Postconditioning Protective Effects Of Propofol To Myocardial And Cerebral Ischemia/Reperfusion Injury

Myocardial and cerebral ischemic disease is one of the leading causes of mortality in China. The primary treatment for ischemia is to revascularize the occluded blood vessels to allow early reperfusion. However, reperfusion leads to reperfusion injury in the ischemic heart and brain. The protective effects of ischemic preconditioning against ischemia have been studied for more than 20 years. In theory, preconditioning may be applicable to clinical cases in which an occurrence of ischemia is predictable, but its clinical application has been unfeasible. Unlike ischemic preconditioning, ischemic postconditioning is a relatively novel concept, as a series of mechanical interruptions of reperfusion performed at immediate reperfusion. Propofol is one of the most popular anesthetic used in clinical cases, either for general anesthesia, or for sedation in intensive care unit (ICU). But there is few researches studying the postconditioning protective effects of propofol against myocardial and cerebral ischemic/reperfusion injury. Therefore, we conduct this research to identify the postconditioning effect of propofol and provide the mechanism for it. We divided this research into 4 parts:Part one: The experimental research of postconditioning effect of propofol against myocardial ischemic/reperfusion injuryObjective: To investigate whether the infusion of propofol during early reperfusion provides ischemic postconditioning (I-postC) on myocardial ischemia-reperfusion injury in rats. Methods:Sixty adult rats were randomly divided into 5 groups (n= 12 each):sham operation (group S); normal saline (group C); propofol 1 mg/kg (group Pi); propofol 2 mg/kg (group P2); propofol 5 mg/kg (group P3). The left anterior descending coronary artery (LAD) was occluded for 60 min and reperfused for 120 min. Normal saline, propofol 1 mg/kg,2 mg/kg or 5 mg/kg (propofol diluted to 2.5 ml with normal saline equally) were intravenously infused 3 min before reperfusion until 5 min after reperfusion. The heart were obtained for determination of (1) the size of area at risk and infarct size (Evans Blue and TTC staining); (2) expression of Caspase-3 (immunohistochemistry staining); (3) percentage of apoptotic cardiomyocytes (flow cytometry); (4) levels of phosphorylated Akt (Western blot). Results: Compared with group C, propofol 1 mg/kg and 2 mg/kg significantly reduced the size of area at risk and infarct size, inhibited the expression of Caspase-3, decreased the percentage of apoptotic cardiomyocytes and promoted the phosphorylation of Akt (P<0.05). The percentage of apoptotic cardiomyocytes was linearly positive correlated with the size of area at risk (r= 0.912, P= 0.0002) and infarct size (r=0.975, P=0.0001); the expression of Caspase-3 was linearly positive correlated with the percentage of apoptotic cardiomyocytes (r= 0.882, P= 0.0001), and negative correlated with the phosphorylation of Akt (r=-0.611, P= 0.0003). Conclusion:Propofol 1 mg/kg and 2 mg/kg can provide I-postC to myocardial ischemia/reperfusion injury in rats by activation of Akt pathway.Part two:The clinical research of postconditioning effect of propofol against myocardial ischemic/reperfusion injuryObjective: To investigate the effect of target controlled infusion (TCI) of propofol 1μg/ml from the end of aortic artery occlusion on myocardial ischemia/reperfusion injury in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Methods:Forty ASA II orⅢpatients undergoing elective CABG with CPB were randomly divided into sevoflurane group (group S) and propofol postconditioning group (group P), each has 20 cases. Group S maintained with sevoflurane 0.5%-2% during the whole period of operation; group P inspirited sevoflurane 0.5%-2% from the beginning of anesthesia, then received TCI of propofol 1μg/ml from the end of aortic artery occlusion, and modulated the inspiratory concentration of sevoflurane to maintain the BIS value at 40 to 60 range. The concentrations of cardiac troponin I (cTnI), MB isoenzyme of creatine kinase (CK-MB), soluble intercellular adhesion molecule-1 (sICAM-1) and expression of CD11b were determined before the induction of anesthesia (To),10 min after the end of aortic artery occlusion (T1), at arrival in the intensive care unit (T2),6,12 and 24 h after arrival in the intensive care unit (T3, T4, T5). Results:There were significant differences between the two groups in concentrations of cTnI, CK-MB, sICAM-1 and CDllb at different time points (P<0.05). As compared with group S, the concentrations of cTnI and CK-MB were significantly decrease at T3-5, the concentrations of sICAM-1 were lower at T2-5, and the expression of CD11b were significantly decrease during T1-5 in group P. There was no significant difference in the incidences of myocardial infarction, atrial fibrillation and myocardial ischemia between the two groups (P>0.05). Conclusion:TCI of propofol 1μg/ml from the end of aortic artery occlusion provided myocardial protection to ischemia/reperfusion injury in patients undergoing CABG with CPB.Part three: The experimental research of postconditioning effect of propofol against cerebral ischemic/reperfusion injuryObjective: To investigate whether propofol could provide postconditioning to ischemic brain injury and the role of phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway in this phenomenon. Methods:Rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion were randomly divided into nine groups (n= 15 each):sham-operated group, MCAO group, propofol 10,20 and 35 mg·kg-1·h-1 group (propofol 10,20,35 mg·kg-1·h-1 infused at the onset of reperfusion for 30 min), wortmannin group (wortmannin 0.6 mg/kg administered 30 min before MCAO), and the other three groups received wortmannin followed by 10,20 and 35 mg·kg-1·h-1 propofol respectively. Results: Propofol at doses of 10 and 20 mg·kg-1·h-1 significantly reduced infarct volume, decreased neurological deficit scores and attenuated neuron apoptosis compared with MCAO group alone. Increased phosphorylated Akt (p-Akt) was observed in the ischemic penumbra of propofol 10 and 20 mg·kg-1·h-1 group after transient MCAO. The selective PI3K inhibitor, wortmannin partly eliminated the neuroprotective effect and the elevation of p-Akt expression in ischemic penumbra induced by propofol. Propofol at dose of 35 mg·kg-1·h-1 did not affect infarct volume, neurological deficit scores, neuronal apoptosis and the level of p-Akt in transient MCAO rats. Conclusion:These results demonstrated that propofol at doses of 10 or 20 mg·kg-1·h-1 infused at the onset of reperfusion for 30 min could provide neuroprotection to transient MCAO rats, and the postconditioning effect induced by propofol partly through maintaining the activity of PI3K/Akt pathway.Part four: The clinical research of postconditioning effect of propofol against cerebral ischemic/reperfusion injuryObjective:To investigate the effect of TCI of propofol 1.2μg/ml from the end of temporary vessel occlusion on cerebral ischemia-reperfusion injury in patients undergoing clipping of intracranial aneurysm. Methods:Thirty ASAⅠorⅡpatients undergoing elective intracranial aneurysm clipping were randomly divided into 2 groups (n= 15 each):group S maintained with sevoflurane 0.5%-2% during the whole period of operation; group P inspirited sevoflurane 0.5%-2% from the beginning of anesthesia, then received TCI of propofol 1.2μg/ml from the end of temporary vessel occlusion, and modulated the inspiratory concentration of sevoflurane to maintain the BIS value at 40 to 60 range. The cerebrospinal fluid pressure (CSFP) were determined before the induction of anesthesia (T0), at the moment of temporary vessel occlusion (T1), the end of temporary vessel occlusion (T2),30 min and 1 h after reopen the vessel (T3, T4) and the end of operation (T5). The concentrations of F2-isoprostanes (F2-IsoPs),α-tocopherol (α-T) andγ-tocopherol (γ-T) in CSF were measured at T0, T3, T5, and 24 h postoperatively (T6). Results: CSFP was significantly lower in group P at T3 and T4 as compared with group S (P< 0.05). The concentration ofα-T was significantly decreased from T3 as compared with the baseline value in both groups, but there was no significantly difference between the two groups (P>0.05). In group P, the concentration ofγ-T in CSF was significantly decreased at T3, T5, and T6 as compared with the baseline value and was significantly higher as compared with group S (P<0.05); whereas the concentration of F2-ISoPs was significantly increased from T3 as compared with T0 and was significantly lower than that of group S (P<0.05). Conclusion:TCI of propofol 1.2μg/ml from the end of temporary vessel occlusion had the antioxidant profile, and provided neuroprotection to cerebral ischemia/reperfusion injury in patients undergoing clipping of intracranial aneurysm.Taking together, propofol can provide postconditioning protective effects against ischemia/reperfusion injury in heart and brain. PI3K/Akt pathway is one of the most important mechanisms in this phenomenon. The results of this study provided theorical basis and direction on how to properly choose anesthetics for patients undergoing myocardial and cerebral ischemia/reperfusion injury perioperatively.