title: (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle.
abstract: Racemic albuterol has been one of the most widely used beta2-adrenoceptor agonists for the relief of the symptoms of asthma, yet the use of beta2 agonists has been known to induce bronchial hyperresponsiveness. To probe a possible role of the S-enantiomer for hyperresponsiveness, we determined the effects of (S)-albuterol on intracellular Ca2+ concentration ([Ca2+]i) in dissociated bovine tracheal smooth muscle cells. Both (S)-and (R,S)-albuterol increased [Ca2+]i at concentrations of >10 pM and 1 nM, respectively, with a maximal response by 150 and 100 nM, respectively. (S)-Albuterol (1 and 10 muM) induced Ca2+ oscillations, reaching 1-2 muM [Ca2+]i. This response is in a stark contrast to that of (R)-albuterol, which decreased [Ca2+]i. The increase in [Ca2+]i was blocked by 100 nM atropine or 500 nM 4-diphenylacetoxy-N-methylpiperidine but was insensitive to the beta2 antagonist ICI 118,551 (10 muM). (S)-Albuterol (10 muM) increased inositol-1,4,5-trisphosphate levels by 213 +/- 34.4% (p < 0.05, four experiments) in cells exposed for 30 sec. The sustained phase of the Ca2+ increase was absent in Ca2+-free solution, suggesting that Ca2+ influx was responsible for the sustained Ca2+ response. The results also suggest that (S)-albuterol may cross-react with muscarinic receptors. As a Ca2+ agonist in airway smooth muscle, (S)-albuterol may have profound clinical implications because 50% of prescribed racemic albuterol is composed of (S)-albuterol.
authors.affiliation: Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.forename: M
authors.initials: M
authors.lastname: Ugur
authors.forename: O
authors.initials: O
authors.lastname: Ugur
authors.forename: H M
authors.initials: HM
authors.lastname: Goodman
authors.forename: J R
authors.initials: JR
authors.lastname: McCullough
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D004963:Estrenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D010738:Type C Phospholipases / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D004963:Estrenes; D010880:Piperidines; D011412:Propanolamines; D011760:Pyrrolidinones; D011976:Receptors, Muscarinic; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C026777:ICI 118551; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D010738:Type C Phospholipases; D000420:Albuterol; D002118:Calcium