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Author Notes:

Address for reprint requests and other correspondence: M. N. Helms, Dept. of Pediatrics, 2015 Uppergate Dr., Suite 316K, Atlanta, GA 30322 (e-mail: mhelms@emory.edu).

Subject:

Research Funding:

This work was supported by NIH grants 5R00HL092226-04 awarded to M. Helms, 5R37DK037963-25 awarded to D. Eaton, and 5R01HL063306-09 awarded to L. Jain.

Keywords:

  • terbutaline
  • denopamine
  • β1-adrenergic receptor
  • β2-adrenergic receptor

β-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo

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Journal Title:

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volume:

Volume 302, Number 11

Publisher:

, Pages L1167-L1178

Type of Work:

Article | Post-print: After Peer Review

Abstract:

β-Adrenergic receptors (β-AR) increase epithelial sodium channel (ENaC) activity to promote lung fluid clearance. However, the effect of selective β-AR agonist on highly selective cation (HSC) channels or nonselective cation (NSC) channels in alveolar type 1 (T1) and type 2 (T2) cells is unknown. We hypothesized that stimulation with β1-AR agonist (denopamine) or β2-AR agonist (terbutaline) would increase HSC and/or NSC channel activity in alveolar epithelial cells. We performed single-channel measurements from T1 and T2 cells accessed from rat lung slices. Terbutaline (20 μM) increased HSC ENaC activity (open probability, NPo) in T1 (from 0.96 ± 0.61 to 1.25 ± 0.71, n = 5, P <0.05) and T2 cells (from 0.28 ± 0.14 to 1.0 ± 0.30, n = 8, P = 0.02). Denopamine (20 μM) increased NSC NPo in T1 cells (from 0.34 ± 0.09 to 0.63 ± 0.14, n = 7, P = 0.02) and in T2 cells (from 0.47 ± 0.09 to 0.68 ± 0.10, P = 0.004). In vivo X-ray imaging of lung fluid clearance and ICI 118,551 selective inhibition of β2-ARs confirmed patch-clamp findings. cAMP concentrations increased following treatment with denopamine or terbutaline (n = 3, P < 0.002). The effects of systemic (intraperitoneal, IP) and local (intratracheal, IT) modes of delivery on lung fluid clearance were assessed. IT delivery of denopamine promoted alveolar flooding, whereas IP delivery promoted delayed fluid clearance. In summary, β-AR agonists differentially regulate HSC and NSC in T1 and T2 cells to promote lung fluid clearance in vivo, and the mode of drug delivery is critical for maximizing β-AR agonist efficacy.

Copyright information:

© 2012 the American Physiological Society

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