| Objective:To investigate the protective effects and possible mechanisms of remifentanil preconditioning against ischemia reperfusion injury(IRI) in the DOX-induced rats with chronic heart failure(CHF) by detecting the expression of protein such as infarct size(IS), area at risk(AAR), extracellular signal-regulated kinase(ERK), protein kinase B(Akt) and glycogen synthase kinase(GSK)-3β in hearts.Methods: 282 Sprague-Dawley male rats, weighed 200-230 g, were treated with doxorubicin(DOX) via tail vein to establish chronic heart failure models, and the control rats were injected with normal saline(NS). At the end of 8th week, left ventricular dimension end diastole(LVESD), left ventricular end-diastolic diameter(LVEDD),left ventricular fractional shortening(LVFS) and left ventricular ejection fraction(LVEF) were performed to evaluate cardiac function by echocardiography. Rats with CHF were divided into eleven groups(n=9) randomly : Sham group, IR group,RPC 0.6μg/kg group, RPC 2.0μg/kg group, RPC6.0μg/kg/min group, Wortmannin +RPC6.0μg/kg group(RWT), PD98059+RPC6.0μg/kg/min group(RPD), mitochondrial permeability transition pore(m PTP) opening agent atractyloside +RPC6.0μg/kg group(RA) and their control groups respectively(PD,WT,AL). Rats in Sham group were treated with threading from left anterior descending coronary artery(LAD) but not ligating it. Rats in IR group were subjected to 30 min ischemia followed by 120 min reperfusion. RPC group were treated with remifentanil preconditioning before ischemia reperfusion, which was elicited with 3 cycles of 5 min of infusion and 5 min of drug-free infusion. RPD group, RWT group and RA group were administered with PD,WT and AL 10 mins before RPC respectively. WT group, PD group and AL group were administered with WT, PD and AL and then suffered from ischemia reperfusion without RPC. The IS and AAR were determined by 2,3,5-triphenyl-tetrazolium(TTC) staining at the end of reperfusion immediately(n=6). The expression of p-ERK/ERK,p-Akt/Akt,p-GSK-3β/GSK-3β, Cyt C and β-actin were detected by western blot(n=3) at 10 mins after reperfusion.Results: At the end of the 8th week, Echocardiography results showed that LVEF and LVFS were significantly decreased in DOX group, with loss of in-take, weight and hair when compared with NS group, which had statistical significance(P<0.05). The mortality rate in DOX group was 50.9%.Results of Remifentanil preconditioning TTC staining result showed that sham group had little infarct size(IS). And compared with sham group, IS/AAR in IR group was much higher but it was decreased in RPC(0.6μg/kg) group mildly and in RPC(2, 6μg/kg) significantly, which had statistical significance compared with IR group(P<0.05). IS/AAR in RWT, RPD and RA groups were much higher than that in RPC group, which had statistical significance(P<0.05).Western blot results showed that RPC could promote the expression of phosphorylated Akt, ERK and GSK-3β, and decrease the expression of Cyt C, while wortmannin and PD98059 inhibited the expression of phosphorylated Akt, ERK and GSK-3β which were induced by RPC, and atractyloside increased the expression of Cyt C.Conclusion: RPC could induce cardioprotection against ischemia reperfusion injury in rats with CHF in vivo. Cardioprotective mechanisms of RPC may be involved in activating PI3 K and ERK signal pathways, and inhibiting the activity of downstream GSK-3β and the opening of mitochondrial permeablity transition pore(m PTP). |
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