Abstract
Nitric oxide (NO) production may depend on the uptake of l-arginine (l-arg), the substrate for NO synthase in inflammatory lung diseases. The cellular transport of l-arg occurs via the cationic amino acid transporters (CAT), and l-lysine (l-lys) competitively inhibits CAT. Neonatal pigs were treated with lipopolysaccharide (LPS) or vehicle for 4 h. LPS increased exhaled NO (exNO; 0.026 ± 0.003 to 0.046 ± 0.003 nmol · kg−1 · min−1; p < 0.005) and decreased mean systemic arterial blood pressure (89 ± 4 to 67 ± 4 mm Hg; p < 0.05), whereas vehicle did not affect exNO or mean systemic arterial blood pressure. The lungs were then isolated and perfused; exNO was greater in lungs from LPS-treated animals (0.08 ± 0.01 nmol/kg/min) than in lungs from vehicle-treated animals (0.05 ± 0.01 nmol · kg−1· min−1; p < 0.05). The addition of l-arg (0.3 mM) significantly (p < 0.05) increased exNO production in both groups of lungs (mean increase 0.04 ± 0.01 nmol · kg−1 · min−1 LPS-treated lungs, p < 0.05; mean increase 0.02 ± 0.01 nmol · kg−1 · min−1vehicle-treated lungs); however, l-arg decreased pulmonary vascular resistance (PVR) only in LPS-treated lungs (mean decrease 0.03 ± 0.01 mm Hg · ml−1 · kg−1 · min−1, p < 0.05). l-lys caused a dose-dependent decrease in exNO production and a dose-dependent increase in PVR in LPS-treated lungs. l-lys decreased exNO only at 30 mM and had no effect on PVR in vehicle-treated lungs. In four lungs each from vehicle-and LPS-treated animals, reverse transcriptase–PCR demonstrated CAT-2 mRNA only in LPS-treated animals. These results suggest that the increased NO production in the lungs from LPS-treated animals depends on the uptake of vascular l-arg.
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Abbreviations
- bPAEC:
-
bovine pulmonary arterial endothelial cells
- CAT:
-
cationic amino acid transporter
- eNOS:
-
endothelial nitric oxide synthase
- exNO:
-
exhaled nitric oxide
- iNOS:
-
inducible nitric oxide synthase
- l-arg:
-
l-arginine
- l-lys:
-
l-lysine
- LPS:
-
lipopolysaccharide
- MAP:
-
mean systemic arterial blood pressure
- nNOS:
-
neuronal nitric oxide synthase
- NO:
-
nitric oxide
- NOS:
-
nitric oxide synthase
- Pa:
-
pulmonary arterial pressure
- PVR:
-
pulmonary vascular resistance
- RR:
-
respiratory rate
- TNF-α:
-
tumor necrosis factor-α
- Vt:
-
tidal volume
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Acknowledgements
We thank Kelly Billings for excellent technical assistance and Prof. Benjimen R. Walker for assistance with study design.
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This work was supported by a Grant-in-Aid from the American Heart Association, Desert Mountain Affiliate (L.D.N.) and National Heart, Lung and Blood Institute Grant HL-004050 (L.G.C.).
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Carter, B., Chicoine, L. & Nelin, L. l-Lysine Decreases Nitric Oxide Production and Increases Vascular Resistance in Lungs Isolated from Lipopolysaccharide-Treated Neonatal Pigs. Pediatr Res 55, 979–987 (2004). https://doi.org/10.1203/01.pdr.0000127722.55965.b3
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DOI: https://doi.org/10.1203/01.pdr.0000127722.55965.b3
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