The Mechanism Of The Improvements To Systolic And Diastolic Functions Of The Rats’ Isolated Thoracic Aorta By Glutathione

BackgroundPatients with obstructive jaundice maybe have some important clinical featuresincluding hemodynamic instability and tendencies of hypotension. The definition ofhyporesponsiveness of obstructive jaundice is decreased peripheral vascular resistance andblood pressure, and bluntness of blood vessels to endogenous and exogenous compressivesubstances. Recent studies demonstrate that great generation of various types of reactiveoxygen species (ROS) and aggravation of oxidative stress-induced injury cause greatdamage of organs in cholestasis. Overproducted ROS can result in vascularhyporesponsiveness through lipid peroxidation and vascular injury under the obstructivejaundiced pathological state. In addition, OS caused injuries such as promoted proliferationof smooth muscle cells, macrophages adhesion, platelet activation, increased lipidperoxidation damage are also the pathogens and precipitating factors of high bloodpressure, diabetes, coronary heart disease and other cardiovascular diseases. The currentresearches are prone to committing to improving hypovolemic state, cardiac inhibition andreduced vascular activity, and to reducing endotoxemia induced by generation andabsorbance of intestinal inflammatory cytokines in order to prevent and treat low reactivityof obstructive jaundiced vascellum. Noteworthily, the mechanism, that overproducted ROSand aggravated injuries of ROS give rise to hemodynamic instability, is not yet in-depth.Whether antioxidant therapies can improve vascular reactivity status or not remainscontroversial.Redox state of the body is closely associated with cardiovascular events. Glutathione(GSH), as the body’s most important antioxidative small molecules, is a class ofcompounds containing the most abundant thiol group in cells. Glutathione peroxidase (GPx)and glutathione-S-transferases (GST) which are GSH-related are also importantantioxidants that maintain redox balance of the body. Therefore, we assume there are someimprovements to systolic and diastolic functions by administrating GSH to enhance thebody’s total antioxidant capacity, thus combating with overproducted ROS and ROScaused injuries.Methods 1. Model establishment: adult male SD rats were randomly administered GSHsolution (300mg/kg/d) by intragastric administration for7days. After that, bile ductligation was carried out in half of rats. Intragastric administration was undertaken foranother7days. All rats were separated into four groups according to whether receivingGSH or not: SHAM, BDL, SHAM+GSH and BDL+GSH. Serum was reserved fordetecting liver function. Serum glutathione level was measured using colorimetry.2. Elisa was used to detect serum inflammatory cytokines TNF-α, IL-1β and proteindamage marker of OS3-nitrotyrosine (3-NT). Serum markers of lipid peroxidation injurymalondialdehyde (MDA), the body’s antioxidant enzyme glutathione peroxidase (GPx),catalase (CAT), and vasoactive related to nitric oxide (NO) and inducible nitric oxidesynthase (iNOS) were measured by colorimetry/spectrophotometry.3. Contractile responses of rats’thoracic aortic rings to different concentrations ofnorepinephrine (NE) and relaxation response to acetylcholine (Ach) and sodiumnitroprusside (SNP) were determined by in vitro experiment of vascular tone. Pretreatmentwith the nitric oxide synthase inhibitor and mechanical remove of thoracic aortaendotheliocytes were used to evaluate the effect of NO and endothelial cells on vasomotorreactions of vascular rings.Results1. Exogenous antioxidant GSH supplementary in BDL rats could ameliorate liverfunction, ALT, AST and bilirubin levels.2. GSH improved the body’s SH reserves and antioxidant enzymes CAT and Gpxlevels, reduced inflammatory cytokines TNF-α, IL-1β, relieved over-expression of iNOSinduced by excessive synthesis of NO, fought against oxidative damage of ROS and OS,manifesting lower MDA and3-NT.3. GSH had a prominently protective effect to vasoconstrictor response of isolatedthoracic aorta to NE which could be eliminated by administered non-selective nitric oxidesynthase inhibitor. Endothelium-dependent vasodilation induced by Ach was significantlystrengthened in GSH group, while SNP-induced vasodilation, independently fromendothelium, was unaffected.ConclusionThis study focus on the impact of reduced GSH on low reactivity of cholestatic vessels on the whole animal level. Experimental results show that exogenous GSHsupplementary significantly increases antioxidant capacity, improves systolic and diastolicblood vessels’reaction in vitro, the mechanisms of which are related with reducingoxidative stress, hydrogen peroxide（H2O2）and superoxide anion（O2.-）, suppressing thetransformation of NO into peroxynitrite（ONOO.）, improving NO bioavailability andprotecting vascular endothelial function.