Bronchodilatory effects of S-isopetasin, an antimuscarinic sesquiterpene of Petasites formosanus, on obstructive airway hyperresponsiveness

Ling Hong Lin, Tzu Jung Huang, Sheng Hao Wang, Yun Lian Lin, Sheng Nan Wu, Wun Chang Ko

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In the presence of neostigmine (0.1 μM), S-isopetasin competitively antagonized cumulative acetylcholine-induced contractions in guinea pig trachealis, because the slope [1.18 ± 0.15 (n = 6)] of Schild's plot did not significantly differ from unity. The pA2 value of S-isopetasin was calculated to be 4.62 ± 0.05 (n = 18). The receptor binding assay for muscarinic receptors of cultured human tracheal smooth muscle cells (HTSMCs) was performed using [3H]-N-methylscopolamine ([3H]-NMS). Saturation binding assays were carried out with [3H]-NMS in the presence (non-specific binding) and absence (total binding) of atropine (1 μM). Analysis of the Scatchard plot (y = 0.247-1.306x, r2 = 0.95) revealed that the muscarinic receptor binding sites in cultured HTSMCs constituted a single population (nH = 1.00). The equilibrium dissociation constant (Kd) and the maximal receptor density (Bmax) for [3H]-NMS binding were 766 pM and 0.189 pmol/mg of protein, respectively. The - logIC50 values of S-isopetasin, methoctramine, and 1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) for displacing 0.4 nM [3H]-NMS-specific binding were 5.05, 6.25, and 8.56, respectively, which suggests that [3H]-NMS binding is predominantly on muscarinic M3 receptors of cultured HTSMCs. The inhibitory effects of S-isopetasin on enhanced pause (Penh) value were similar to that of ipratropium bromide, a reference drug. The duration of action of S-isopetasin (20 μM), also similar to that of ipratropium bromide (20 μM), was 3 h. In contrast to ipratropium bromide, which non-selectively acts on muscarinic receptors, S-isopetasin preferentially acts on muscarinic M3 receptors. In conclusion, S-isopetasin may be beneficial as a bronchodilator in the treatment of chronic obstructive pulmonary disease and asthma exacerbations.

Original languageEnglish
Pages (from-to)398-404
Number of pages7
JournalEuropean Journal of Pharmacology
Volume584
Issue number2-3
DOIs
Publication statusPublished - Apr 28 2008

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Petasites
Muscarinic Antagonists
Sesquiterpenes
Ipratropium
Muscarinic Receptors
Muscarinic M3 Receptors
Smooth Muscle Myocytes
N-Methylscopolamine
Neostigmine
Bronchodilator Agents
Iodides
isopetasin
Atropine
Chronic Obstructive Pulmonary Disease
Acetylcholine
Disease Progression
Guinea Pigs
Asthma
Binding Sites

Keywords

  • [H]-N-Methylscopolamine
  • Acetylcholine
  • Guinea pig trachealis
  • Human tracheal smooth muscle cell
  • Muscarinic receptor
  • S-isopetasin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Bronchodilatory effects of S-isopetasin, an antimuscarinic sesquiterpene of Petasites formosanus, on obstructive airway hyperresponsiveness. / Lin, Ling Hong; Huang, Tzu Jung; Wang, Sheng Hao; Lin, Yun Lian; Wu, Sheng Nan; Ko, Wun Chang.

In: European Journal of Pharmacology, Vol. 584, No. 2-3, 28.04.2008, p. 398-404.

Research output: Contribution to journalArticle

Lin, Ling Hong ; Huang, Tzu Jung ; Wang, Sheng Hao ; Lin, Yun Lian ; Wu, Sheng Nan ; Ko, Wun Chang. / Bronchodilatory effects of S-isopetasin, an antimuscarinic sesquiterpene of Petasites formosanus, on obstructive airway hyperresponsiveness. In: European Journal of Pharmacology. 2008 ; Vol. 584, No. 2-3. pp. 398-404.
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abstract = "In the presence of neostigmine (0.1 μM), S-isopetasin competitively antagonized cumulative acetylcholine-induced contractions in guinea pig trachealis, because the slope [1.18 ± 0.15 (n = 6)] of Schild's plot did not significantly differ from unity. The pA2 value of S-isopetasin was calculated to be 4.62 ± 0.05 (n = 18). The receptor binding assay for muscarinic receptors of cultured human tracheal smooth muscle cells (HTSMCs) was performed using [3H]-N-methylscopolamine ([3H]-NMS). Saturation binding assays were carried out with [3H]-NMS in the presence (non-specific binding) and absence (total binding) of atropine (1 μM). Analysis of the Scatchard plot (y = 0.247-1.306x, r2 = 0.95) revealed that the muscarinic receptor binding sites in cultured HTSMCs constituted a single population (nH = 1.00). The equilibrium dissociation constant (Kd) and the maximal receptor density (Bmax) for [3H]-NMS binding were 766 pM and 0.189 pmol/mg of protein, respectively. The - logIC50 values of S-isopetasin, methoctramine, and 1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) for displacing 0.4 nM [3H]-NMS-specific binding were 5.05, 6.25, and 8.56, respectively, which suggests that [3H]-NMS binding is predominantly on muscarinic M3 receptors of cultured HTSMCs. The inhibitory effects of S-isopetasin on enhanced pause (Penh) value were similar to that of ipratropium bromide, a reference drug. The duration of action of S-isopetasin (20 μM), also similar to that of ipratropium bromide (20 μM), was 3 h. In contrast to ipratropium bromide, which non-selectively acts on muscarinic receptors, S-isopetasin preferentially acts on muscarinic M3 receptors. In conclusion, S-isopetasin may be beneficial as a bronchodilator in the treatment of chronic obstructive pulmonary disease and asthma exacerbations.",
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AU - Ko, Wun Chang

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N2 - In the presence of neostigmine (0.1 μM), S-isopetasin competitively antagonized cumulative acetylcholine-induced contractions in guinea pig trachealis, because the slope [1.18 ± 0.15 (n = 6)] of Schild's plot did not significantly differ from unity. The pA2 value of S-isopetasin was calculated to be 4.62 ± 0.05 (n = 18). The receptor binding assay for muscarinic receptors of cultured human tracheal smooth muscle cells (HTSMCs) was performed using [3H]-N-methylscopolamine ([3H]-NMS). Saturation binding assays were carried out with [3H]-NMS in the presence (non-specific binding) and absence (total binding) of atropine (1 μM). Analysis of the Scatchard plot (y = 0.247-1.306x, r2 = 0.95) revealed that the muscarinic receptor binding sites in cultured HTSMCs constituted a single population (nH = 1.00). The equilibrium dissociation constant (Kd) and the maximal receptor density (Bmax) for [3H]-NMS binding were 766 pM and 0.189 pmol/mg of protein, respectively. The - logIC50 values of S-isopetasin, methoctramine, and 1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) for displacing 0.4 nM [3H]-NMS-specific binding were 5.05, 6.25, and 8.56, respectively, which suggests that [3H]-NMS binding is predominantly on muscarinic M3 receptors of cultured HTSMCs. The inhibitory effects of S-isopetasin on enhanced pause (Penh) value were similar to that of ipratropium bromide, a reference drug. The duration of action of S-isopetasin (20 μM), also similar to that of ipratropium bromide (20 μM), was 3 h. In contrast to ipratropium bromide, which non-selectively acts on muscarinic receptors, S-isopetasin preferentially acts on muscarinic M3 receptors. In conclusion, S-isopetasin may be beneficial as a bronchodilator in the treatment of chronic obstructive pulmonary disease and asthma exacerbations.

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