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Updated: Aug 18, 2026
A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
Inducible nitric oxide synthase inhibition potentiates multiple organ dysfunction induced by endotoxin in conscious
Chia-Chi Lee1, Nien-Tseng Lin, Yung Hsing Hsu
1Institute of Medical Science, Tzu Chi University, Hualien, Taiwan.
Abstract:
This study was designed to investigate the effects of inducible nitric oxide synthase (iNOS) inhibition with S-methylisothiourea (SMT) and L-N-(1-iminoethyl)-lysine (L-Nil) on the endotoxemia induced by intravenous lipopolysaccharide (LPS, 10 mg/kg) in conscious rats. Arterial pressure (AP), heart rate (HR), WBC, platelets, plasma nitrite/nitrate, tumor necrosis factor alpha (TNF alpha), and biochemical factors were measured for 24 hours after LPS with or without iNOS inhibitors. RT-PCR was employed to determine the iNOS and endothelial NOS (eNOS) mRNA. Pathologic examinations of the liver and heart were performed. SMT and L-Nil improved the systemic hypotension and increased the HR after LPS. These agents attenuated the LPS-induced leukocytopenia and thrombocytopenia and the increase in nitrite/nitrate. However, iNOS inhibition aggravated the LPS-induced changes in TNF alpha, all biochemical factors, and the hepatic and cardiac tissue damage. The iNOS mRNA, but not the eNOS, was reduced. Our results in conscious rats indicate that iNOS inhibition enhances the organ dysfunction and tissue damage in sepsis. The discrepancy may be attributed to the method for evaluating the sepsis and the effects of anesthesia. Further investigation is required to ensure the effects of iNOS inhibition on sepsis before iNOS inhibitors can be applied in clinical cases with sepsis.
Insights
Inducible nitric oxide synthase (iNOS) inhibition worsened sepsis outcomes in rats, increasing organ damage and biochemical abnormalities. These findings suggest iNOS inhibitors may not be suitable for sepsis treatment.
Area of Science:
- Pharmacology
- Physiology
- Pathology
Background:
- Sepsis is a life-threatening condition characterized by a dysregulated host response to infection.
- Inducible nitric oxide synthase (iNOS) plays a complex role in sepsis pathophysiology.
- Nitric oxide (NO) produced by iNOS can have both protective and detrimental effects during sepsis.
Purpose of the Study:
- To investigate the effects of iNOS inhibition on endotoxemia-induced sepsis in conscious rats.
- To evaluate the impact of S-methylisothiourea (SMT) and L-N-(1-iminoethyl)-lysine (L-Nil) on physiological and biochemical parameters during sepsis.
- To assess the influence of iNOS inhibition on organ damage and inflammatory markers in a rat sepsis model.
Main Methods:
- Induction of endotoxemia using intravenous lipopolysaccharide (LPS) in conscious rats.
- Administration of iNOS inhibitors (SMT and L-Nil) or vehicle.
- Monitoring of arterial pressure, heart rate, white blood cells, platelets, nitrite/nitrate, TNF alpha, and biochemical factors for 24 hours.
- RT-PCR analysis of iNOS and eNOS mRNA expression.
- Histopathological examination of liver and heart tissues.
Main Results:
- iNOS inhibition improved systemic hypotension and heart rate, and attenuated leukocytopenia and thrombocytopenia.
- However, iNOS inhibition aggravated LPS-induced increases in TNF alpha, biochemical factors, and hepatic/cardiac tissue damage.
- iNOS mRNA levels were reduced by inhibitors, while eNOS mRNA levels remained unchanged.
- Reduced iNOS expression correlated with enhanced organ dysfunction and tissue damage.
Conclusions:
- Inhibition of iNOS in conscious rats exacerbated organ dysfunction and tissue damage during LPS-induced endotoxemia.
- The findings suggest that iNOS inhibition may worsen sepsis outcomes, contrary to some previous studies.
- Further research is needed to clarify the role of iNOS in sepsis and its potential as a therapeutic target.
