The Protective Effects Of Dexmedetomidine On The Heart And The Brain During Cardiopulmonary Bypass

PART 1 DEXMEDETOMIDINE REDUCES CEREBRAL INJURY ASSOCIATED WITH CARDIOPULMONARY BYPASS VIA JAK2/STAT3 PATHWAYObjective To investigate the effects and mechanisms of dexmedetomidine on the neuronal apoptosis caused by CPB,different dose of dexmedetomidine was intravenously infused 2 h after CPB in a rat model of CPB.Methods Ninety-six adult male SPF SD rats were randomly divided into 6groups: the sham group(group sham),the CPB group(group CPB),the low dose dexmedetomidine group(group L),the high dose dexmedetomidine group(group H),the AG490 group(group AG490),and the DMSO group(group DMSO).Rats in the sham group were not treated with the CPB procedure.A CPB rat model was established in the other five groups and the CPB procedure lasted 2 hours.The load of intravenous infusion of dexmedetomidine in two groups was: 2.5 ?g/kg in group L and 5 ?g/kg in group H.The maintenance doseof intravenous injection of dexmedetomidine in two groups was: 2.5 ?g/kg?h in group L,5 ?g/kg?h in group H.Rats in the AG490 group were given AG490 at a dose of 10 mg/kg 30 min before anaesthesia.Rats in the DMSO group were given DMSO as the same dose as the AG490 group.First,brain water content was determined.Moreover,the plasma levels of IL-6,IL-10,S100? and NSE,and the cortex levels of IL-6 and IL-10 were detected by ELISA.Furthermore,the apoptosis of neurons was detected by TUNEL assay.In addition,real-time PCR analysis and western blot analysis were used to detect the m RNA and the protein expression of the related factors in hippocampus.Finally,the expression of p JAK2 and p STAT3 protein in hippocampal CA1 region was detected by immunohistochemistry.Results A total of 96 rats were used.Two rats(one in the CPB group and one in the DMSO group)were excluded due to survival failure.In the experiment,we observed that when the rats underwent CPB,the brain water content was increased,and the apoptosis of hippocampal neurons and cortex was significantly increased,and also the levels of IL-6,IL-10,S100? and NSE in plasma were increased.In addition,the expression of p JAK2 and p STAT3 protein was increased.While dexmedetomidine reduced the brain water content,the apoptosis of hippocampal neurons and cortex,and the levels of S100? and NSE in plasma in the rats undergoing CPB.At the same time,dexmedetomidine reduced the expression of p JAK2 and p STAT3 protein,and the level of the inflammatory cytokine,IL-6 in the plasma and cortex.And there is a certain correlation between the effect of cerebral protection and the dose of dexmedetomidine.AG490,the inhibitor of JAK2,was used to verify that dexmedetomidine exerted its neuroprotective effect via inhibiting JAK2/STAT3 signaling.All the effects of dexmedetomidine were similar to the group treatedwith AG490.Conclusions Dexmedetomidine provides neuroprotective effects by inhibiting inflammation and reducing neuronal apoptosis.And there is a certain correlation between the effect of cerebral protection and the dose of dexmedetomidine.In addition,dexmedetomidine administration resulted in a reduction of p JAK2 and p STAT3 protein in the hippocampus of rats 2 h after CPB.Thus,we speculate that JAK2/STAT3 pathway plays an important role in the neuroprotective effects of dexmedetomidine following brain injury induced by CPB.PART 2 DEXMEDETOMIDINE REDUCES MYOCARDIAL INJURY ASSOCIATED WITH CARDIOPULMONARY BYPASS VIA JAK2/STAT3 PATHWAYObjective To investigate the effects and mechanisms of dexmedetomidine on the myocardial apoptosis caused by CPB,different dose of dexmedetomidine was intravenously infused 2 h after CPB in a rat model of CPB.Methods Forty-eight adult male SPF SD rats were randomly divided into 6groups: the sham group(group sham),the CPB group(group CPB),the lowdose dexmedetomidine group(group L),the high dose dexmedetomidine group(group H),the AG490 group(group AG490),and the DMSO group(group DMSO).The experimental method is the same as the part 1.First,the levels of IL-6 and IL-10 in plasma were detected by ELISA.Furthermore,the apoptosis of myocardial cells was detected by TUNEL assay.In addition,real-time PCR analysis and western blot analysis were used to detect the m RNA and the protein expression of the related factors in myocardial tissue.Finally,the expression of p JAK2 and p STAT3 protein in myocardial tissue was detected by immunohistochemistry.Results A total of 48 rats all survived during the experimental.In the experiment,we observed that when the rats underwent CPB,the apoptosis of myocardial cells was significantly increased,and the levels of IL-6 and IL-10 in plasma were significantly increased.In addition,the expression of p JAK2,p STAT3 and cleaved Caspase-3 protein was increased.While dexmedetomidine reduced the apoptosis of myocardial cells and the level of IL-6 in plasma in the rats undergoing CPB.At the same time,dexmedetomidine reduced the expression of p JAK2,p STAT3 and cleaved Caspase-3 protein.And there is a certain correlation between the myocardial protective effect and the dose of dexmedetomidine.AG490,the inhibitor of JAK2,was used to verify that dexmedetomidine exerted its myocardial protective effect via inhibiting JAK2/STAT3 signaling.All the effects of dexmedetomidine were similar to the group treated with AG490.Conclusions Dexmedetomidine provides the myocardial protective effects by inhibiting inflammation and reducing the apoptosis of myocardial cells.And there is a certain correlation between the myocardial protective effect and the dose of dexmedetomidine.In addition,dexmedetomidine administration resultedin a reduction of p JAK2 and p STAT3 protein in the myocardium of rats 2 h after CPB.Thus,we speculate that JAK2/STAT3 pathway plays an important role in the myocardial protective effects of dexmedetomidine following myocardial injury induced by CPB.PART 3 EFFECTS OF DEXMEDETOMIDINE ON MYOCARDIAL AND CEREBRAL PROTECTION IN PATIENTS UNDERGOING MITRAL VALVE REPLACEMENTObjective To investigate the protective effects of dexmedetomidine on the brain and the heart in patients undergoing mitral valve replacement under CPB,different dose of dexmedetomidine was intravenously infused.Methods Eighty patients were randomly divided into 4 groups(n=20,each):the CPB group(group CPB),the low dose dexmedetomidine group(group L),the middle dose dexmedetomidine group(group M)and the high dose dexmedetomidine group(group H).Routine anesthesia induction and maintenance were conducted in the four groups.Dexmedetomidine was added to the three dexmedetomidine groups as the following: The load of intravenous infusion of dexmedetomidine in three groups was: 0.3 ?g/kg in group L,0.5?g/kg in group M and 0.7 ?g/kg in group H.The maintenance dose of intravenous injection of dexmedetomidine in three groups was: 0.3 ?g/kg?h in group L,0.5 ?g/kg?h in group M and 0.7 ?g/kg?h in group H.The same volume of saline was added to group CPB as the three dexmedetomidine groups.Observed and recorded the following indicators: CPB time,aortic clamping time,postoperative ventilator using time,ICU stay time,postoperative hospital stay,MMSE score,detection of levels of IL-6,IL-10,S100?,NSE,troponin I and creatine kinase(CK-MB)in serum at different time points.Results One patient was excluded in the CPB group.Finally,79 patients were included in the data statistical analysis.There was no significant difference between the four groups in gender,age,height and weight,CPB time,aortic occlusion time,postoperative ventilation time and postoperative hospital stay(P>0.05).Compared with group CPB,ICU stay time was significantly decreased in group M and group H(P<0.05),and also the levels of IL-6,IL-10,S100?,NSE,troponin I and CK-MB in serum in group L,group M and group H were significantly decreased after operation(P<0.05).In addition,compared with group CPB,the MMSE score of M group and H group was significantly higher on the 2 day and 4 day after operation(P<0.05).Compared with group L,there was no significant difference in group M and group H(P>0.05),and the levels of IL-6,IL-10,S100?,NSE,troponin I and CK-MB in serum in group M and group H were significantly decreased after operation(P<0.05),in addition,the MMSE score of M group and H group was significantly higher on the 4 day after operation(P<0.05).Compared with group M,the levels of IL-10 in serum in group H was significantly decreased at the end of operation.And there was no significant difference between H group and M group on other indicators(P>0.05).The levels of IL-6,IL-10,S100? and NSE in serum peaked at the endof operation,and then decreased gradually.The MMSE score decreased to the lowest on 2 days after operation,and then gradually increased.Serum levels of troponin I and creatine kinase isoenzyme peaked at 1 day after operation,and then decreased gradually.Conclusions Dexmedetomidine provides neuroprotection and myocardial protective effects by reducing the systemic inflammatory response following CPB.And there is a certain correlation between the effect of cerebral protection and the dose of dexmedetomidine.