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Publication Detail
Effect of antioxidants on airway smooth muscle contraction: action of lipoic acid and some of its novel derivatives on guinea pig tracheal smooth muscle
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Assem ESK, Mann S, Wan BYC, Marson CM
  • Publisher:
  • Publication date:
  • Pagination:
    235, 237
  • Journal:
  • Volume:
  • Print ISSN:
  • Language:
  • Keywords:
    Smooth muscle, Antioxidants, Lipoic acid, Histone deacetylase inhibitors, MGCD0103, HUMAN-LEUKOCYTES, HISTAMINE, INHIBITION, RELEASE
  • Addresses:
    Marson, CM
    Dept Chem
    WC1H 0AJ

    Div Neurosci Physiol & Pharmacol
    WC1E 6BT
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.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.All antioxidants tested showed a relaxant effect on resting tension and on tension induced by histamine or carbachol, with EC50(s) of 0.2-5.0 mM and a rank order of potency: LA derivatives > glutathione (GSH) > ascorbic acid (AA). However, low concentrations (< 50 mu M) 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.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.
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