Effects of (R)- and (S)-isomers of β-adrenergic agonists on eosinophil response to interleukin-5

Background: Racemic β₂-adrenergic receptor agonists (β₂-agonists) are used frequently to treat patients with asthma. Potential differences in the biological activities and clinical efficacies among racemic β₂-agonists and their isomers are controversial, and research into these possible differences is limited. Objective: We hypothesized that the (S)- and the (R)-isomers of β₂-agonists have opposing effects on the activation of inflammatory cells. Methods: Isolated human eosinophils were pretreated with 1: 1 racemic (R,S)-, (R)- or (S)-albuterol, isobutyl methylxanthine (IBMX), and stimulated with IL-5. The kinetics of superoxide production were examined by reduction of cytochrome c, and the effects of pharmacological agents on superoxide production were monitored for 180 min. Results: (R,S)-albuterol inhibited IL-5-induced superoxide production. This inhibition was enhanced by a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, IBMX, and was reversed by the selective β₂-adrenergic receptor antagonist, ICI 118, 551, verifying the involvement of both cAMP and the β₂-adrenergic receptor. In addition, (R)-albuterol alone, similarly to (R,S)-albuterol, significantly inhibited IL-5-induced superoxide production up to 60 min (P<0.05, n=4), but the inhibition was lost with longer incubation. In contrast, (S)-albuterol with IBMX did not inhibit IL-5-induced superoxide production before 60 min, but it significantly enhanced IL-5-mediated superoxide production after 60 min (P<0.05, n=4). When both were present as racemic (R,S)-albuterol, the inhibitory effect of (R)-albuterol was not affected by (S)-albuterol. Conclusion: When incubated with IL-5-activated eosinophils, (R)-albuterol shows anti-inflammatory effects and (S)-albuterol shows pro-inflammatory effects in the presence of IBMX. The kinetics of these effects are different, and when used simultaneously, (R)-albuterol predominates. When marked usage of the (S)-isomer is anticipated, racemic (R,S)-albuterol should be used clinically with caution.