Effects Of ?-Opioid Receptor Agonist On Cardiac Function In Resuscitated Rats With Cardiac Arrest

Background and Purpose:Clinically,Cardiac dysfunction following resuscitation from cardiac arrest is the leading cause of early death following cardiac arrest/cardiopulmonary resuscitation(CA/CPR).The physiological effects of kappa-opioid receptor(KOR)on cardiovascular and nervous system has been one of the research hotspots.Studies have confirmed that preconditioning of KOR before myocardial ischemia can largely reduce ischemia-reperfusion(I-R),reduce infarct size,reduce myocardial cell apoptosis after injury,and improve cardiac function after infarction.The survival rate after 72 hrs.Although ischemic preconditioning can reduce myocardial I-R injury,its occurrence time is unpredictable,and its clinical application is limited.Studies have shown that lipid and DNA peroxidation are associated with myocardial damage and cardiac dysfunction at the early stage of resuscitation.Reducing or blocking oxidative stress after resuscitation is one of the keys to reducing early mortality from resuscitation.Therefore,the purpose of this study was to simulate systemic I-R injury in asphyxiated cardiac arrest/resuscitated rats and to investigate the effects of KOR agonist U50,488H postconditioning on cardiac function,to observe the effects of KOR agonist on oxidative stress and to explore the possible mechanisms of improving cardiac function at early stage of resuscitated rats.Material and methods:SD rats were randomly divided into three groups:operation control(group Con),epinephrine treatment(group Epi),combination of epinephrine and U50,488H(group EU),20 resuscitated rats were needed per group.The cardiac arrest model was established by asphyxiation with clipping endotracheal catheter at end-expiratory.CA was untreated for 6 min.Before CPR,including mechanical chest compression and ventilation,both group Con and Epi were injected normal sodium(9g·L-1)0.2 ml,and group EU was administrated U50,488H(1 mg·kg-1)0.2 ml by femoral vein.After that,group Epi and EU were administrated respectively epinephrine during resuscitating.Cardiac function was evaluated by ultrasound Doppler at 2 hrs,4 hrs,and 72 hrs after the return of spontaneous circulation at Epi and EU group.Indicators are heart rate(HR),stroke volume(SV),cardiac output(CO),and ejection fraction(EF).Femoral venous blood was sampled at the time points of 2 hrs,4 hrs,and 72 hrs after return of spontaneous circulation in order to detect plasma high-sensitivity cardiac troponin T(hs-cTnT)to evaluate myocardial injury,isoprostanes(IsoP)to assess lipid peroxidation,and 8-Hydroxyguanosine(8-OHG),a marker of DNA oxidation damage;also to detect indicators of anti-oxidative stress:glutathione(GSH)and asymmetric dimethylarginine(ADMA),an inhibitor of nitric oxide synthase.Results:Both the resuscitation successful rate at 30 mins and survival rate at 2 hrs had no significant statistical difference between group Epi and EU(P>0.05).Compared with group Con,the time of spontaneous circulation recovery(Tcpr)was significantly decreased in both group Epi and EU(P<0.Ol),while both of which had not a significant statistical difference in the interval time(P>0.05).Compared with the group Epi,all parameters including HR?MAP?dp·dtmax-1.-dp·dtmax-1 and LVEDP had no significant statistical difference in group EU within the observed 2 hrs(P>0.05).At 2 hrs,MAP,dp·dtmax-1and-dp·dtmax-1 were significantly higher in group EU compared with group Epi(P<0.05),while LVEDP was significantly lower(P<0.05).hs-cTnT in the plasma of both groups Epi and EU increased significantly at 2 hrs and 4 hrs after resuscitation(P<0.05),and returned to basal level after 72 hrs,but the hs-cTnT of the group EU was significantly lower than that of the group Epi(P<0.05).IsoP and 8-OHG significantly increased at 4 hrs after resuscitation(P<0.05)and returned to normal levels at 72 hrs,but both indexes of group EU were significantly lower than those of group Epi(P<0.05).As an indicator of anti-oxidative stress,GSH and ADMA were significantly inhibited at 2 hrs and 4 hrs after resuscitation(P<0.05),but after KOR agonist U50,488H treatment,inhibition was significantly reduced(P<0.05).Conclusion:These results demonstrate that a combination of epinephrine and K-opioid agonist U50,488H(1 mg·kg-1)doesn't reduce the success rate of early resuscitation in rats with cardiac arrest,but U50,488H can improve left ventricular systolic and diastolic function after 2 hrs,4 hrs and 72 hrs after return of spontaneous circulation.It may be related to the effect of KOR agonist U50,488H on decreasing oxidative stress in the plasma of early resuscitated rats,increasing the anti-oxidative stress effects of GSH and ADMA,and reducing myocardial injury.