| Acute myocardial Infarction is a kind of myocardial necrosis caused by persistently lacking of perfusion and hypoxia of the heart.The incidence of acute myocardial infarction(AMI)is on the increasing trend,and the most effective therapeutic measure against myocardial ischemia is to restore the perfusion of the heart.However,the most serious consequence is myocardial ischemia and reperfusion injury(I/R).Myocardial ischemia and reperfusion injury occurred when heart received the blood again,it is reported that the mechanism may as follows:(1)excess reactive oxygen species(ROS)attack the cells in reperfused area,(2)calcium overload and(3)cell injury caused by activated neutrophilic granulocyte.The ultrastructural damage of myocardium is irreversible,which can lead to the disorder of metabolism and function.Dexmedetomidine(DEX)is a novel ?-2 agonist with properties of sedative,analgesia,anti-convulsion,anti-anxiety and anti-stress reaction during general anesthesia.DEX is the most perspective ancillary drug in clinical anesthesia.It can also reduce the drugs during general anesthesia which ameliorate the conditions of patients in recovery period.Besides,it has been proved that DEX has protective effect on several organs of the body,such as brain,lung,heart,liver and kidney.It is reported that DEX plays a role in the cardiovascular protection in isolated hearts suffered ischemia and reperfusion injury,while the effect of DEX on hearts in vivo is rarely reported.So we established themodels of myocardial I/R injury on adult Spragus-Dawley rats to investigate the effect of DEX on acute myocardial I/R injury.We used wortmannin,the inhibitor of PI3K/Akt signal pathway,and DEX to observe the changes of hemodynamics,the levels of related serum factors,pathological section and molecular biology indexes of heart tissue.Our study divided into two parts:1.Effect of dexmedetomidine postconditioning on myocardial ischemia and reperfusion Injury in vivo rats.Forty-eight male SD rats(250~300g)were randomly assigned to the following six groups: Sham group,I/R group,IPO group,DEX 5 group,DEX 10 group and DEX 20 group.We established acute myocardial I/R model by ligating the left ascending artery of rats,and monitoring hemodynamics indexes during the surgery including heart rate(HR),left ventricular diastolic pressure(LVDP),left ventricular end-diastolic pressure(LVEDP),maximal rate of the increase of left ventricular pressure(+dp/dtmax)and maximal rate of the decrease of left ventricular pressure(-dp/dtmax),and then calculated ratepressure production(RPP).Lactate dehydrogenase(LDH),cardiac troponin I(c Tn I),creatine kinase isoenzymes(CK-MB),superoxide dismutase(SOD)and malondialdehyde(MDA)levels in serum were measured by ultraviolet spectrophotometer after the reperfusion of 2h.We measured the size of infarction by Evan's blue-TTC double stain method.The pathological changes of heart tissue were observed by hematoxylin-eosin(HE)staining.The results showed,when compared with Sham group,HR,LVDP,±dp/dtmax and RPP were decreased(P <0.05~P< 0.01)in I/R group,while LVDEP was increased(P <0.05~P<0.01),when compared with I/R group,HR,LVDP,±dp/dtmax and RPP were increased(P<0.05~P<0.01)in DEX(5,10,20)groups,while LVDEP was decreased(P<0.05~P<0.01).As expected I/R caused myocardial infarction thus increasing the serum levels of LDH,c Tn I,CK-MB,and MDA and decreasing that of SOD(P<0.05~P<0.01),when compared with I/R group,the serum levels of LDH,c Tn I,CK-MB,and MDA were decreasing while the activity of SOD was increased(P<0.05~P<0.01).The pathological results showed the exudation of inflammatory cells and myocardial cell was damaged severely,but the situation was ameliorated after given DEX.Compared with I/R group,infarct sizes in IPO and DEX(10,20)groups were decreased.In a conclusion,dexmedetomidine postconditioning on rats could reduce myocardial ischemia and reperfusion injury and ameliorated the function of left ventricle.The protective effect was dose dependent in a certain range,and its mechanism might be related to the decrease of LDH activity,CTn I,CK-MB and MDA contents and the increase of SOD activity in serum.2.The role of PI3K/Akt signaling pathway and apoptosis in the effect of dexmedetomidine postconditioning on myocardial ischemia and reperfusion injury.Thirty-two male SD rats(250~300g)were randomly assigned to the following four groups: I/R group,DEX 20 group,DEX 20+Wort group and Wort group.We established acute myocardial I/R model by ligating the left ascending artery of rats,and monitoring hemodynamics indexes during the surgery including HR,LVDP,LVEDP,±dp/dtmax,and then calculated RPP.LDH,c Tn I,CK-MB,SOD and MDA levels in serum were measured by ultraviolet spectrophotometer after the reperfusion of 2 h.We measured the size of infarction by Evan's blue-TTC double stain method.The pathological changes of heart tissue were observed by hematoxylin-eosin(HE)staining.The protein expressions of P-Akt,Ser9-phosphorylated GSK-3?(p-GSK 3?)and cleaved caspase-3 in heart tissue were detected by Western blotting.The Bax and Bcl-2 at m RNA level were measured by RT-PCR.Compared with I/R group HR,LVDP,±dp/dtmax and RPP were increased(P<0.05~P<0.01)in DEX20 group,while LVDEP was decreased(P<0.05~P<0.01),when compared with DEX20 group,HR,LVDP,±dp/dtmax and RPP were decreased(P<0.05~P<0.01)in DEX20+Wort and Wort groups,while LVDEP was increased(P<0.05~P<0.01).The serum levels of LDH,c Tn I,CK-MB,and MDA were decreased while the activity of SOD was increased(P<0.05~P<0.01)in DEX20 group when compared with I/R group.When compared with DEX20 group,the serum levels of LDH,c Tn I,CK-MB,and MDA were increased while the activity of SOD was decreased(P<0.05~P <0.01)in DEX20+Wort group and Wort group.In our study,we also observed that the levels of p-Akt and p-GSK3? in DEX20 group were greater than those in I/R group(P < 0.05 ~ P < 0.01).The levels p-Akt and p-GSK3? in DEX20+Wort group were lower than those in DEX20 group(P<0.05~P<0.01).Compared with I/R group,cleaved caspase-3 level in DEX20 group was decreased(P<0.01),while highly increased in DEX20+Wort group when compared with DEX20 group.The results also showed a distinguished increase in Bcl-2 level and the ratio of Bcl-2/Bax in DEX20group(P<0.01)compared with I/R group,while Bax level was decreased(P<0.01).In DEX20+Wort group,Bcl-2 level and the ratio of Bcl-2/Bax showed a highly significant decrease when compared with DEX20 group(P<0.01),while Bax level was increased(P < 0.01).The pathological results showed that to compare with DEX20 group,the exudation of inflammatory cells and myocardial cell was damaged severely after given Wort,the effects of Dex were attenuated by Wort.Compared with I/R group,infarct sizes in IPO and DEX20 groups were decreased((P < 0.01)).When compared with DEX20 group,infarct size of DEX20 + Wort group was considerably increased.The observation indicated that DEX plays an important role in myocardial protection and attenuating apoptosis by activating the PI3K/Akt signaling pathway possibly by activating GSK-3?.Myocardial ischemia-reperfusion injury is a common complication in adults undergoing cardopulmonary bypass and affect the recovery of cardiac function.Myocardial ischemia-reperfusion and Cardiopulmonary bypass(CPB)are associated with a marked systemic inflammatory response.It is very important for us to seek effective measures to attenuates myocardial ischemia-reperfusion injury and inflammatory reaction in patients undergoing cardopulmonary bypass(suffering cardiac valve replacement surgery).The aim of this study is to investigate the effect of dexmedetomidine postconditioning on myocardial injury and inflammatory mediators undergoing cardiac valve replacement during cardopulmonary bypass and investigate the mechanism.Thirty patients who had cardiac valve replacement surgery with CPB were randomly allocated into two groups(n=15 each).(ASA grade II or III,NYHA class II or III)of both sexes aged33 ~ 61: normal saline control group(group C),and dexmedetomidine group(group D).in group D,Dex was administered at a loading dose of 0.6?g·kg-1for 15 min after clamping the aorta,followed by a continuous infusion of0.2?g· kg-1·h-1 until the completion of the cardiac surgery.In group C,equal volume of normal saline was infused.Blood samples were taken from radial artery before induction of anesthesia(T0)and at 2h(T1),4h(T2),8h(T3),24h(T4)and 48h(T5)after aortic unclamping for determination of plasma concentrations of cardiac troponin-I(c Tn I),CK-MB,MDA,SOD,IL-6 and TNF-?.The patients' invasive arterial blood pressure,Mean arterial pressure(MAP)and heart rate(HR)were recorded before induction of anesthesia,immediately before and after administered loading dose of Dex,and at 4h after declamping the aorta.The time of CPB and aortic clamping,the spontaneous recovery of heart beat,extubation time and ICU duration,and cardiovascular events were recorded.As a result,The case of patients,MAP and HR,the CPB time,the aortic clamping time,the rate of recovery of spontaneous heart beat were no significant difference between the two groups(P> 0.05).the plasma c Tn I,CK-MB,SOD,MDA,IL-6and TNF-? concentrations were no significant difference between the two groups in T0(P> 0.05).Compared with group C,the plasma c Tn I,CK-MB,IL-6 and TNF-?concentrations were significantly lowe in T1? T2 ?T3 ?T4(P<0.05),while the plasma SOD concentration was significantly higher at T1~T4 in group D,Compared with T0,the plasma c Tn I,CK-MB,IL-6 and TNF-? concentrations were significantly higher in T1?T2 ?T3 ?T4(P<0.05),while the plasma SOD activity was significantly higher at T1~T4 in both group C and D.The time of extubation and ICU duration we resignificantly lower in groups D than in group C(P<0.05).the incidence of cardiovascular events in group C was higher than in groups D.In a conclusion,Cardiopulmonary bypass(CPB)is associated with a marked systemic inflammatory response and myocardial injury.These findings demonstrate that Dex regulates anti-inflammatory as well as myocardial protection potential in cardiac valve replacement with CPB. |
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