Can Chronic Nitric Oxide Inhibition Improve Liver and Renal Dysfunction in Bile Duct Ligated Rats?

Mona Fouad Mahmoud,Sara Zakaria,Ahmed Fahmy

doi:10.1155/2015/298792

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.

Highlights

Increased nitric oxide (NO) is well recognized in patients with cholestatic liver diseases
High levels of circulating bile salts during cholestasis disrupt intestinal mucosal barrier resulting in translocation of enteric bacteria to the mesenteric lymph nodes and the liver [1] and resulting endotoxemia is responsible for augmented nitric oxide (NO) synthesis by inducible NO synthase [2]
The induction of NO synthesis in abnormal situations allows a more efficient defense because of local vascular effects and because NO is thought to be involved in the macrophage-dependent killing of parasites and possibly cancer cells

Summary

Introduction

Increased nitric oxide (NO) is well recognized in patients with cholestatic liver diseases. High levels of circulating bile salts during cholestasis disrupt intestinal mucosal barrier resulting in translocation of enteric bacteria to the mesenteric lymph nodes and the liver [1] and resulting endotoxemia is responsible for augmented nitric oxide (NO) synthesis by inducible NO synthase (iNOS) [2]. The increase in hepatic and plasma circulating levels of NO and cytokines is the determinant for the hepatocellular injury and the rapid progression of hepatic dysfunction in cholestatic settings [3]. Beneficial role is mediated by its circulatory effects and its free radical scavenger properties. Under normal conditions NO has beneficial effect on vascular control including modulation of vascular tone and inflammation. The induction of NO synthesis in abnormal situations allows a more efficient defense because of local vascular effects and because NO is thought to be involved in the macrophage-dependent killing of parasites and possibly cancer cells

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