Reduced beta 2-adrenoceptor responsiveness in exercise-induced asthma

Beta-adrenoceptor responsiveness was studied both in vivo and in vitro in patients with exercise-induced asthma (EIA), asthmatic patients without EIA (NEIA), and control subjects. All subjects were age- and sex-matched and without medication at least one week prior to the tests. In vivo, beta-adrenoceptor responsiveness was evaluated by plasma concentration-effect studies for intravenously infused isoprenaline (0.02-0.1 micrograms X kg-1 X min-1). Mainly beta 2-adrenoceptor mediated responses to isoprenaline, ie, decreases in diastolic blood pressure and increases in plasma cyclic AMP, were reduced in EIA patients but not in NEIA patients. Heart rate and plasma glycerol responses to isoprenaline did not differ between the groups. In vitro, the beta 2-adrenoceptor mediated accumulation of cyclic AMP in lymphocytes stimulated by isoprenaline was attenuated (p less than 0.05) in EIA patients, whereas the beta 2-adrenoceptor responsiveness of lymphocytes from NEIA patients was normal. Thus, beta 2-adrenoceptor mediated responses were reduced both in vivo and in vitro in EIA patients, but not in NEIA patients. This finding that beta 2-adrenoceptor responsiveness was reduced only in a subgroup of asthmatic patients could explain some of the controversies in the literature concerning beta-adrenoceptor function in asthma.     

Long-acting beta2-agonists in asthma: an overview of Cochrane systematic reviews

According to major asthma management guidelines, long-acting beta2-agonists (LABAs) should be used only when asthma remains symptomatic in patients already receiving regular inhaled corticosteroids (ICSs). A large Cochrane systematic review provides evidence that LABAs are safe and beneficial in control of asthma; sub-group analyses indicating that this is true when ICSs are used and in their absence. Two other Cochrane systematic reviews have found that LABAs are more effective than regular short-acting beta2-agonists, and are as effective as theophylline with fewer side-effects. These reviews support guidelines in the use of LABA as additional therapy when asthma is inadequately controlled by ICS at moderate dose. However, guidelines may be too conservative, and more studies in stable mild asthma comparing their use and safety with placebo and ICS are required.     

Long-acting beta(2)-agonists in the management of asthma exacerbations

PURPOSE OF REVIEW: Asthma exacerbations are a major cause of morbidity in the United States. Although long-acting beta2-agonists have a defined role in maintenance therapy, their potential use in exacerbations remains largely undetermined. This paper reviews recent literature on long-acting beta2-agonists in the context of the management of acute asthma. RECENT FINDINGS: Although clinical experience with long-acting beta2-agonists now approaches 20 years, their applicability in asthma exacerbations has only recently been explored. Formoterol, with a rapid onset of action similar to albuterol, has already been approved in Europe as a reliever medication and there are emerging data to support its use in the outpatient management of mild exacerbations of asthma. Salmeterol added to conventional therapy has been found to be safe and potentially beneficial in patients hospitalized for an exacerbation. SUMMARY: Long-acting beta2-agonists have proved to be useful in the chronic management of asthma and the prevention of exacerbations. Recent data suggest a role for patient-guided management using adjustable dosing of long-acting beta2-agonists with inhaled corticosteroids during periods of worsening asthma. Further research to evaluate the potential role of long-acting beta2-agonists in the management of acute asthma is needed.     

Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update.

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.     

Past, present and future--beta2-adrenoceptor agonists in asthma management

The beta-adrenoceptor agonists (beta-agonists) have been used to relieve bronchoconstriction for at least 5000 years. beta-agonists are based on adrenaline and early forms, such as isoprenaline, Lacked bronchial selectivity and had unpleasant side effects. Modern beta-agonists are more selective for the beta2-adrenoceptors (beta2-receptors) located in bronchial smooth muscle and have less cardiotoxicity. Traditional beta2-adrenoceptor agonists (beta2-agonists), such as salbutamol, terbutaline and fenoterol, were characterised by a rapid onset but relatively short duration of action. While valuable as reliever medication, their short duration gave inadequate night-time relief and limited protection from exercise-induced bronchoconstriction. beta2-agonists with longer durations of action, formoterol and salmeterol, were subsequently discovered or developed. When combined with inhaled corticosteroids they improved lung function, and reduced symptoms and exacerbations more than an increased dose of corticosteroids. However, tolerance to the bronchprotective effects of long-acting beta2-agonists and cross-tolerance to the bronchodilator effects of short-acting beta2-agonists is apparent despite use of inhaled corticosteroids. The role of beta2-receptor polymorphisms in the development of tolerance has yet to be fully determined. Formoterol is unique in having both a long-lasting bronchodilator effect (> 12 h) and a fast onset of action (1-3min from inhalation), making it effective both as maintenance and reliever medication. The recent change in classification from short- and long-acting beta2-agonists to rapid-acting and/or long-acting agents reflects the ongoing evolution of beta2-agonist therapy.     

Potential value of oral beta 2-adrenoceptor agonists in congestive heart failure: a haemodynamic and metabolic study

This study was designed to investigate and compare the haemodynamic and metabolic responses to pirbuterol and salbutamol in patients with congestive heart failure and coronary artery disease. Attention was directed towards the effects these beta 2-adrenoceptor agonists have on left ventricular systolic function, systemic and coronary haemodynamics and myocardial substrate metabolism. Sixteen patients were randomly allocated to treatment with either pirbuterol 20 mg or salbutamol 6 mg. Since no statistically significant differences between the responses to these drugs were observed, combined data for both agents are presented. Ninety minutes after the drug intervention cardiac index increased from 2.2 +/- 0.1 to 2.9 +/- 0.2 1/min per m2 (P less than 0.001) in association with marked reductions in systemic vascular resistance (from 22 +/- 1 to 15 +/- 1 units, P less than 0.001) and increments in left ventricular dp/dtmax (from 1074 +/- 85 to 1422 +/- 133 mm Hg/sec, P less than 0.05). Modest reductions in left ventricular end-diastolic pressure (from 21 +/- 1 to 15 +/- 1 mm Hg, P less than 0.01) were observed. Heart rate increased from 82 +/- 5 to 91 +/- 4 beats/min (P less than 0.01) but the small fall in mean arterial pressure (from 86 +/- 3 to 78 +/- 3 mm Hg) was not significant. Drug-induced coronary vasodilatation reduced coronary coronary vascular resistance from 0.65 +/- 0.06 to 0.47 +/- 0.04 units (P less than 0.01) and led to a marked increase in coronary sinus blood flow (from 124 +/- 9 to 155 +/- 9 ml/min, P less than 0.05). Arterial levels of free fatty acids increased from 0.78 +/- 0.13 to 1.05 +/- 0.18 mmol/l (P less than 0.05) resulting in the preferential utilization of this substrate as a myocardial energy source. Despite the substantial haemodynamic improvement, however, no significant increase in myocardial oxygen uptake or lactate production was observed. Thus, in patients with coronary artery disease and congestive heart failure pirbuterol and salbutamol improve left ventricular function by a combination of afterload reduction and positive inotropism such that no appreciable deterioration in myocardial energetics occurs.     

Long-acting beta(2)-agonists in management of childhood asthma: A critical review of the literature

This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled salmeterol or formoterol cause prolonged bronchodilatation (>12 h) and extended bronchoprotection against exercise-induced bronchoconstriction in children, some children achieving full protection for more than 12 h. Heterogeneity in bronchoprotection has been observed, and individual dose-titration may be attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting beta(2)-agonists are used as regular treatment, including cross-tolerance to short-acting beta(2)-agonists. Regular treatment with salmeterol in children with or without corticosteroids provides statistically significant bronchodilatation, but the degree of improvement in lung function or bronchoprotection against exercise and nonspecific irritants is small with regular use. There is no evidence of anti-inflammatory effects from inhaled long-acting beta(2)-agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting beta(2)-agonists as monotherapy, nor does it support their general use as regular add-on therapy. In conclusion, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue medication instead of short-acting beta(2)-agonists for pediatric asthma management.     

Positive inotropic effects of the beta2-adrenoceptor agonist terbutaline in the human heart: Effects of long-term beta1-adrenoceptor antagonist treatment

Objectives. This study was conducted to determine whether activation of cardiac beta₂-adrenoceptors increases contractility in humans and whether this is affected by long-term beta₁-adrenoceptor antagonist treatment.Background. Coexistence of beta₁- and beta₂-adrenoceptors in the human heart is generally accepted. The functional importance of cardiac beta₂-adrenoceptors for increases in contractility in humans, however, has not been completely established.Methods. We studied 1) the beta-adrenoceptor subtype mediating positive inotropic effects of the beta₂-adrenoceptor agonist terbutaline in vitro (on right atrial and left ventricular preparations from nonfailing human hearts) and increases in contractility (by measurement of systolic time intervals) in vivo in seven healthy male volunteers; and 2) in vivo whether long-term treatment of volunteers with the beta₁-adrenoceptor antagonist bisoprolol affects terbutaline-induced increases in contractility.Results. In vitro terbutaline caused a concentration-dependent increase in atrial and ventricular adenylate cyclase activity and force of contraction. Terbutaline effects were antagonized only by the beta₂-adrenoceptor antagonist ICI 118,551, indicating that they were mediated by beta₂-adrenoceptor stimulation. In vivo intravenous infusions of terbutaline (dose range 25 to 300 ng/kg body weight per min for 15 min) dose dependently increased heart rate and shortened the pre-ejection period and heart rate-corrected electromechanical systole (QS₂) time. These effects are mediated predominantly by beta₂-adrenoceptor stimulation because they were only marginally affected by the beta₁-adrenoceptor antagonist bisoprolol (1 × 10 mg orally), either given 2 h before infusion or long term for 3 weeks.Conclusions. Stimulation of cardiac beta₂-adrenoceptors in humans causes not only in vitro but also in vivo positve inotropic effects. Long-term beta₁-adrenoceptor antagonist treatment does not considerably affect beta₂-adrenoceptor-mediated in vivo increases in contractility. Thus, it may be possible to treat patients with chronic heart failure and long-term beta₁-adrenoceptor antagonist therapy with beta₂-adrenoceptor agonists if immediate inotropic support is needed.     

Bronchodilator response in relation to beta2-adrenoceptor haplotype in patients with asthma

RATIONALE: Genetic variation of the beta2-adrenoceptor (ADRB2) influences receptor function in vitro. There are reports that, in vivo, bronchodilator response is related to ADRB2 genotype, and that clinical outcomes during chronic therapy with beta2-agonist drugs are also influenced by genotype. Whether these features are related to single nucleotide polymorphisms or to combinations (haplotypes) is unclear. OBJECTIVES: Our aim was to measure bronchodilator response in patients with asthma stratified by ADRB2 haplotype. This was done after eliminating the confounding effect of prior drug treatment with inhaled beta2-agonists and corticosteroids. METHODS: ADRB2 haplotype was determined in 176 patients with asthma, of whom 161 harbored the six most common combinations. Treatment with inhaled beta2-agonists and inhaled corticosteroids was withheld for appropriate intervals. Spirometric changes 20 minutes after a single dose of albuterol (2.5 mg by nebulizer) were then recorded. RESULTS: There were no significant differences in bronchodilator response (% improvement in FEV(1)) with respect to any of the major ADRB2 haplotypes or genotypes. CONCLUSIONS: Genetic variation of the ADRB2 does not influence the immediate response to inhaled beta2-agonist. The confounding effect of tolerance resulting from regular beta2-agonist use must be controlled when assessing the pharmacogenetic influences on clinical outcomes with beta2-agonists.     

Role of long-acting beta2-adrenergic agonists in asthma management based on updated asthma guidelines

PURPOSE OF REVIEW: This review examines the role of long-acting beta2-adrenergic agonists in the management of asthma, particularly focusing on recommendations in the newly revised Global Initiative for Asthma (GINA) and National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines. RECENT FINDINGS: GINA guidelines recommend increasing inhaled corticosteroid doses in all children with asthma not controlled on low-dose inhaled corticosteroids before adding a long-acting beta2-adrenergic agonist, whereas NHLBI guidelines have different age-based recommendations for children. In patients younger than 5 years, NHLBI guidelines recommend increasing the inhaled corticosteroid dose before adding a long-acting beta2-adrenergic agonist; in children aged 5-11 years, equal weight is given to increasing the inhaled corticosteroid dose or including add-on therapy to low-dose inhaled corticosteroids. In adults and adolescents aged 12 years and older, GINA recommends adding long-acting beta2-adrenergic agonists to low-dose inhaled corticosteroids over increasing the inhaled corticosteroid dose. NHLBI guidelines give equal weight to these choices, with alternative, although not preferred, therapies including the addition of theophylline, zileuton, or leukotriene receptor antagonists to low-dose inhaled corticosteroids. SUMMARY: In the recently updated GINA and NHLBI asthma guidelines, long-acting beta2-adrenergic agonists are an important class of agents for the management of persistent asthma in patients whose asthma is not well controlled with inhaled corticosteroid monotherapy.     

Regulation of human airway mesenchymal cell proliferation by glucocorticoids and beta2-adrenoceptor agonists

Altered rates of cell proliferation play important roles in the pathogenesis of a variety of conditions, including cancer, inflammation and several airway and cardiovascular diseases. One of the most consistently observed changes in asthmatic airways is an increased volume of airway smooth muscle (ASM), that has been explained by proliferation, hypertrophy, extracellular matrix deposition within the smooth muscle bundles, and more recently, the migration of mesenchymal precursor cells to the airways. The best characterised of these is proliferation of ASM cells. In vitro studies suggest that the proliferation is driven by various mitogens, and ECM proteins found in asthma, such as collagen type I. Therefore, we compared the anti-mitogenic actions of two classes of anti-asthma agents, the glucocorticoids and the beta2-adrenoceptor agonists, in ASM cells grown on collagen type I. Culture on collagen type I prevented the anti-mitogenic actions of glucocorticoids, but not beta2-adrenoceptor agonists. In contrast, glucocorticoids are efficacious in regulating ASM production of GM-CSF, whereas beta2-adrenoceptor agonists are without effect. Therefore, combination therapy may have increased efficacy over glucocorticoids alone in controlling remodelling events due to complementary actions of the two classes of compounds.