Review article
β-Adrenoceptor responses of the airways: For better or worse?

https://doi.org/10.1016/j.ejphar.2005.12.060Get rights and content

Abstract

β2-adrenoceptor agonists are the first-line treatment of asthma and chronic obstructive pulmonary disease (COPD), in which a short-acting β2-adrenoceptor agonist is used as required for relief of bronchoconstriction. A long-acting β2-adrenoceptor agonist may be added to an inhaled corticosteroid as step 3 in the management of chronic asthma. Long-acting β2-adrenoceptor agonists may also be added in treatment of COPD. This review examines the beneficial and detrimental effects of β2-adrenoceptor agonists. The beneficial effects of β2-adrenoceptor agonists are mainly derived from their bronchodilator activity which relieves the bronchiolar narrowing and improves air flow. The potential anti-inflammatory actions of stabilizing mast cell degranulation and release of inflammatory and bronchoconstrictor mediators, is considered. Other potential beneficial responses include improvements in mucociliary clearance and inhibition of extravasation of plasma proteins that is involved in oedema formation in asthma. The side effects of β2-adrenoceptor agonists are primarily related to β2-adrenoceptor-mediated responses at sites outside the airways. Of major concern has been the development of tolerance and this is discussed in relation to incidence of increased morbidity and mortality to asthma over the past three decades. A clinical aspect of β2-adrenoceptor pharmacology in recent years has been the recognition of genetic polymorphism of the receptor and how this affects responses to and tolerance to β2-adrenoceptor agonists. A controversial feature of β2-adrenoceptor agonists is their stereoisomerism and whether the inactive (S)-isomer of salbutamol had detrimental actions in the commercially used racemate. The consensus is that despite these adverse properties, β2-adrenoceptor agonist remains the most useful pharmacological agents in the management of asthma and COPD.

Introduction

β-Adrenoceptors are subdivided into three types; β1, β2 and β3. They are members of the seven-transmembrane spanning family of G-protein-coupled receptors related to bacteriorhodopsin. They are widely distributed in the lungs, the dominant subtype being β2-adrenoceptors, which have been located in the airways smooth muscle, epithelial cells, mast cells and type II alveolar cells (Johnson, 1998). Adrenoceptors of the β1-subtype have also been located in the lungs by radioligand binding and functional studies. Radioligand binding studies with homogenates from human, guinea-pig and rat lungs have found mixed populations of between 20% and 30% of β1-adrenoceptors (Engel, 1981). The relaxations of guinea-pig and cat isolated tracheal preparations in response to β-adrenoceptor agonist were shown to be mediated via a mixed population of β1- and β2-adrenoceptors. This was demonstrated by different pA2 values for selective antagonists depending on whether a β1-selective (noradrenaline) or β2-selective (fenoterol) agonist was used (O'Donnell and Wanstall, 1979, Zaagsma et al., 1983). The same applied to human tracheal smooth muscle, main bronchus and intrapulmonary smooth muscle obtained from patients undergoing pneumocotomy (Zaagsma et al., 1983). In more peripheral airways of the guinea-pig parenchymal strips, the relaxation is mediated by a homogeneous population of β2-adrenoceptors.

In this review, the beneficial effects of airway responses to stimulation of β-adrenoceptors will be examined as well as some of the detrimental aspects associated with β-adrenoceptor activation. These are summarized in Table 1.

Section snippets

Bronchodilatation

The major response of the airways to stimulation of β-adrenoceptors is relaxation of airway smooth muscle. This is evident as bronchodilatation when β-adrenoceptor agonists are inhaled. Bronchodilator responses can be observed in normal subjects as an increase in specific airways conductance (sGaw) and a small increase in forced expiratory volume in 1 s (FEV1) (Jameson et al., 1987). Bronchodilatation was also measured by partial flow volume curves which yielded a dose for half maximal response

Newer improvements in β-adrenoceptor agonist activity

Two approaches to improving β-adenoceptor effectiveness are to combine the agonist with another drug with different mechanism of action in the same formulation or to combine activities within the same drug molecule.

The most effective combination in the treatment of moderate to severe asthma is a dual product of long-acting β2-adrenoceptor agonists, salmeterol and formoterol, with an inhaled steroid in a single inhaler. The effective control of asthma symptoms by the combination therapy is more

Side effects

Because of their selectivity for bronchial and not cardiac muscle (β1-adrenoceptors), β2-adrenoceptor agonists have a low incidence of side effects such as tachycardia. There is nevertheless some risk of cardiac actions and they should therefore be used with caution in hyperthyroidism and cardiovascular disease (arrhythmias, hypertension, QT-interval prolongation). They should also be used with caution in diabetes because of risk of ketoacidosis. β2-adrenoceptor stimulation in the liver induces

Adverse effects of bronchodilatation

One disadvantage of the bronchodilator action of β2-adrenoceptor agonists and the consequential opening up of the airways is that it will allow more inhaled allergen to reach the lower airways and cause a greater degree of inflammation. There is evidence from clinical studies that with regular administration of β2-adrenoceptor agonist there is an increase in the inflammatory response measured as an increase in bronchial inflammatory cells in bronchoalveolar lavage or bronchial biopsy after

β2-adrenoceptor desensitization

It has been well established that prolonged agonist exposure of G-protein-coupled receptors, including the β-adenoceptors, exposes them to desensitization. That is, they become downregulated or tolerance to the stimulant effects of agonists develops. There are three mechanisms of receptor desensitization: 1. Uncoupling of the receptor from the adenylyl cyclase occurs after phosphorylation of the receptor by cAMP-independent β-adrenoceptor kinase (βARK). This results in binding of β-arrestin and

Mast cell heparin

As well as the asthmagenic mediators — histamine, tryptase and leukotrienes — released from mast cells, there is a substantial release of heparin. This is a glycosaminoglycan, which is a large polyanionic molecule closely related to the anticoagulant, heparin sulphate (Lever and Page, 2001). The highly charged nature of the heparin molecule can exert anti-inflammatory effects by neutralizing the granular cationic proteins released from eosinophils, including major basic protein (MBP) and

Isomerism

The chemical structure of β2-adrenoceptor agonists virtually always includes an asymmetric carbon atom bearing the β-hydroxy group necessary for receptor interaction. This leads to the occurrence of at least two optical isomers (enantiomers) of the drug — laevo (R) and dextro (S). To date the clinically available form has been the racemate in which both enantiomers exist in approximately equal proportions. It has been assumed that the biological activity attributed to β2-adrenoceptor

Genetic polymorphism

A single change in the wild-type amino acid sequence of the β2-adrenoceptor at different positions, arising from a single base change in the coding sequence of the gene has led to variants of the β2-adrenoceptor. These are genetic polymorphisms and a total of nine polymorphisms have been identified. There is redundancy in the amino acid code so that some of these are clinically irrelevant, but there are four polymorphisms that can affect the amino acid sequence of the receptor and three of

Conclusions

The major benefit of β2-adrenoceptor agonists in the treatment of asthma and COPD is the improvement in airflow and reduction of airway restriction derived from their bronchodilator activity. The contribution from anti-inflammatory (inhibition of mast cell degranulation and oedema through plasma protein extravasation) and pro-inflammatory (inhibition of heparin release) activities appears to be minimal. The roles of β2-adrenoceptor polymorphism and stereoisomerism of the β2-adrenoceptor agonist

Acknowledgement

The author was supported by grants from the British Heart Foundation, MRC/Novartis and BBSRC while this review was being written.

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