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Effects of Albuterol Isomers on the Contraction and Ca²⁺ Signaling of Small Airways in Mouse Lung Slices

¹ Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Correspondence and requests for reprints should be addressed to Michael J. Sanderson, Ph.D., Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail: michael.sanderson{at}umassmed.edu

The β₂-adrenergic agonist, albuterol, is used as a bronchodilator by patients with asthma and consists of a racemic mixture of (R)- and (S)-albuterol. However, the action of the individual enantiomers is poorly understood. Consequently, we investigated the effects of (R)-, (S)- and racemic-albuterol on airway smooth muscle cell (SMC) contraction and Ca²⁺ signaling in mouse lung slices with phase-contrast and confocal microscopy. (R)-albuterol relaxed airways contracted with methacholine (MCh) in a dose-dependent manner. By contrast, (S)-albuterol had no effect on airways. (R)-albuterol had a greater relaxant effect than a double concentration of racemic albuterol. Because MCh-induced contraction of airway SMCs is mediated by Ca²⁺ oscillations and an increase in Ca²⁺ sensitivity, the effects of albuterol on these responses were examined. Both (R)- and racemic albuterol decreased the frequency of the MCh-induced Ca²⁺ oscillations by a similar amount. However, (R)-albuterol was more effective than racemic albuterol in decreasing the Ca²⁺ sensitivity of the airway SMCs in "model" lung slices with a clamped [Ca²⁺]_i. In contrast, (S)-albuterol had no effect on the Ca²⁺ oscillations or the Ca²⁺ sensitivity. In conclusion, (R)-albuterol consistently induced a greater airway relaxation than racemic albuterol, and (S)-albuterol appears to be responsible for this reduced efficacy.

Key Words: hyper-reactivity • β₂-agonist • relaxation • Ca²⁺ oscillations • Ca²⁺ sensitivity

CLINICAL RELEVANCE Albuterol is commonly used to relieve bronchial constriction and acts by relaxing airway smooth muscle. This study focused on the influence of (R)- and (S)-enantiomers of albuterol on airway contraction in lung slice preparations from mice.