Effects of albuterol isomers on the contraction and Ca2+ signaling of small airways in mouse lung slices.
The beta(2)-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 Ca(2+) 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 Ca(2+) oscillations and an increase in Ca(2+) sensitivity, the effects of albuterol on these responses were examined. Both (R)- and racemic albuterol decreased the frequency of the MCh-induced Ca(2+) oscillations by a similar amount. However, (R)-albuterol was more effective than racemic albuterol in decreasing the Ca(2+) sensitivity of the airway SMCs in "model" lung slices with a clamped [Ca(2+)](i). In contrast, (S)-albuterol had no effect on the Ca(2+) oscillations or the Ca(2+) 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.
Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Philippe
P
Delmotte
Michael J
MJ
Sanderson
D000420:Albuterol / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D001993:Bronchodilator Agents / Q000737:chemistry* / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D013237:Stereoisomerism
D001993:Bronchodilator Agents; D000420:Albuterol