title: Effect of antioxidants on airway smooth muscle contraction: action of lipoic acid and some of its novel derivatives on guinea pig tracheal smooth muscle.
abstract: OBJECTIVE
  The aim of this study was to investigate the ability of (a) antioxidants, some related to alpha-lipoic acid (LA), (b) histone deacetylase (HDAC) inhibitors, and (c) hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity to inhibit guinea pig smooth muscle contraction.
  
  
  METHODS
  Guinea pig isolated tracheal rings (GPTR) were prepared and their isometric tension measured using a transducer. Histamine, carbachol and 5-hydroxytryptamine (5-HT) served as agonists. Tests with antigen (ovalbumin) used GPTR from sensitised guinea pigs or rings from non-sensitised animals that had been incubated for at least 2 h with diluted serum from sensitised animals.
  
  
  RESULTS
  All antioxidants tested showed a relaxant effect on resting tension and on tension induced by histamine or carbachol, with EC(50)(s) of 0.2-5.0 mM and a rank order of potency: LA derivatives > glutathione (GSH) > ascorbic acid (AA). However, low concentrations (<50 microM) of GSH, AA and LA potentiated histamine-induced contractions. The benzamide HDAC inhibitor MGCD0103 inhibited mast cell activation and GPTR contraction produced by antigen and certain agonists, although a 2-6 h pre-incubation was required for those effects to be apparent. Two LA-benzamide HDAC hybrid compounds, UCL M084 and UCL M109 inhibited GPTR contraction after 30 min pre-incubation; however, even after long pre-incubation (up to 6 h) those hybrid compounds showed less potent inhibition of agonist-induced contraction than did MGCD0103.
  
  
  CONCLUSIONS
  The results showed that GSH more potently inhibited contraction induced by histamine than that induced by 5-HT or carbachol, whereas LA, and especially UCL M084 and UCL M109, more potently blocked contraction induced by carbachol and 5-HT than that induced by histamine. For GSH, and possibly also for LA-type compounds, the inhibition of agonist-induced tracheal smooth muscle contractions may be due to NO formation. This study did not detect a synergistic relaxant effect in two compounds incorporating the structural union of a benzamide HDAC inhibitor terminus with a LA-derived antioxidant moiety.
authors.affiliation: Division of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors.forename: E S K
authors.initials: ES
authors.lastname: Assem
authors.forename: S
authors.initials: S
authors.lastname: Mann
authors.forename: B Y C
authors.initials: BY
authors.lastname: Wan
authors.forename: C M
authors.initials: CM
authors.lastname: Marson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004357:Drug Synergism; D005978:Glutathione / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010047:Ovalbumin / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D012132:Respiratory Muscles / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D001549:Benzamides; D006633:Histamine Antagonists; D018721:Muscarinic Agonists; D011743:Pyrimidines; D012701:Serotonin; D008063:Thioctic Acid; D006632:Histamine; D002217:Carbachol; D010047:Ovalbumin; C523184:mocetinostat; D005978:Glutathione; D001205:Ascorbic Acid