Rapid corticosteroid effect on long-acting β2-agonist disposal by smooth muscle cells in the airway

A new paradigm of inhaled combination therapy

Gabor Horvath, Eliana Mendes, Nathalie Schmid, Andreas Schmid, Gregory E Conner, Matthias A Salathe, Adam Wanner

Research output: Contribution to journalArticle

Abstract

Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies, [3H]-formoterol (FORM) and [3H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48 ± 0.09, 1.88 ± 0.24, 4.48 ± 0.31 μmol·l-1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5¡1.3% vs. 27.4¡3.1%, respectively; p,0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4 ± 1.7 vs. 327.5 ± 13.7 pmol·mg-1 protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma. Copyright

Original languageEnglish
Pages (from-to)41-42
Number of pages2
JournalEuropean Respiratory Review
Volume17
Issue number107
DOIs
StatePublished - Apr 1 2008

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Smooth Muscle Myocytes
Adrenal Cortex Hormones
Vascular Smooth Muscle
Cations
Bronchodilator Agents
Fluorescent Antibody Technique
Therapeutics
Budesonide
Polymerase Chain Reaction
Tissue Distribution
Corticosterone
Pharmaceutical Preparations
Inhibitory Concentration 50
Asthma
Tissue Donors
Staining and Labeling
Drug Therapy
Messenger RNA
Formoterol Fumarate
Proteins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

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title = "Rapid corticosteroid effect on long-acting β2-agonist disposal by smooth muscle cells in the airway: A new paradigm of inhaled combination therapy",
abstract = "Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies, [3H]-formoterol (FORM) and [3H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48 ± 0.09, 1.88 ± 0.24, 4.48 ± 0.31 μmol·l-1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5¡1.3{\%} vs. 27.4¡3.1{\%}, respectively; p,0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4 ± 1.7 vs. 327.5 ± 13.7 pmol·mg-1 protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma. Copyright",
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T1 - Rapid corticosteroid effect on long-acting β2-agonist disposal by smooth muscle cells in the airway

T2 - A new paradigm of inhaled combination therapy

AU - Horvath, Gabor

AU - Mendes, Eliana

AU - Schmid, Nathalie

AU - Schmid, Andreas

AU - Conner, Gregory E

AU - Salathe, Matthias A

AU - Wanner, Adam

PY - 2008/4/1

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N2 - Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies, [3H]-formoterol (FORM) and [3H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48 ± 0.09, 1.88 ± 0.24, 4.48 ± 0.31 μmol·l-1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5¡1.3% vs. 27.4¡3.1%, respectively; p,0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4 ± 1.7 vs. 327.5 ± 13.7 pmol·mg-1 protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma. Copyright

AB - Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies, [3H]-formoterol (FORM) and [3H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48 ± 0.09, 1.88 ± 0.24, 4.48 ± 0.31 μmol·l-1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5¡1.3% vs. 27.4¡3.1%, respectively; p,0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4 ± 1.7 vs. 327.5 ± 13.7 pmol·mg-1 protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma. Copyright

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