ABSTRACT
Objective To evaluate the role of reperfusion injury salvage kinase signaling pathway in reduction of myocardial ischemia-reperfusion (I/R) injury by sevoflurane postconditioning in rats.Methods Seventy SPF healthy adult male Sprague-Dawley rats,weighing 300-350 g,were divided into 7 groups (n =10 each) using a random number table:sham operation group (group S),group I/R,sevoflurane postconditioning group (group SP),phosphatidylinositol 3-kinase inhibitor LY294002 group (group LY),sevoflurane postconditioning plus LY294002 group (group SPLY),mitogen-activated protein kinase kinase 1/2 inhibitor U0126 group (group U) and sevoflurane postconditioning plus U0126 group (group SPU).Myocardial I/R was induced by occlusion of the left anterior descending branch of the coronary artery for 30 min followed by 120 min of reperfusion.In group SP,1.8％ sevoflurane was inhaled for 5 min starting from the beginning of reperfusion.In LY and U groups,LY294002 0.3 mg/kg and U0126 0.5 mg/kg were intravenously injected,respectively,at 10 min before reperfusion.In SPLY and SPU groups,LY294002 0.3 mg/kg and U0126 0.5 mg/kg were intravenously injected,respectively,at 10 min before reperfusion,and 1.8％ sevoflurane was inhaled for 5 min starting from the beginning of reperfusion.At 15 min of reperfusion,myocardial specimens were obtained from the left ventricular area at risk for determination of the phosphorylation of protein kinase B (Akt) and extra-cellular signal-regulated kinase 1/2 (ERK1/2) (by Western blot) and NAD+ content in myocardial tissues (by fluorescence spectrophotometry).At the end of reperfusion,blood samples were collected from the jugular vein for measurement of serum cardiac troponin Ⅰ (cTnI) concentrations (by photoelectric colorimetry),and myocardial specimens were obtained from the left ventricular area at risk for determination of myocardial infarct size (IS).Resuits Compared with group S,the IS and serum cTnI concentrations were significantly increased,the NAD+ content was decreased (P＜0.05),and no significant change was found in the phosphorylation of Akt or ERK1/2 in group I/R (P＞0.05).Compared with group I/R,the IS and serum cTnI concentrations were significantly decreased,and the NAD+ content and phosphorylation of Akt and ERK1/2 were increased in group SP (P＜0.05),and no significant change was found in the parameters mentioned above in LY,SPLY,U and SPU groups (P＞0.05).Compared with group SP,the IS and serum cTnI concentrations were significantly increased,and the NAD+ content was decreased in SPLY and SPU groups,the phosphorylation of Akt was significantly decreased in group SPLY,and the phosphorylation of ERK1/2 was significantly decreased in group SPU (P＜0.05).Conclusion The mechanism by which sevoflurane postconditioning reduces myocardial I/R injury may be related to activation of reperfusion injury salvage kinase signaling pathway in rats.
ABSTRACT
Objective To evaluate the effect of gender and treatment strategy on remote ischemic preconditioning (RIPC)-induced reduction of myocardial damage in patients undergoing cardiac surgery.Methods We systematically searched the literature in PubMed,EMBase,and Cochrane Library (from Feb 1990 to Feb 2012) using the related keywords.Randomized control trials (RCTs) published in English with report on postoperative biomarkers of myocardial damage concerning RIPC-induced myocardial protection in adult patients undergoing cardiac surgery were included.Standardized mean difference (SMD) was calculated.Publication bias and sensitivity analysis were used to evaluate the reliability of overall enzymatic estimate.Meta-regression analysis was performed to explore the potential sources of significant heterogeneity among results of studies.Data were analyzed using Stata 12.0.Results Thirteen RCTs involving 985 patients were included in our study.Compared with controls,RIPC significantly reduced postoperative serum levels of biomarkers of myocardial damage with significant heterogeneity (SMD=-0.539; 95％CI:-0.926to-0.152; P＜0.05; I2 =88.7％,P＜0.01).No evidence of obvious publication bias was observed (P =0.083,Begg' s test; P =0.077,Egger' s test).Sensitivity analysis showed that each individual study produced no effect on the direction and magnitude of the overall effect size (P ＜ 0.05).Meta-regression analysis revealed that male (％) (coefficient =0.02 ; 95 ％ CI:-0.002-0.042 ; P =0.070 ; adjusted R2 =19.61％) and total ischemic time (min) (coefficient=-0.08; 95％CI:-0.154-0.002; P =0.055; adjusted R2 =19.47％) were the two major influential factors.Conclusion Gender affects RIPC-induced reduction of myocardial damage after cardiac surgery in patients,RIPC-induced reduction of myocardial damage infemale patients is superior to that in male patients and a better efficacy can be achieved by prolonging the single ischemic time or by increasing the ischemic cycles.
ABSTRACT
Objective To evaluate the effects of sevoflurane postconditioning on ischemia-reperfusion injury in chronically-infarcted rat hearts.Methods Left anterior descending coronary artery was ligated to induce myocardial infarction in male Sperague-Dawley rats.Six weeks later,chronically-infarcted hearts were isolated and passively perfused in a Langendorff apparatus.Eighty chronically-infarcted hearts were randomized into 8 groups (n =10 each)∶ Ⅰ-Ⅷ groups.In group Ⅰ,hearts were continously perfused with Krebs-Henseleit (K-H) solution for 90 min.In group Ⅱ,hearts were subjected to 30 min of global ischemia,followed by 60 min of reperfusion.In groups Ⅲ to Ⅵ,hearts were exposed to 30 min of global ischemia,specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 15 μmol/L and mitogen-activated extracellular regulated kinase 1/2 (MEK1/2) inhibitor PD98059 20 μmol/L,0.02％ dimethyl sulfoxide,and K-H solution saturated with 3％ sevoflurane were administered,respectively,during the first 15 min of reperfusion,followed by perfusion with plain K-H solution for 45 min.In groups Ⅶ and Ⅷ,hearts were exposed to 30 min of global isehemia,K-H solution saturated with 3％sevoflurane was given during the first 15 min of reperfusion,LY294002 15 μmol/L and PD98059 20 μmol/L were simultaneously administered,respectively,followed by perfusion with plain K-H solution for 45 min.Coronary flow (CF),left ventricular developed pressure (LVDP),± dp/dt,left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were recorded after 20 min of equilibration (baseline,T0),immediately before ischemia (T1),and at 15,30 and 60 min of reperfusion (T2-4).The concentrations of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the collected coronary effluent were determined at T0 and T4.Acute myocardial infarct size was determined at T4.Left ventricular tissue samples were collected at T2 to measure the phosphorylation of protein kinase B/Akt (PKB/Akt),and extracellular regulated kinase 1/2 (ERK1/2) and degree of mitochondrial permeability transition pore (rnPTP) opening.Results Compared with group Ⅰ,LVDP,± dp/dt,HR and CF were significantly decreased,LVEDP was increased,the acute myocardial infarct size was enlarged,and the concentrations of LDH and CK-MB in the coronary effluent and degree of mPTP opening were increased during reperfusion in groups Ⅱ-Ⅷ (P ＜ 0.05).LVDP,± dp/dt,HR and CF were significantly higher,LVEDP was lower,the acute myocardial infarct size was smaller,the concentrations of LDH and CK-MB in the coronary effluent were lower,the phosphorylation of PKB/Akt and ERK1/2 was higher,and the degree of mPTP opening was lower during reperfusion in group Ⅵ than in group Ⅱ (P ＜ 0.05).Conclusion Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activating PI3K-PKB/Akt and MEK1/2-ERK1/2 and inhibiting mPTP opening.