The Role of Alpha-1 and Alpha-2 Adrenoceptors in Restraint Stress-Induced Liver Injury in Mice

Qing Zhu,Li Jia,Zengming Zhao,Linsheng Lei,Liwei Gu,Shuangqing Peng,Yimei Wang,Matias A Avila

doi:10.1371/journal.pone.0092125

Abstract

Acute stress affects cellular integrity in many tissues including the liver, but its underlying mechanism is still unclear. The aim of the present study was to investigate the potential involvement of catecholamines and adrenoceptors in the regulation of acute restraint stress-induced liver injury. Restraint was achieved by placing mice in restraint tubes. Mice were treated with either an α-l antagonist, prazosin, an α-2 antagonist, yohimbine, a β-l antagonist, betaxolol, a β-2 antagonist, ICI 118551, or a central and peripheral catecholamine depleting agent, reserpine, and followed by restraint stress. Assessment of liver injury (serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) , hepatic total GSH, GSSG and GSH/GSSG ratio) , histopathology and of apoptosis, by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay and western blotting, was performed. Three hours of restraint stress resulted in liver injury, as indexed by elevated serum transaminase levels, decreased hepatic total GSH levels and GSH/GSSG ratio, increased hepatic GSSG levels as well as enhanced hepatocytes apoptosis. Either reserpine or prazosin or yohimbine was found to attenuate liver injury. Furthermore, prazosin and yohimbine protected against restraint-induced hepatocytes apoptosis through attenuating the activation of caspases-9 and -3 and reducing the Bax/Bcl-2 ratio. These results suggest that α-1 and α-2 adrenoceptors mediate restraint-induced liver oxidative injury through caspase-9 and Bcl-2 family of apoptotic regulatory proteins.

Highlights

Stress is an ever-present part of modern life
According to ‘‘Hy’s Law’’ adopted by the U.S Food and Drug Administration (FDA), severe hepatocellular injury has been defined as being cases where the serum alanine transaminase (ALT) or aspartate transaminase (AST) is . 3 times the upper limit of normal [26]
Similar to plasma ALT and AST activities, restrained animals exhibited a progressive changes in hepatic GSH (GSH+GSSG) (Fig. 2, A), GSSG (Fig. 2, B) and GSH/GSSG ratio (Fig. 2, C)

Summary

Introduction

Stress is an ever-present part of modern life. The general concept of ‘‘stress’’ describes the state of a living organism when, under the influence of internal or external stimuli or ‘‘stressors’’, the dynamic equilibrium of the organism (homeostasis) is threatened [1]. The adaptive response to stressors comprises the activation of the hypothalamic–pituitary–adrenal (HPA) axis and components of the sympathoadreno-medullary (SAM) system, releasing the key peripheral mediators, i.e. glucocorticoids and catecholamines [2]. The current focus on the stress and disease phenomenon is directed towards the interactions of the immune system, the CNS, cardiovascular disease, liver injury, HIV/AIDS and carcinomas [3,4,5]. Studies reveal that stress plays a role in suppressing functions of specific immunity, in triggering or worsening depression, cardiovascular disease, and liver injury,and in speeding the progression of HIV/ AIDS and carcinomas [6]. Catecholamines, which are released in response to SAM activation, work in concert with the autonomic nervous system to exert regulatory effects on the cardiovascular, pulmonary, hepatic, skeletal muscle, and immune systems. Prolonged or repeated activation of the HPA and SAM systems can interfere with their control of other physiological systems, resulting in increased risk for physical and psychiatric disorders [6]

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