Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats (original) (raw)

Abstract

Endotoxin shock is characterized by systemic hypotension, hyporeactiveness to vasoconstrictors and acute lung edema. A nitric oxide synthase (NOS) inhibitor, NG-monomethyl-_L_-arginine (_L_-NMMA) has been shown to be effective in reversing acute lung injury. In the present study, we evaluated the effects of NOS blockade by different mechanisms on the endotoxin-induced changes. In anesthetized rats, lipopolysaccharide (LPS,Klebsiella pneumoniae) was administered intravenously in a dose of 10 mg/kg. LPS caused sustained systemic hypotension accompanied by an eightfold increase of exhaled NO during an observation period of 4 h. After the experiment, the lung weight was obtained and lung tissues were taken for the determination of mRNA expressions of inducible NOS (iNOS), interleukin-1β (IL-1β) and tumor necrosis factor-α-(TNF-α). Histological examination of the lungs was also performed. In the control group injected with saline solution, mRNA expressions of iNOS, IL-1β and TNF-α were absent. Four hours after LPS, the mRNA expressions of iNOS and IL-1β were still significantly enhanced, but TNF-α was not discernibly expressed. LPS also caused a twofold increase in lung weight. Pathological examination revealed endothelial damage and interstitial edema. Various NOS inhibitors were given 1 h after LPS administration. These agents included Nω-nitro-_L_-arginine methyl ester (_L_-NAME, 10 mg/kg), a constitutive NOS and iNOS inhibitor; S,S′-1,4-phenylene-bis-(1,2-ethanedinyl) bis-isothiourea dihydrobromide (1,4-PBIT, 10 mg/kg), a relatively specific iNOS inhibitor, and dexamethasone (3 mg/kg), an inhibitor of iNOS expression. These NOS inhibitors all effectively reversed the systemic hypotension, reduced the exhaled NO concentration and prevented acute lung injury. The LPS-induced mRNA expressions of iNOS and IL-1β were also significantly depressed by these NOS inhibitors. Our results suggest that NO production through the iNOS pathway is responsible for endotoxin-induced lung injury. Certain cytokines such as IL-1β are possibly involved. These changes are minimized by NOS inhibitors through different mechanisms.

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Authors and Affiliations

  1. Department of Medical Research, Cheng Hsin General Hospital, Taipei
    David Wang, Jeng Wei & Tai-Jong Chao
  2. Department of Physiology, National Defense Medical Center, Taipei
    Kang Hsu, Jin-Chi Jau & Mei-Wen Lieu
  3. Department of Physiology, Tzu Chi College of Medicine, Hualien, Taiwan, Republic of China
    Hsing I. Chen
  4. Research Division of Cardiovascular Surgery, Cheng Hsin General Hospital, Cheng Hsin Street 45, Taipei 112, Taiwan (ROC)
    Jeng Wei

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  1. David Wang
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  2. Jeng Wei
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  3. Kang Hsu
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  4. Jin-Chi Jau
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  5. Mei-Wen Lieu
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  6. Tai-Jong Chao
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  7. Hsing I. Chen
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Wang, D., Wei, J., Hsu, K. et al. Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats.J Biomed Sci 6, 28–35 (1999). https://doi.org/10.1007/BF02256421

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