Transpulmonary flux of S-nitrosothiols and pulmonary vasodilation during nitric oxide inhalation: role of transport.
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.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Jordan A
JA
Torok
Mulugu V
MV
Brahmajothi
Hongmei
H
Zhu
Brian T
BT
Tinch
Richard L
RL
Auten
Timothy J
TJ
McMahon
D000280:Administration, Inhalation; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D003545:Cysteine / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D007930:Leucine / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D026403:S-Nitrosothiols / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D000598:Amino Acids, Cyclic; D026403:S-Nitrosothiols; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D009569:Nitric Oxide; D007930:Leucine; D003545:Cysteine