| Background:Myocardial ischemia-reperfusion injury has been one of the study focus with the rapid development of percutaneous coronary intervention. At present, the mechanism of ischemia-reperfusion injury has not entirely beem clarified. That oxygen free radical generation, vascular endothelial injury, calcium overload and leukocyte activation may be the major mechanism, but it can't not explain all the phenomena. Recent studies have shown that myocardial ischemia-reperfusion injury is related with the inflammatory factor production, apoptosis, adhesion molecule expression and regulation of nuclear factors and other mechanisms etc. Studies have shown that reperfusion initiated a typical inflammatory response, polymorpho-nuclear neutrophil infiltration,this became the major problem in myocardial ischemia-reperfusion.Toll-like receptor 4 is a newly discovered transmembrane receptor and pathogen pattern recognition receptors in the innate immune cells, addition to participating in the inflammatory response triggered by pathogenic micro-organisms, there are research suggests that TLR-4 may also be involved in the inflammatory response of the ischemic tissue. The endothelial cell continuously synthasize a small amount of nitric oxide by constitutive nitric oxide synthase under normal physiological circumstances. This plays an important role in the maintenance of normal vascular endothelial function. There are studies showed that the reduction of NO is an important factor in PMN activation in recent years. It can lead to endothelial cell dysfunction in myocardial ischemia reperfusion, then endogenous NO synthesis reduced, weakening the role of anti-PMN and increasing the myocardial ischemia-reperfusion injury.Objective:Perindopril has the effect of anti-myocardial ischemia-reperfusion injury in animal experiments, it can reduce myocardial ischemia-reperfusion injury caused by the changes in the structure of myocardial cells, myocardial hemorrhage, myocardial stunning, and arrhythmias, etc. The specific mechanism of myocardial protection remains to be further studied.This study can be divided into two parts:The first study was undertaken to study the effect of Perindopril on the expression of toll like receptor-4 in rats with early myocardial ischemia-reperfusion injury and to explor the possible mechanisms of Perindopril on inhibition of myocardial ischemia-reperfusion injury. The second part was to determine the relationship between Perindopril on myocardial ischemia-reperfusion injury and the NO protective effect on myocardial ischemia-reperfusion injury by intraperitoneal injection of non-selective NO inhibitor (L-NAME), to explore the early protection mechanism of perindopril on myocardial ischemia reperfusion injury.Part one: Methods:Thirty Wistar rats were randomly divided into 3 group:sham operation group, myocardial IR group and perindopril group. In the perindopril group,The rats were treated with perindopril 4mg/kg,once a day,for 7 days and equal quantity of normal saline were treated in IR group and sham-operated group. The left anterior descending artery in Wister rats was ligated to establish IR model. Wistar rats were subjected to 30 minutes of coronary ligation, followed by 1 hours of reperfusion.Morphology of myocardial tissue was observed with optics microscope, the numbers of apoptotic cardiomyocyte was determined by Tunnel staining and TLR4 expressions was detected by immunohistochemistry.Result:①Compared with IR group, Inflammatory injury in perindopril group was significantly lower than that in IR group;②Cardiomyocyte apoptosis index (AI) in perindopril group was significantly lower than that in IR group but higher than that in the sham-operated group(P< 0.05);③TLR-4 in perindopril group was significantly lower than that in the IR group but higher than that in the sham-operated group(P< 0.05).Part Two:Methods:40 Wistar rats were randomly divided into four groups:sham operation group, ischemic reperfusion group, perindopril group and combination group. Sham operation group and ischemic reperfusion group were drenched equal quantity of normal saline;perindopril group were drenched perindopril 4mg/kg, cobination group were drenched perindopril 4mg/kg, intraperitoneal injection of L-NAME 15mg/kg; once a day,7 days. The left anterior descending coronary artery in Wistar rats were ligated to establish ischemia-reperfusion model, the determination of hemodynamic parameters, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), left ventricular pressure maximum rate of rise and fall (+dP/dTmax and-dP/dTmax) were measured. Morphology of myocardial tissue was observed with optics microscope, the number of apoptotic cardiomyovyte were determined by Tunnel staining.Result:(1) LVSP,LVEDP,+dP/dTmax,-dP/dTmax were no statistically significant differences among the four groups of animals before the LAD in Wistar rats were ligated (P> 0.05); There were no statistically significant differences when the LAD in Wistar rats were ligated 30 min and that were reperfused 30 min,60min(P< 0.05); There were significantly decreased among the late three groups of animals when the LAD in Wistar rats were ligated 30 min among the late three groups of animals(P< 0.05) and there were no statistically significant differences among the late three groups of animals(P>0.05); There were no statistically significant differences in ischemic reperfusion group and and combination group when the LAD in Wistar rats were reperfused 30 min,60min(P>0.05); there were increased significantly in perindopril group when the LAD in Wistar rats were reperfused 30 min,60min(P< 0.05), ischemic reperfusion group and combination group were no statistically significant differences (P>0.05)。LVEDP in the late three groups were significantly increased when the LAD in Wistar rats were ligated 30 min and there were no statistically significant differences among the three groups of animals(P> 0.05); LVEDP were no significant change in ischemic reperfusion group and combination group when the LAD in Wistar rats were reperfused 30 min,60min(P> 0.05); LVEDP decreased slightly in the perindopril group,there was statistically significant in perindopril group with ischemia-reperfusion group and the combination group and combination group (P<0.05); (2) Myocardial fibers swelling degeneration and interstitial edema were little found in sham operation group. Myocardial fibers fracture, necrosis and lots of inflammatory cells were found in the ischemia-reperfusion group and combined group, but hemorrhage and necrosis were attenuated and a little inflammatory cells infiltrating were found in perindopril group. (3) Compared with ischemic reperfusion group and combined group, perindopril can significantly reduce myocardial cell apoptosis(P< 0.05), there were statistically significant difference in perindopril group and combination group (P< 0.05), there were statistically significant difference in sham operation group and ischemic reperfusion group, perindopril group, combination group (P< 0.05).Conclusion:(1) Apoptosis can be found in cardiocytes during ischemia-reperfusion. Myocardial apoptosis and the expression of Toll-like receptor 4 are dynamic changing in ischemia-reperfusion injury. Perindopril could reduce cardiomyocyte apoptosis following ischemia-reperfusion, The mechan-ism may be by inhibiting the expression of inflammatory response which was induced by Toll-like receptor 4.(2)Perindopril could reduce cardiomyocyte apoptosis following ischemia reperfusion, the myocardial protective effect of perindopril can partially be inhibited by L-NAME, a non-selective NO inhibitor.its relationship between NO and the myocardial protective effect were obvious,but the exat mechanism remains to be further studied.
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