Effects of inducible nitric oxide synthase inhibitors on asthma depending on administration schedule.
The effectiveness of two inducible nitric oxide synthase (iNOS) inhibitors on allergic airway inflammation was investigated under different administration schedules. Rats sensitized to ovalbumin (OVA) were exposed to OVA for 3 consecutive days. Both iNOS inhibitors showed markedly different effects between two pretreatment schedules: pretreatment before each of three OVA exposures S1 and before the third exposure alone S2. S1 pretreatment resulted in higher pulmonary resistance than triple OVA alone. This potentiation was associated with increased eosinophil infiltration and malondialdehyde levels in the lungs, which were suppressed by superoxide dismutases (SODs) but not by methylprednisolone. However, the S2 administration of both iNOS inhibitors completely suppressed the airway response. Administration by schedule S1 completely suppressed plasma nitrite and nitrate levels, but that by S2 caused only a slight suppression. The triple OVA exposures resulted in the upregulation of iNOS in alveolar macrophages and arginase activity, Mn- and Cu/Zn-SOD expression, and nitrotyrosine and lipid peroxide deposition in the airway. However, inhibitors administered by schedule S1 suppressed this upregulation, but further potentiated nitrotyrosine, which in turn was inhibited by SOD. Although iNOS inhibitors may be beneficial for asthma, repeated administration may be detrimental because of extensive reduction of NO and downregulation of SOD.
Abe
Masayoshi
M
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. abemasa@fukuoka-u.ac.jp
Hayashi
Yuri
Y
Murai
Akira
A
Shibata
Kazuhiko
K
Sakata
Noriyuki
N
Igarashi
Rie
R
Katsuragi
Takeshi
T
Tanaka
Keiichi
K
D000578:Amidines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use*; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology / Q000627:therapeutic use; D008054:Lipid Peroxides / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D013482:Superoxide Dismutase / Q000096:biosynthesis
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006146:Guanidines; D006574:Heterocyclic Compounds, 2-Ring; D008054:Lipid Peroxides; D010047:Ovalbumin; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D001119:Arginase; C004479:pimagedine