2-adrenergic action and desensitization of β2-adrenergic receptors are not attenuated ; on the in airway smooth muscle． contrary those effects are significantly augmented.27 As described above , the phosphorylation of β2- Moreover, β2-agonist activity is still intact after expo- adrenergic receptors elicits a fuctional uncoupling be- sure to PGE2, which activates Gs via its own receptor tween the receptors and the Gs proteins. It is well which is different from β-adrenergic receptors. These known that cholera toxin (CTX) irreversibly activates results indicate that after excessive exposure of air- Gs mediated by ADP-rybosylation of α-subunit with a waysmoothmuscletoβ2-agonists, relaxation induced remarkable reduction of guanosinetriphosphatase ac- by these agonists is markedly diminished mediated tivity. When airway smooth muscle is treated with

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Table 1 in taking the clinical effects of these agonists. In con- β Intrinsic effi- trast, intrinsic efficacy may reflect the capability of 2- β-agonists EC (μM) 50 cacy (%) agonists to activate the receptors in the clinical administration. If the values of intrinsic efficacy are ac- Formoterol 0.0007 100.0 curately measured, it would be an important parame- Procaterol 0.005 100.0 ter in a rational clinical use of β2-agonists. However, Isoproterenol 0.062 100.0 international guidelines for asthma management have Salbutamol 0.041 81.4 never described anything about it． Salmeterol 0.096 62.4 Some agonists completely activate receptors, how- Tulobuterol ------34.6 ever others partially activate them. The former are re-

Values of intrinsic efficacy of β2-agonists measured as a physiol- ferred to as a full agonist, and the latter are as a par- ogic response in airway smooth muscle. The values of intrinsic tial agonist. Moreover, partial agonists are classified efficacy are expressed as the maximum percent inhibition for β2- into two subtypes, i.e. 1) its efficacy is lower (weak agonists against 1 μM methacholine-induced contraction in partial agonists) and 2) its efficacy is higher (strong guinea pig tracheal smooth muscle. agonists). 30 Activation of β2-adrenergic receptors is directly measured as a conformational change using receptor fluorescence. Intrinsic efficacy is also meas- CTX before continuous or repeated exposure to β2- ured indirectly as a response to activation of the post- agonists, CTX causes an inhibition in a subsequent receptor signal transduction pathways (changing in reduction in the relaxation action by β2-agonists and cAMP formation),31 and as a physiological response lysophosphatidylcholine in a concentration- and time- (changing in smooth muscle relaxation in vitro and dependent manner. 7,14,15,28 This inhibitory action of airway resistance in vivo).32 Measurement of agonist CTX is not affected in the presence of Rp-cAMP. The efficacy markedly depends on variable factors in the reduced responsiveness to β2-agonists after repeated target cells, such as receptor number and presence of exposure to the agonists is enhanced in the presence functional antagonism.33 Intrinsic efficacy of each ag- of a selective inhibitor of KCa channels,14 and is asso- onist is expressed by difference between Kd (the dis- ciated with an elevation in intracellular Ca2+ concen- sociation constant : the dependency of receptor occu- tration.29 On the other hand, the reduced responsive- pancy on agonist concentration) and EC50 (agonist ness to β2-agonists after continuous exposure to the concentration that produces 50% inhibition of the agonists and lysophosphatidylcholine is not associ- maximal contraction).30,31 The values of Kd and EC50 ated with an increase in intracellular Ca2+ concentra- are common parameters in affinity and potency of an tion, and is antagonized by an inhibition in Rho, a agonist, respectively. More efficacious agonists have small G protein, in the presence of Y-27632, an inhibi- greater difference of these two parameters. Partial ag- tor of Rho-kinase, in a concentration-dependent man- onists need to occupy a large fraction of receptors to ner. 7 These results indicate that in airway smooth produce an equivalent effect that full agonists achieve muscle β2-adrenergic desensitization is due to Ca2+ by occupying much less receptors. The ratio of the in- mobilization mediated by suppression of the Gs!KCa trinsic efficacy of any two β2-agonists is expressed as channel stimulatory linkage and to Ca2+ sensitization a fraction between 0 and 1, taking that of adrenaline induced by Rho!Rho-kinase pathways (Fig. 1). More- as 1． over, an irreversible activation of Gs leads to preven- Barber et al. have expressed values of intrinsic effi- tion of β2-adrenergic desensitization, independent of cacy by measuring receptor activation as a biochemi- cAMP!PKA processes. If a complete dissociation be- cal response to activation of cAMP!PKA processes tween the receptors and G proteins occurs in the re- using human embryonic renal and cultured murine duced responsiveness to β2-agonists, the activation of lymphoma cells other than airway smooth muscle Gs may have no effects on prevention of the desensiti- cells. Under this experimental condition, the rank of zation of β2-adrenergic receptors. Impairment of Gs order of intrinsic efficacies is : isoproterenol > activity may be involved in this phenomenon. fenoterol = procaterol > formoterol > albuterol > sal- 30,34 β meterol > tulobuterol. These results indicate that MEASUREMENT OF 2-ADRENERGIC IN- procaterol can activate approximately 15 times more TRINSIC EFFICACY β2-adrenergic receptors than tulobuterol when these An agonist’s potency depends on its affinity for a re- two agonists occupy the same number of receptors． ceptor and on its intrinsic efficacy. Affinity refers to β the attraction between an agent and its receptors, and -ADRENERGIC INTRINSIC EFFICACY IN intrinsic efficacy refers to the ability of an agent to ac- AIRWAY SMOOTH MUSCLE tivate its receptors . Since the limited dose of β2- β2-agonists are administrated to patients with asthma agonists is inhaled as a bronchodilator therapy for an improvement of airflow limitation via relaxation against acute asthma exacerbations, affinity for the of airway smooth muscle. Although medications for receptors may be a relatively unimportant parameter asthma can be administered in different ways, the

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Control % Inhibition Procaterol Salbutamol 100

60 ＊＊

＊＊ 0 Formoterol Salmeterol Tulobuterol

Fig. 2 Pre exposure to long-acting β2-agonists results in a reduction in the inhibitory ac-

tion of short-action β2-agonists against 1 μM methacholine-induced contraction in guinea pig tracheal smooth muscle. The relaxation responses were expressed as a percentage of the maximal relaxation produced by free Ca2+ solution. ＊ : p < 0.05, ＊＊ : p < 0.01.

most advantageous route of administration of β2- formoterol > procaterol > isoproterenol = salbutamol agonists is thought to deliver directly into airways via > salmeterol > > tulobuterol . Isoproterenol , for- inhalation. This route leads to the direct and rapid on- moterol, and procaterol caused the complete inhibi- set of action, and to avoidance of the systemic side ef- tion against 1 μM methacholine-induced contraction fects. It is currently unclear whether β-agonists in- (100% inhibition), indicating that these agents are full hibit clinically the airway inflammation elicited by ac- agonists. In contrast salmeterol, salbutamol, and tu- tivated eosinophils. Moreover, as described above, β2- lobuterol did not cause complete inhibition under this agonists have cAMP-independent pathways and there experimental condition, indicating that these agents are discrepancies between cAMP formation and re- are partial agonists. The order of efficacy (the mini- laxation induced by these agonists. Hence , in this mum percent inhibition) was : isoproterenol = for- study β2-adrenergic intrinsic efficacy was expressed moterol = procaterol > salbutamol > salmeterol > tu- as receptor activation based on smooth muscle re- lobuterol. When the functional antagonism was inten- laxation. Isometric tension records demonstrate the sified by application of 10-fold higher concentration of direct action of β2-agonists on airway smooth muscle methacholine, isoproterenol caused complete relaxa- independent of indirect action via inflammatory cells, tion against this contraction, but the maximal effects similar to inhalation, because these agonists are di- in the curves for formoterol and procaterol were at- rectly applied to the strips in the organ bath. Recep- tenuated. The values of the maximum percent inhibitor number and functional antagonism have an affect tion for isoproterenol , formoterol , procaterol were on measurement of agonist efficacy. However, these 100, 59.4 ± 9.2, 71.9 ± 10.9%, respectively (data not two factors are probably not affected when the experi- shown). Under these experimental conditions, for- ments are performed under the condition that the in- moterol and procaterol behave as partial agonists for tact tissues are used and that an equivalent concen- relaxation in comparison with isoproterenol. There- tration of antagonists is applied . According to the fore, it is considered that isoproterenol is a full ago- methods similar to those described previously, iso- nist, and that procaterol and formoterol are strong ag- metric tension was recorded using guinea pig tra- onists. Our data are roughly consistent with the rank cheal smooth muscle . 35 β2-agonists were cumula- order of intrinsic efficacy measured as a biochemical tively applied to the intact tissues pre contracted by 1 response to the adenylyl cyclase!cAMP pathway.30,34 μM methacholine. The values of EC50 and the maxi- β mal effects in the concentration-inhibition curves for RELATIONSHIP BETWEEN 2-ADRENERGIC DESENSITIZATION AND AGONIST INTRIN- a β2-agonist express its potency and efficacy, respec- SIC EFFICACY IN AIRWAY SMOOTH MUS- tively. The values of EC50 and the maximum percent CLE inhibition for these β2-agonists in the curves are shown in Table 1. The order of potency (EC50)was: Inhalation of procaterol or salbutamol, which has a

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(Controller medications)

Full or Strong Weak partial Initial application agonists agonists

Impairment of relatively strong relatively weak β-adrenergic receptors

(Reliever medications) Subsequent response to Full or Strong agonists less reduced intact to Weak partial agonists more reduced less reduced Fig. 3 Causal relationship between intrinsic efficacy and desensi-

tization to β2-agonists. Induced impairment of β2-adrenergic function is intensified in proportion to values of intrinsic efficacy after

excessive exposure to β2-agonists. The subsequent reduced re-

sponsiveness to β2-agonists is intensified in inverse proportion to them.

rapid onset and short duration of action, is used clini- which is weak, for an equivalent time, the inhibitory cally as a reliever medication to suppress bron- effects of both procaterol and salbutamol on choconstriction elicited by acute asthma attacks. In- methacholine-induced contraction were not attenu- halation of formoterol or salmeterol, which have dura- ated. Those values for procaterol and salbutamol after tion of action lasting for approximate 12 hour, is given exposure to tulobuterol were 83.0 ± 5.4 and 73.0 ± 6.6, twice daily as a controller medication in addition to in- respectively (n = 8, each not significant). The rank or- haled glucocorticosteroid therapy. A patch formula- der of causing β2-adrenergic desensitization is : for- tion of tulobuterol, a sustained-release β2-agonist, also moterol > salmeterol > tulobuterol. This rank order is used as a controller medication because of a 24- was identical with that of intrinsic efficacy of β2- hour duration of action. 36 To determine whether a agonists． controller medication using β2-agonists leads to a re- When receptor activation is measured as a relaxa- duction in the inhibitory effects of β2-agonists for a re- tion response, β2-adrenergic desensitization occurs in liever medication against acute asthma exacerba- proportion to the strength of intrinsic efficacy of ago- tions, subsequent response to these rapid- and short- nists. In airway smooth muscle full agonists cause acting β2-agonists was examined after exposure to more desensitization of the receptors, whereas partial these long-acting β2-agonists in guinea pig tracheal agonists cause less desensitization. These results are smooth muscle using isometric tension recording consistent with those obtained by measurements of (Fig. 2). When 0.1 μM formoterol, the intrinsic effi- biochemical responses to activation of the postrecep- cacy of which is strong, was applied to the intact tor signal transduction pathways.30,34 Although PKA- strips for 10 min, subsequent inhibition by 0.03 μM mediated phosphorylation by partial agonists is simi- procaterol and 0.3 μM salbutamol against contraction lar to that by strong and full agonists, βARK- and induced by 1 μM methacholine was markedly attenu- GRKs- mediated phosphorylation by partial agonists ated. The values of percent inhibition for procaterol are less than that by strong and full agonists.33 Strong were decreased from 87.4 ± 4.4 to 38.0 ± 10.7% (n =8, and full agonists cause both homologous and het- p < 0.05 ) . Those values for salbutamol were de- erologous desensitization, in contrast, partial agonists creased from 77.4 ± 7.9 to 2.6 ± 0.9% (n =8,p <0.01). primarily cause hetrologous desensitization. There- After exposure to equi-molar salmeterol, the intrinsic fore, it is generally considered that partial agonists efficacy of which is moderate, for an equivalent time, are less potent in causing desensitization.37 Our re- the inhibitory effects of salbutamol on 1 μM sults also indicate that cAMP!PKA processes are not methacholine-induced contraction were attenuated . involved in a reduction in the relaxant action of β- The value of percent inhibition for salbutamol was de- agonists after excessive exposure to the agonists, and cerased to 48.0 ± 8.2% (n =8,p <0.05).Incontrast, that the reduced responsiveness to β2-agonists is me- those effects of procaterol were not significantly at- diated by homologous desensitization , not by het- tenuated. Those values for procaterol before and after erologous desensitization in tracheal smooth muscle exposure to salmeterol were 87.4 ± 4.4 and 81.7 ± (Fig. 1). 4.1%, respectively (n = 8, not significant). After expo- On the other hand, in inverse proportion to the sure to equi-molar tulobuterol, intrinsic efficacy of rank order of intrinsic efficacy, the reduced respon-

94 Allergology International Vol 54, No1, 2005 www.js-allergol.gr.jp! β2-adrenergic Desensitization by Efficacy siveness to salbutamol was intensified more than that also demonstrated that strong and full agonists to procaterol after exposure to each of these long- should be used as needed to relieve asthma symp- acting β-agonists (Fig. 2). The effects of full agonists toms and weak partial agonists should be used regu- are not affected under the condition of either high or larly to keep persistent asthma under control (Fig. 3). low receptor density in the cell surface. In contrast, the effects of partial agonists may be intact with high CONCLUSIONS receptor density, but the effects of these agonists are The membrane-delimited, cAMP-independent Gs acti- attenuated as receptor number is lowered. When the vation plays an important functional role in both the uncoupling of the receptors from Gs and the receptor physiologic response and desensitization to β- internalization occurs in airway smooth muscle, full agonists. The intrinsic efficacy of β2-agonists, which agonists can yield a full relaxation response, whereas is involved in an increase in Gs activity, is responsible partial agonists cannot do so. In the presence of func- for causing desensitization to these agonists. In air- tional antagonism (contractile agents), the maximal way smooth muscle excessive exposure to β2- effects of β2-agonists are attenuated because effects of agonists of high intrinsic efficacy gives rise to greater β2-agonists are antagonized by signal transduction desensitization of the receptors than that to these ag- pathways of contractile agents, such as methacholine, onists of low intrinsic efficacy . When the β2- histamine, prostaglandins, and leukotrienes. Airway adrenergic receptor function declines under the con- contraction leads to a reduction in β2-adrenergic in- ditions of uncoupling from Gs, lowered receptor den- trinsic efficacy. Hence, the effects of partial agonists sity, and functional antagonisms, β2-agonists of lower can be attenuated when an acute asthma attack oc- intrinsic efficacy do not generate a full intracellular curs． signal, leading to a reduction in the relaxation re- β sponse to partial agonists. Although the clinical rele- RATIONAL CHOICE OF INHALED 2- vance of our data is still unclear, they may provide the AGONISTS IN THE MANAGEMENT OF evidence that β2-agonists with a long duration of ac- BRONCHIAL ASTHMA tion and low intrinsic efficacy are optimal for the Since the induced desensitization to β2-agonists in- maintenance therapy of bronchial asthma, and that creases as the values of intrinsic efficacy of agonists those agonists with rapid onset of action and high in- are elevated, daily administration of strong and full trinsic efficacy are optimal for rescue therapy against agonists may be harmful for long-term asthma man- acute asthma attacks． agement. Weak partial agonists are appropriate for controller medications. On the other hand, as the val- ACKNOWLEDGEMENTS ues of intrinsic efficacy are lowered, the reduced re- I would like to thank Dr. Kaoru Shimokata (Division sponsiveness to β2-agonists increases by decreased of Respiratory Medicine, Department of Medicine, receptor density after excessive exposure to these ag- Nagoya University Graduate School of Medicine) for onists and by functional antagonism . Inhalation of helpful comments. weak partial agonists, taken as needed, may not be beneficial for the management of acute asthma . REFERENCES Strong and full agonists are appropriate for reliever 1. Sears M, Taylor DR, Print CG et al. Regular inhaled beta- medications . Previous clinical trials have demon- agonist treatment in bronchial asthma. Lancet 1990;336: strated that regular inhalation of salmeterol and tu- 1391-1396. lobuterol (weak partial agonists) as controller medi- 2. Barnes PJ. Beta-adrenergic receptors and their regulation. 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