Effects of (R)- and (S)-isomers of beta-adrenergic agonists on eosinophil response to interleukin-5.
BACKGROUND
Racemic beta2-adrenergic receptor agonists (beta2-agonists) are used frequently to treat patients with asthma. Potential differences in the biological activities and clinical efficacies among racemic beta2-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 beta2-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 beta2-adrenergic receptor antagonist, ICI 118, 551, verifying the involvement of both cAMP and the beta2-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.


CONCLUSIONS
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.
Volcheck
G W
GW
Department of Internal Medicine, Division of Allergic Diseases, The Allergic Diseases Research Laboratory, Mayo Clinic and Foundation, Mayo Graduate School of Medicine, Rochester, MN 55905, USA.
Kelkar
P
P
Bartemes
K R
KR
Gleich
G J
GJ
Kita
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D002478:Cells, Cultured; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013237:Stereoisomerism; D013481:Superoxides / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D013481:Superoxides; D000420:Albuterol; D015056:1-Methyl-3-isobutylxanthine