| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, Miami, FL, USA; Department of Respiratory Medicine, Semmelweis University, Budapest, Hungary
2 Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL, USA
3 Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, Miami, FL, USA
* To whom correspondence should be addressed. E-mail: awanner{at}miami.edu.
Inhaled glucocorticosteroids (GSs) cause acute, 
1-adrenoreceptor (AR)-mediated bronchial vasoconstriction. After release from sympathetic nerves, norepinephrine (NE) has to be taken up into cells for deactivation by intracellular enzymes. Since postsynaptic cellular NE uptake is steroid sensitive, GSs could increase NE concentrations at 1-AR, thereby causing vasoconstriction. We therefore evaluated mRNA expression of different NE transporters in human bronchial arterial smooth muscle and pharmacologically characterized NE uptake into these cells. RT-PCR demonstrated mRNA expression of the extraneuronal monoamine transporter (EMT) and organic cation transporter 1 (OCT-1). A fluorometric uptake assay showed time (within minutes) and concentration-dependent NE uptake by freshly isolated bronchial arterial smooth muscle cells (SMC) with an estimated Km of 240 µM. Corticosterone and O-methyl-isoprenaline but not desipramine (1 µM each) inhibited NE uptake, a profile indicative of NE uptake by EMT but not OCT-1. Budesonide and methylprednisolone inhibited uptake with IC50 values of 0.9 µM and 5.6 µM, respectively. Corticosterone's action was reversible and not sensitive to RU486 (GS receptor antagonist), actinomycin D (transcription inhibitor), or cycloheximide (protein synthesis inhibitor). Corticosterone made membrane impermeant by coupling to BSA also blocked NE uptake. Immunocytochemistry indicated a specific membrane binding site for corticosterone in bronchial arterial SMC. These data demonstrate that while human bronchial arterial SMCs express both OCT-1 and EMT, EMT is the predominant plasma membrane transporter for NE uptake. This process can be inhibited by GSs, likely via a specific membrane binding site. This nongenomic GS action (increasing NE concentrations at 1-AR) could explain acute bronchial vasoconstriction caused by inhaled GSs.
This article has been cited by other articles:
|
|
 |
|
  A. E. Linder, W. Ni, T. Szasz, R. Burnett, J. Diaz, T. J. Geddes, D. M. Kuhn, and S. W. Watts A Serotonergic System in Veins: Serotonin Transporter-Independent Uptake J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 714 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Horvath, N. Schmid, M. A. Fragoso, A. Schmid, G. E. Conner, M. Salathe, and A. Wanner Epithelial Organic Cation Transporters Ensure pH-Dependent Drug Absorption in the Airway Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 53 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Horvath and A. Wanner Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma Eur. Respir. J., January 1, 2006; 27(1): 172 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Lips, C. Volk, B. M. Schmitt, U. Pfeil, P. Arndt, D. Miska, L. Ermert, W. Kummer, and H. Koepsell Polyspecific Cation Transporters Mediate Luminal Release of Acetylcholine from Bronchial Epithelium Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 79 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Mendes, M. A. Campos, A. Hurtado, and A. Wanner Effect of Montelukast and Fluticasone Propionate on Airway Mucosal Blood Flow in Asthma Am. J. Respir. Crit. Care Med., May 15, 2004; 169(10): 1131 - 1134. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
