Different mechanisms underlie the effects of acute and long-term inhibition of nitric oxide synthases in antigen-induced pulmonary eosinophil recruitment in BALB/C mice.
Nitric oxide synthase (NOS) inhibitors are largely used to evaluate the NO contribution to pulmonary allergy, but contrasting data have been reported. In this study, pharmacological, biochemical and pharmacokinetic assays were performed to compare the effects of acute and long-term treatment of BALB/C mice with the non-selective NOS inhibitor L-NAME in ovalbumin (OVA)-challenged mice. Acute L-NAME treatment (50 mg/kg, gavage) significantly reduced the eosinophil number in bronchoalveolar lavage fluid (BALF). The inducible NOS (iNOS) inhibitor aminoguanidine (20 mg/kg/day in the drinking water) also significantly reduced the eosinophil number in BALF. In contrast, 3-week L-NAME treatment (50 and 150 mg/kg/day in the drinking water) significantly increased the pulmonary eosinophil influx. The constitutive NOS (cNOS) activity in brain and lungs was reduced by both acute and 3-week L-NAME treatments. The pulmonary iNOS activity was reduced by acute L-NAME (or aminoguanidine), but unaffected by 3-week L-NAME treatment. Acute L-NAME (or aminoguanidine) treatment was more efficient to reduce the NOx- levels compared with 3-week L-NAME treatment. The pharmacokinetic study revealed that L-NAME is not bioavailable when given orally. After acute L-NAME intake, serum concentrations of the metabolite Nomega-nitro-L-arginine decreased from 30 min to 24 h. In the 3-week L-NAME treatment, the Nomega-nitro-L-arginine concentration was close to the detection limit. In conclusion, 3-week treatment with l-NAME yields low serum Nomega-nitro-L-arginine concentrations, causing preferential inhibition of cNOS activity. Therefore, eosinophil influx potentiation by 3-week L-NAME treatment may reflect removal of protective cNOS-derived NO, with no interference on the ongoing inflammation due to iNOS-derived NO.
Lintomen
Leticia
L
Department of Pharmacology, State University of Campinas (UNICAMP), Faculty of Medical Sciences, PO Box 6111, 13084-971 Campinas, São Paulo, Brazil.
Souza-Filho
Luis Gustavo
LG
Ferreira
Tatiane
T
Camargo
Enilton A
EA
Teixeira
Simone A
SA
Muscará
Marcelo N
MN
Landgraf
Richardt G
RG
Jancar
Sonia
S
Mendes
Gustavo D
GD
De Nucci
Gilberto
G
Antunes
Edson
E
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001992:Bronchoalveolar Lavage Fluid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004804:Eosinophils / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010047:Ovalbumin
D004791:Enzyme Inhibitors; D010047:Ovalbumin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester