Effect of Adrenergic Drugs on the Lipopolysaccharide-Induced Oxidative Stress and Liver Damage in the Rat| Stephy Publishers

 

SOJ Diabetes and Endocrinology Care - (SOJDEC)| Stephy Publishers

Abstract

Aim: We aimed to investigate the effect of the adrenergic system on oxidative stress and liver damage during mild systemic inflammation in rats.

Methods: For this purpose, Eschrechia coli lipopolysacchride (LPS; 300 μg/kg) was intraperitoneally injected either alone or along with the α-2 adrenoceptor antagonist yohimbine, the non-selective β adrenoceptor antagonist propranolol, the and β-adrenoceptor agonist adrenaline and rats euthanized 4h later. The effects of these drugs in saline-treated rats were also studied. Serum alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase activities were measured. Liver tissue levels of Malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) were determined and liver histology evaluated.

Results: In saline-treated rats (i) yohimbine caused significantly increased ALT, AST and ALP in serum. In addition, yohimbine increased MDA, NO and decreased GSH in liver tissue and caused cytoplasmic vacuolations and cellular infiltration: (ii) adrenaline treatment increased serum ALT, AST, liver MDA, decreased liver GSH and caused minute vacuolar degeneration and foci of necrosis; (iii) in contrast, there were no biochemical or histologic alterations after propranolol treatment. In endotoxaemic rats; (i) serum aminotransferases and alkaline phosphatase were significantly increased by yohimbine together with increased liver MDA, NO and decreased GSH content; (ii) serum ALT decreased by propranolol and adrenaline while serum ALP increased by adrenaline; (iii) liver GSH increased by propranolol; (iv) LPS administration caused acute liver damage in the form of foci of necrosis, vacuolar degeneration and aggregates of inflammatory cellular infiltration. Compared with the LPS only group, treatment with yohimbine increased while propranolol or adrenaline produced less liver damage.

Conclusions: Thus, blockade of α-2 adrenoceptors increased while β adrenoceptor antagonism decreased oxidative stress and liver damage following LPS administration in rats. Collectively, these results indicate a benefit from blockade of beta-adrenoceptors in protecting the liver during mild systemic inflammation in part by decreasing oxidative stress.

Keywords

Catecholamines, Lipopolysaccharide endotoxin, Oxidant stress, Hepatic injury, Adrenergic receptors, Yohimbine, β Adrenoceptor antagonist

Introduction

Lipopolysaccharide, a structural component of the outer wall of Gram-ve bacteria, is the cause of septic shock and multi-organ failure.¹ LPS is recognized by Toll-like receptor 4 (TLR4), a member of transmembrane pattern recognition receptors on the outer membrane of immune cells, the activation of which acts to induce an innate immune response and inflammation. Consequent to their stimulation, immune cells eg., macrophages and neutrophils induces the activation of the transcription factor nuclear factor kappa-B (NF-kB)) and the cellular expression of genes encoding proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin-1β (IL-1β) and IL-6, monocyte chemoattractant protein, cell adhesion molecules, with resultant systemic inflammatory syndrome manifested by tissue injury, increased vascular permeability, and, ultimately, multiple organ failure and shock.^2,3 The peripheral administration of LPS in rodents induces the release of proinflammatory cytokines, lipid mediators of inflammation, reactive oxygen species (ROS) and nitric oxide both in periphery and brain.^4,5 TLR4 is expressed by hepatocytes, Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells and dendritic cells in the liver. LPS exerts hepatic injury by stimulating inflammatory cells and hepatic Kupffer cells, the resident macrophages of the liver, to produce various inflammatory cytokines and interferon-gamma (IFN-g).^6,7 TNF-α is a major determinant of liver injury. It induces activation of caspases and apoptosis in hepatocytes prior to secondary necrosis and release of aminotransferases by activation of TNF receptor-1.⁸ Recruited neutrophils and Kupffer cells in liver sinusoids also produce large amounts of reactive oxygen species (ROS) e.g. H2O2 and superoxide anion, causing oxidative stress which is also an important contributor to hepatocyte death via mechanisms that involve mitochondrial dysfunction, inhibit mitochondrial respiration and ATP depletion.^9,10


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