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Published on: February 10, 2015
Can Chronic Nitric Oxide Inhibition Improve Liver and Renal Dysfunction in Bile Duct Ligated Rats?
Mona Fouad Mahmoud1, Sara Zakaria1, Ahmed Fahmy1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Zagazig, Zagazig 44519, Egypt.
Abstract:
The aims of the present work were to study the effects of chronic NO inhibition on liver cirrhosis and to analyze its relationship with liver and kidney damage markers. Two inhibitors of NO synthesis (inducible NO synthase (iNOS) inhibitor, aminoguanidine (AG), and nonselective NOS inhibitor, L-nitroarginine methyl ester (L-NAME)) were administered for 6 weeks to bile duct ligated (BDL) rats 3 days after surgery. The present study showed that BDL was associated with liver injury and renal impairment. BDL increased liver NO content and myeloperoxidase (MPO) activity. This was corroborated by increased oxidative stress, TNF-α, TGF-1β, and MMP-13 genes overexpression. Although both drugs reduced NO synthesis and TNF-α gene overexpression, only AG improved renal dysfunction and liver damage and reduced liver oxidative stress. However, L-NAME exacerbated liver and renal dysfunction. Both drugs failed to modulate TGF-1β and MMP-13 genes overexpression. In conclusion, inhibition of NO production by constitutive nitric oxide synthase (cNOS) plays a crucial role in liver injury and renal dysfunction while inhibition of iNOS by AG has beneficial effect. TNF-α is not the main cytokine responsible for liver injury in BDL model. Nitric oxide inhibition did not stop the progression of cholestatic liver damage.
Insights
Chronic nitric oxide (NO) inhibition impacts liver cirrhosis. While aminoguanidine (AG) showed benefits in liver and kidney damage, L-nitroarginine methyl ester (L-NAME) worsened outcomes in bile duct ligated rats.
Area of Science:
- Hepatology
- Nephrology
- Pharmacology
Background:
- Bile duct ligation (BDL) in rats induces liver injury and renal impairment.
- BDL is associated with increased nitric oxide (NO) production, oxidative stress, and inflammatory markers like TNF-α, TGF-1β, and MMP-13.
- The role of NO synthesis inhibition in cholestatic liver disease progression and associated renal dysfunction requires further investigation.
Purpose of the Study:
- To investigate the effects of chronic NO synthesis inhibition on liver cirrhosis induced by BDL.
- To analyze the relationship between NO inhibition and markers of liver and kidney damage.
- To differentiate the effects of inhibiting inducible NO synthase (iNOS) versus nonselective nitric oxide synthase (NOS).
Main Methods:
- Rats underwent bile duct ligation (BDL) surgery.
- Aminoguanidine (AG), an iNOS inhibitor, and L-nitroarginine methyl ester (L-NAME), a nonselective NOS inhibitor, were administered for 6 weeks post-surgery.
- Liver and kidney function markers, NO content, myeloperoxidase (MPO) activity, oxidative stress, and gene expression (TNF-α, TGF-1β, MMP-13) were assessed.
Main Results:
- BDL rats exhibited liver injury, renal impairment, elevated liver NO, MPO activity, oxidative stress, and overexpression of TNF-α, TGF-1β, and MMP-13.
- Both AG and L-NAME reduced NO synthesis and TNF-α gene expression.
- AG treatment improved renal function and liver damage while reducing oxidative stress; L-NAME exacerbated both liver and renal dysfunction.
- Neither drug affected TGF-1β or MMP-13 gene expression.
- Inhibition of constitutive nitric oxide synthase (cNOS) appears detrimental, while iNOS inhibition (AG) is beneficial.
Conclusions:
- Inhibition of cNOS contributes to liver injury and renal dysfunction in the BDL model.
- Inhibition of iNOS using AG demonstrates a protective effect against liver and kidney damage.
- TNF-α is not the primary driver of liver injury in this cholestatic model.
- Overall NO inhibition does not halt the progression of cholestatic liver damage.
