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Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport.

Publication ,  Journal Article
Torok, JA; Brahmajothi, MV; Zhu, H; Tinch, BT; Auten, RL; McMahon, TJ
Published in: Am J Respir Cell Mol Biol
July 2012

Inhaled nitric oxide (iNO) is used to treat pulmonary hypertension and is being investigated for prevention of bronchopulmonary dysplasia in neonates. Extrapulmonary effects of iNO are widely recognized, but the underlying chemistry and pharmacology are poorly understood. Growing evidence suggests that, in addition to acting via diffusion, NO can be converted into nitrosants capable of reacting with endogenous L-cysteine (L-Cys) in the alveolar lining fluid, forming S-nitrosothiol (SNO)-L-cysteine (CSNO). CSNO can then enter cells via the type L amino acid transporter (LAT). To determine the influence of LAT and supplemental L-Cys on the functional activity of iNO and transpulmonary movement of SNOs or other related species, we exposed C57Bl6 mice to nebulized L-Cys or D-cysteine (D-Cys) and/or LAT competitors. Isolated lungs were then perfused with physiologic buffer while effluent was collected to assay perfusate SNOs. Nebulized L-Cys, but not D-Cys, augmented the iNO-induced increase in circulating SNOs in the effluent without altering iNO-induced pulmonary vasodilation. Addition to the perfusate of either L-leucine (L-Leu) or 2-amino-2-norborane carboxylic acid, two distinct LAT competitors, inhibited appearance in the perfusate of SNOs in L-Cys-exposed lungs; a higher concentration of L-Leu significantly inhibited the iNO-induced pulmonary vasodilation as well as SNO accumulation. We conclude that iNO-induced pulmonary vasodilation and the transpulmonary movement of iNO-derived SNOs are mediated in part by formation of extracellular CSNO, uptake by alveolar epithelial LAT, and/or export by LAT from the pulmonary endothelium into the circulation. Therapies that exploit and optimize LAT-dependent SNO transport might improve the efficacy of and clinical outcomes with NO-based therapy by improving systemic SNO delivery.

Duke Scholars

Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

July 2012

Volume

47

Issue

1

Start / End Page

37 / 43

Location

United States

Related Subject Headings

  • Vasodilation
  • S-Nitrosothiols
  • Respiratory System
  • Nitric Oxide
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Leucine
  • Hypertension, Pulmonary
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Torok, J. A., Brahmajothi, M. V., Zhu, H., Tinch, B. T., Auten, R. L., & McMahon, T. J. (2012). Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport. Am J Respir Cell Mol Biol, 47(1), 37–43. https://doi.org/10.1165/rcmb.2011-0439OC
Torok, Jordan A., Mulugu V. Brahmajothi, Hongmei Zhu, Brian T. Tinch, Richard L. Auten, and Timothy J. McMahon. “Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport.Am J Respir Cell Mol Biol 47, no. 1 (July 2012): 37–43. https://doi.org/10.1165/rcmb.2011-0439OC.
Torok JA, Brahmajothi MV, Zhu H, Tinch BT, Auten RL, McMahon TJ. Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport. Am J Respir Cell Mol Biol. 2012 Jul;47(1):37–43.
Torok, Jordan A., et al. “Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport.Am J Respir Cell Mol Biol, vol. 47, no. 1, July 2012, pp. 37–43. Pubmed, doi:10.1165/rcmb.2011-0439OC.
Torok JA, Brahmajothi MV, Zhu H, Tinch BT, Auten RL, McMahon TJ. Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport. Am J Respir Cell Mol Biol. 2012 Jul;47(1):37–43.

Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

July 2012

Volume

47

Issue

1

Start / End Page

37 / 43

Location

United States

Related Subject Headings

  • Vasodilation
  • S-Nitrosothiols
  • Respiratory System
  • Nitric Oxide
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Leucine
  • Hypertension, Pulmonary